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Publisher: Elsevier   (Total: 3158 journals)

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Showing 1 - 200 of 3157 Journals sorted alphabetically
Academic Pediatrics     Hybrid Journal   (Followers: 36, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 24, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 97, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 27, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 37, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 5)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 7)
Acta Astronautica     Hybrid Journal   (Followers: 423, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 28, SJR: 1.967, CiteScore: 7)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 2)
Acta de Investigación Psicológica     Open Access   (Followers: 3)
Acta Ecologica Sinica     Open Access   (Followers: 10, SJR: 0.18, CiteScore: 1)
Acta Haematologica Polonica     Free   (Followers: 1, SJR: 0.128, CiteScore: 0)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 284, SJR: 3.263, CiteScore: 6)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.504, CiteScore: 1)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.542, CiteScore: 1)
Acta Oecologica     Hybrid Journal   (Followers: 12, SJR: 0.834, CiteScore: 2)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription  
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 2, SJR: 0.307, CiteScore: 0)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 1, SJR: 1.793, CiteScore: 6)
Acta Poética     Open Access   (Followers: 4, SJR: 0.101, CiteScore: 0)
Acta Psychologica     Hybrid Journal   (Followers: 27, SJR: 1.331, CiteScore: 2)
Acta Sociológica     Open Access   (Followers: 1)
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.052, CiteScore: 2)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 3, SJR: 0.374, CiteScore: 1)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 2)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.344, CiteScore: 1)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 1)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 6, SJR: 0.19, CiteScore: 0)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 8)
Acute Pain     Full-text available via subscription   (Followers: 14, SJR: 2.671, CiteScore: 5)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.53, CiteScore: 4)
Addictive Behaviors     Hybrid Journal   (Followers: 17, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 8, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 11, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 23)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 171, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 12, SJR: 1.167, CiteScore: 4)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.694, CiteScore: 3)
Advances in Accounting     Hybrid Journal   (Followers: 8, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 15, SJR: 2.384, CiteScore: 5)
Advances in Anesthesia     Full-text available via subscription   (Followers: 28, SJR: 0.126, CiteScore: 0)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 10, SJR: 0.992, CiteScore: 1)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 11, SJR: 1.551, CiteScore: 4)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 24, SJR: 2.089, CiteScore: 5)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 14, SJR: 0.572, CiteScore: 2)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.61, CiteScore: 7)
Advances in Botanical Research     Full-text available via subscription   (Followers: 2, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 32, SJR: 3.043, CiteScore: 6)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 1.453, CiteScore: 2)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 1.992, CiteScore: 5)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 4)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 13)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 28, SJR: 0.156, CiteScore: 1)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.713, CiteScore: 1)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 10, SJR: 1.316, CiteScore: 2)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 26, SJR: 1.562, CiteScore: 3)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 20, SJR: 1.977, CiteScore: 8)
Advances in Computers     Full-text available via subscription   (Followers: 14, SJR: 0.205, CiteScore: 1)
Advances in Dermatology     Full-text available via subscription   (Followers: 15)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 12)
Advances in Digestive Medicine     Open Access   (Followers: 11)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 7)
Advances in Drug Research     Full-text available via subscription   (Followers: 25)
Advances in Ecological Research     Full-text available via subscription   (Followers: 44, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 29, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 8)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 47, SJR: 5.39, CiteScore: 8)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 1)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 60, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
Advances in Genetics     Full-text available via subscription   (Followers: 19, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 10, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 24, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 12, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 23)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.193, CiteScore: 0)
Advances in Immunology     Full-text available via subscription   (Followers: 36, SJR: 4.433, CiteScore: 6)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 10, SJR: 1.163, CiteScore: 2)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 2, SJR: 1.938, CiteScore: 3)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6, SJR: 0.176, CiteScore: 0)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 3)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, SJR: 0.682, CiteScore: 2)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 8)
Advances in Marine Biology     Full-text available via subscription   (Followers: 18, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 11, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 7, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 23)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 8)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.182, CiteScore: 0)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 4)
Advances in Oncobiology     Full-text available via subscription   (Followers: 2)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 17, SJR: 1.875, CiteScore: 4)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.174, CiteScore: 0)
Advances in Parasitology     Full-text available via subscription   (Followers: 5, SJR: 1.579, CiteScore: 4)
Advances in Pediatrics     Full-text available via subscription   (Followers: 25, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 12)
Advances in Pharmacology     Full-text available via subscription   (Followers: 16, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.574, CiteScore: 1)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.109, CiteScore: 1)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 10)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 19)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 0.791, CiteScore: 2)
Advances in Psychology     Full-text available via subscription   (Followers: 65)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (Followers: 1, SJR: 0.263, CiteScore: 1)
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.101, CiteScore: 0)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 6)
Advances in Space Research     Full-text available via subscription   (Followers: 409, SJR: 0.569, CiteScore: 2)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Surgery     Full-text available via subscription   (Followers: 12, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 34, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 19)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 15)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 48, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 359, SJR: 0.796, CiteScore: 3)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.42, CiteScore: 2)
African J. of Emergency Medicine     Open Access   (Followers: 6, SJR: 0.296, CiteScore: 0)
Ageing Research Reviews     Hybrid Journal   (Followers: 11, SJR: 3.671, CiteScore: 9)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 472, SJR: 1.238, CiteScore: 3)
Agri Gene     Hybrid Journal   (Followers: 1, SJR: 0.13, CiteScore: 0)
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 17, SJR: 1.818, CiteScore: 5)
Agricultural Systems     Hybrid Journal   (Followers: 31, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 42, SJR: 1.272, CiteScore: 3)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 4)
Agriculture and Natural Resources     Open Access   (Followers: 3)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 57, SJR: 1.747, CiteScore: 4)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.589, CiteScore: 3)
Air Medical J.     Hybrid Journal   (Followers: 6, SJR: 0.26, CiteScore: 0)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.19, CiteScore: 0)
Alcohol     Hybrid Journal   (Followers: 12, SJR: 1.153, CiteScore: 3)
Alcoholism and Drug Addiction     Open Access   (Followers: 11)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.604, CiteScore: 3)
Alexandria J. of Medicine     Open Access   (Followers: 1, SJR: 0.191, CiteScore: 1)
Algal Research     Partially Free   (Followers: 10, SJR: 1.142, CiteScore: 4)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.504, CiteScore: 1)
Allergology Intl.     Open Access   (Followers: 5, SJR: 1.148, CiteScore: 2)
Alpha Omegan     Full-text available via subscription   (SJR: 3.521, CiteScore: 6)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 10, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 52, SJR: 4.66, CiteScore: 10)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 4, SJR: 1.796, CiteScore: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 4, SJR: 1.108, CiteScore: 3)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 6)
American Heart J.     Hybrid Journal   (Followers: 57, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 60, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 44, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 11)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 13, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 34, SJR: 7.45, CiteScore: 8)
American J. of Infection Control     Hybrid Journal   (Followers: 29, SJR: 1.062, CiteScore: 2)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 35, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 48)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3, SJR: 1.967, CiteScore: 2)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 229, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 66, SJR: 3.184, CiteScore: 4)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 5, SJR: 0.265, CiteScore: 0)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.289, CiteScore: 1)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, CiteScore: 1)
American J. of Pathology     Hybrid Journal   (Followers: 29, SJR: 2.139, CiteScore: 4)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 29, SJR: 2.164, CiteScore: 4)
American J. of Surgery     Hybrid Journal   (Followers: 38, SJR: 1.141, CiteScore: 2)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.767, CiteScore: 1)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 7)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.144, CiteScore: 3)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 63, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 19, SJR: 0.411, CiteScore: 1)
Anales de Cirugia Vascular     Full-text available via subscription   (Followers: 1)
Anales de Pediatría     Full-text available via subscription   (Followers: 3, SJR: 0.277, CiteScore: 0)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription  
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 5, SJR: 4.849, CiteScore: 10)
Analytica Chimica Acta     Hybrid Journal   (Followers: 43, SJR: 1.512, CiteScore: 5)
Analytical Biochemistry     Hybrid Journal   (Followers: 196, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 12, SJR: 0.411, CiteScore: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 14)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 2)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 23, SJR: 0.683, CiteScore: 2)
Angiología     Full-text available via subscription   (SJR: 0.121, CiteScore: 0)
Angiologia e Cirurgia Vascular     Open Access   (Followers: 1, SJR: 0.111, CiteScore: 0)
Animal Behaviour     Hybrid Journal   (Followers: 207, SJR: 1.58, CiteScore: 3)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 5, SJR: 0.937, CiteScore: 2)
Animal Reproduction Science     Hybrid Journal   (Followers: 7, SJR: 0.704, CiteScore: 2)

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Similar Journals
Journal Cover
Neurobiology of Disease
Journal Prestige (SJR): 2.674
Citation Impact (citeScore): 5
Number of Followers: 5  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0969-9961 - ISSN (Online) 1095-953X
Published by Elsevier Homepage  [3158 journals]
  • Beta synchrony in the cortico-basal ganglia network during regulation of
           force control on and off dopamine
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Petra Fischer, Alek Pogosyan, Alexander L. Green, Tipu Z. Aziz, Jonathan Hyam, Thomas Foltynie, Patricia Limousin, Ludvic Zrinzo, Michael Samuel, Keyoumars Ashkan, Mauro Da Lio, Mariolino De Cecco, Alberto Fornaser, Peter Brown, Huiling Tan Beta power suppression in the basal ganglia is stronger during movements that require high force levels and high movement effort but it has been difficult to dissociate the two. We recorded scalp EEG and basal ganglia local field potentials in Parkinson's disease patients (11 STN, 7 GPi) ON and OFF dopaminergic medication while they performed a visually-guided force matching task using a pen on a force-sensitive graphics tablet. Force adjustments were accompanied by beta power suppression irrespective of whether the force was increased or reduced. Before the adjustment was completed, beta activity returned. High beta power was specifically associated with slowing of the force adjustment. ON medication, the peak force rate was faster and cortico-basal ganglia beta phase coupling was more readily modulated. In particular, phase decoupling was stronger during faster adjustments. The results suggest that beta power in the basal ganglia does not covary with force per se, but rather with a related factor, the absolute force rate, or a more general concept of movement effort. The results also highlight that beta activity reappears during stabilization of isometric contractions, and that dopamine-related suppression of cortico-basal ganglia beta coupling is linked to faster force adjustments.
       
  • Advances in molecular and cell biology of dystonia: Focus on torsinA
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Pedro Gonzalez-Alegre During the last two decades, our knowledge on the genetic bases of Mendelian forms of dystonia has expanded significantly. This has translated into the generation of multiple cell and animal models to explore the neurobiological bases of this hyperkinetic movement disorder. A majority of these studies have focused on DYT1 dystonia, caused by dominant mutations in the gene encoding for the protein torsinA. Since its discovery, work in multiple laboratories helped identify the subcellular localization of torsinA, key structural features, functionally important physical interactions and biological pathways and physiological events influenced by torsinA. Moreover, recent experimental work indicates potential shared pathogenic pathways between different genetic forms of dystonia. This review will summarize our current knowledge on the molecular and basic biological features of torsinA and its dysfunction when carrying disease-causing mutation, identifying future research priorities and proposing a model of dystonia pathogenesis that might extend beyond DYT1.
       
  • Unit firing and oscillations at seizure onset in epileptic rodents
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Lin Li, Anatol Bragin, Richard Staba, Jerome Engel Epileptic seizures result from a variety of pathophysiological processes, evidenced by different electrographic ictal onset patterns, as seen on direct brain recordings. The two most common electrographic patterns of focal ictal onset in patients are hypersynchronous (HYP) and low-voltage fast (LVF). Whereas LVF ictal onsets were believed to result from disinhibition; based on similarities with absence seizures, focal HYP ictal onsets were believed to result from increased synchronizing inhibition. Recent findings, however, suggest the differences between these seizure onset types are more complicated and, in some cases, the opposite of these concepts are true. The following review presents evidence that a reduction of tonic inhibition on small pathologically interconnected neuron (PIN) clusters generating pathological high-frequency oscillations (pHFOs), which reflect abnormal synchronously bursting neurons may be the cause of HYP ictal onsets. Increased inhibition preceding LVF ictal onsets are discussed in other reviews in this issue. We postulate that neuronal cell loss following epileptogenic insults can result in structural reorganization, giving rise to small PIN clusters, which generate pHFOs. These clusters have a heterogeneous distribution and are spatially stable over time. Studies have demonstrated that a transient reduction in tonic inhibition causes these clusters to increase in size. This could result in consolidation and synchronization of pHFOs until a critical mass leads to propagation of HYP ictal discharges. Viewed within a network neuroscience framework, local disturbances such as PIN clusters are likely to contribute to large-scale brain network alterations: a better understanding of these epileptogenic networks promises to elucidate mechanisms of ictogenesis, epileptogenesis, and certain comorbidities of epilepsy.
       
  • Multiscale recordings reveal the dynamic spatial structure of human
           seizures
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Catherine A. Schevon, Steven Tobochnik, Tahra Eissa, Edward Merricks, Brian Gill, R. Ryley Parrish, Lisa M. Bateman, Guy M. McKhann, Ronald G. Emerson, Andrew J. Trevelyan The cellular activity underlying human focal seizures, and its relationship to key signatures in the EEG recordings used for therapeutic purposes, has not been well characterized despite many years of investigation both in laboratory and clinical settings. The increasing use of microelectrodes in epilepsy surgery patients has made it possible to apply principles derived from laboratory research to the problem of mapping the spatiotemporal structure of human focal seizures, and characterizing the corresponding EEG signatures. In this review, we describe results from human microelectrode studies, discuss some data interpretation pitfalls, and explain the current understanding of the key mechanisms of ictogenesis and seizure spread.
       
  • Reciprocal modulation between amyloid precursor protein and synaptic
           membrane cholesterol revealed by live cell imaging
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Claire E. DelBove, Claire E. Strothman, Roman M. Lazarenko, Hui Huang, Charles R. Sanders, Qi Zhang The amyloid precursor protein (APP) has been extensively studied because of its association with Alzheimer's disease (AD). However, APP distribution across different subcellular membrane compartments and its function in neurons remains unclear. We generated an APP fusion protein with a pH-sensitive green fluorescent protein at its ectodomain and a pH-insensitive blue fluorescent protein at its cytosolic domain and used it to measure APP's distribution, subcellular trafficking, and cleavage in live neurons. This reporter, closely resembling endogenous APP, revealed only a limited correlation between synaptic activities and APP trafficking. However, the synaptic surface fraction of APP was increased by a reduction in membrane cholesterol levels, a phenomenon that involves APP's cholesterol-binding motif. Mutations at or near binding sites not only reduced both the surface fraction of APP and membrane cholesterol levels in a dominant negative manner, but also increased synaptic vulnerability to moderate membrane cholesterol reduction. Our results reveal reciprocal modulation of APP and membrane cholesterol levels at synaptic boutons.
       
  • Curcumin restores innate immune Alzheimer's disease risk gene expression
           to ameliorate Alzheimer pathogenesis
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): B. Teter, T. Morihara, G.P. Lim, T. Chu, M.R. Jones, X. Zuo, R.M. Paul, S.A. Frautschy, G.M. Cole Alzheimer's disease (AD) genetics implies a causal role for innate immune genes, TREM2 and CD33, products that oppose each other in the downstream Syk tyrosine kinase pathway, activating microglial phagocytosis of amyloid (Aβ). We report effects of low (Curc-lo) and high (Curc-hi) doses of curcumin on neuroinflammation in APPsw transgenic mice. Results showed that Curc-lo decreased CD33 and increased TREM2 expression (predicted to decrease AD risk) and also increased TyroBP, which controls a neuroinflammatory gene network implicated in AD as well as phagocytosis markers CD68 and Arg1. Curc-lo coordinately restored tightly correlated relationships between these genes' expression levels, and decreased expression of genes characteristic of toxic pro-inflammatory M1 microglia (CD11b, iNOS, COX-2, IL1β). In contrast, very high dose curcumin did not show these effects, failed to clear amyloid plaques, and dysregulated gene expression relationships. Curc-lo stimulated microglial migration to and phagocytosis of amyloid plaques both in vivo and in ex vivo assays of sections of human AD brain and of mouse brain. Curcumin also reduced levels of miR-155, a micro-RNA reported to drive a neurodegenerative microglial phenotype. In conditions without amyloid (human microglial cells in vitro, aged wild-type mice), Curc-lo similarly decreased CD33 and increased TREM2. Like curcumin, anti-Aβ antibody (also reported to engage the Syk pathway, increase CD68, and decrease amyloid burden in human and mouse brain) increased TREM2 in APPsw mice and decreased amyloid in human AD sections ex vivo. We conclude that curcumin is an immunomodulatory treatment capable of emulating anti-Aβ vaccine in stimulating phagocytic clearance of amyloid by reducing CD33 and increasing TREM2 and TyroBP, while restoring neuroinflammatory networks implicated in neurodegenerative diseases.
       
  • A mouse model for SPG48 reveals a block of autophagic flux upon disruption
           of adaptor protein complex five
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Mukhran Khundadze, Federico Ribaudo, Adeela Hussain, Jan Rosentreter, Sandor Nietzsche, Melanie Thelen, Dominic Winter, Birgit Hoffmann, Muhammad Awais Afzal, Tanja Hermann, Cecilia de Heus, Eva-Maria Piskor, Christian Kosan, Patricia Franzka, Lisa von Kleist, Tobias Stauber, Judith Klumperman, Markus Damme, Tassula Proikas-Cezanne, Christian A. Hübner Hereditary spastic paraplegia is a spastic gait disorder that arises from degeneration of corticospinal axons. The subtype SPG48 is associated with mutations in the zeta subunit of the adaptor protein complex five (AP5). AP5 function and the pathophysiology of SPG48 are only poorly understood. Here, we report an AP5 zeta knockout mouse, which shows an age-dependent degeneration of corticospinal axons. Our analysis of knockout fibroblasts supports a trafficking defect from late endosomes to the transGolgi network and reveals a structural defect of the Golgi. We further show that both autophagic flux and the recycling of lysosomes from autolysosomes were impaired in knockout cells. In vivo, we observe an increase of autophagosomes and autolysosomes and, at later stages, the accumulation of intracellular waste in neurons. Taken together, we propose that loss of AP5 function blocks autophagy and thus leads to the aberrant accumulation of autophagic cargo, which finally results in axon degeneration.
       
  • Amyloid beta-mediated KIF5A deficiency disrupts anterograde axonal
           mitochondrial movement
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Qi Wang, Jing Tian, Hao Chen, Heng Du, Lan Guo Mitochondria are crucial organelles for neurophysiology and brain mitochondrial defects constitute a characteristic of Alzheimer's disease (AD). Impaired axonal mitochondrial traffic, especially the anterograde axonal mitochondrial transport is a pronouncing mitochondrial defect that underlies synaptic failure in AD-related conditions. However, the detailed molecular mechanisms of such axonal mitochondrial abnormality have not been fully understood. KIF5A is a key isoform of kinesin-1, which is a key molecular machinery in facilitating anterograde axonal mitochondrial transport. In this study, we have determined a downregulation of KIF5A in postmortem AD temporal lobes. Further experiments on amyloid beta (Aβ)-treated primary neuron culture and 5 × FAD mice suggest a close association of Aβ toxicity and KIF5A loss. Downregulation of KIF5A mimics Aβ-induced axonal mitochondrial transport deficits, indicating a potential role of KIF5A deficiency in AD-relevant axonal mitochondrial traffic abnormalities. Importantly, the restoration of KIF5A corrects Aβ-induced impairments in axonal mitochondrial transport, especially the anterograde traffic, with little or no impact on retrograde axonal mitochondrial motility. Our findings suggest a novel KIF5A-associated mechanism conferring Aβ toxicity to axonal mitochondrial deficits. Furthermore, the results implicate a potential therapeutic avenue by protecting KIF5A function for the treatment of AD.
       
  • Regional vulnerability and spreading of hyperphosphorylated tau in seeded
           mouse brain
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Jan R. Detrez, Hervé Maurin, Kristof Van Kolen, Roland Willems, Julien Colombelli, Benoit Lechat, Bart Roucourt, Fred Van Leuven, Sarah Baatout, Peter Larsen, Rony Nuydens, Jean-Pierre Timmermans, Winnok H. De Vos We have exploited whole brain microscopy to map the progressive deposition of hyperphosphorylated tau in intact, cleared mouse brain. We found that the three-dimensional spreading pattern of hyperphosphorylated tau in the brain of an aging Tau.P301L mouse model did not resemble that observed in AD patients. Injection of synthetic or patient-derived tau fibrils in the CA1 region resulted in a more faithful spreading pattern. Atlas-guided volumetric analysis showed a connectome-dependent spreading from the injection site and also revealed hyperphosphorylated tau deposits beyond the direct anatomical connections. In fibril-injected brains, we also detected a persistent subpopulation of rod-like and swollen microglia. Furthermore, we showed that the hyperphosphorylated tau load could be reduced by intracranial co-administration of, and to a lesser extent, by repeated systemic dosing with an antibody targeting the microtubule-binding domain of tau. Thus, the combination of targeted seeding and in toto staging of tau pathology allowed assessing regional vulnerability in a comprehensive manner, and holds potential as a preclinical drug validation tool.Graphical abstractUnlabelled Image
       
  • NitroSynapsin for the treatment of neurological manifestations of tuberous
           sclerosis complex in a rodent model
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Shu-ichi Okamoto, Olga Prikhodko, Juan Pina-Crespo, Anthony Adame, Scott R. McKercher, Laurence M. Brill, Nobuki Nakanishi, Chang-ki Oh, Tomohiro Nakamura, Eliezer Masliah, Stuart A. Lipton Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by heterozygous mutations in the TSC1 or TSC2 gene. TSC is often associated with neurological, cognitive, and behavioral deficits. TSC patients also express co-morbidity with anxiety and mood disorders. The mechanism of pathogenesis in TSC is not entirely clear, but TSC-related neurological symptoms are accompanied by excessive glutamatergic activity and altered synaptic spine structures. To address whether extrasynaptic (e)NMDA-type glutamate receptor (NMDAR) antagonists, as opposed to antagonists that block physiological phasic synaptic activity, can ameliorate the synaptic and behavioral features of this disease, we utilized the Tsc2+/− mouse model of TSC to measure biochemical, electrophysiological, histological, and behavioral parameters in the mice. We found that antagonists that preferentially block tonic activity as found at eNMDARs, particularly the newer drug NitroSynapsin, provide biological and statistically significant improvement in Tsc2+/− phenotypes. Accompanying this improvement was correction of activity in the p38 MAPK-TSC-Rheb-mTORC1-S6K1 pathway. Deficits in hippocampal long-term potentiation (LTP), histological loss of synapses, and behavioral fear conditioning in Tsc2+/− mice were all improved after treatment with NitroSynapsin. Taken together, these results suggest that amelioration of excessive excitation, by limiting aberrant eNMDAR activity, may represent a novel treatment approach for TSC.
       
  • Fast ripple analysis in human mesial temporal lobe epilepsy suggests two
           different seizure-generating mechanisms
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Jan Schönberger, Birgit Frauscher, Nicolás von Ellenrieder, Massimo Avoli, François Dubeau, Jean Gotman ObjectiveThe distinction of hypersynchronous (HYP) and low-voltage fast (LVF) onset seizures in mesial temporal lobe epilepsy (MTLE) is well established, but classifying individual seizures and patients is often challenging. Experimental work indicates a strong association of HYP with fast ripples (250–500 Hz) and of LVF with ripples (80–250 Hz). We aimed to investigate whether analysis of high-frequency oscillations can be useful for characterizing the process of seizure generation in human MTLE patients.MethodsWe retrospectively compared 19 HYP and 14 LVF onset clinical seizures from ten and six consecutive MTLE patients with a predominance of the respective pattern. Five-second intervals of stereotactic EEGs from the seizure onset zone were selected, each representing the onset of HYP and LVF, the corresponding pre-ictal periods and, after the large spikes of HYP onsets, the LVF-like pattern that frequently followed.ResultsPre-ictal fast ripple density and rate were higher for HYP than for LVF seizures (p 
       
  • Upregulation of tripeptidyl-peptidase 1 by 3-hydroxy-(2,2)-dimethyl
           butyrate, a brain endogenous ligand of PPARα: Implications for
           late-infantile Batten disease therapy
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Sudipta Chakrabarti, Sujyoti Chandra, Avik Roy, Sridevi Dasarathi, Madhuchhanda Kundu, Kalipada Pahan The late-infantile Batten disease or late-infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive lysosomal storage disorder caused by mutations in the Cln2 gene leading to deficiency of lysosomal enzyme tripeptidyl peptidase 1 (TPP1). At present, available options for this fatal disorder are enzyme replacement therapy and gene therapy, which are extensively invasive and expensive. Our study demonstrates that 3-hydroxy-(2,2)-dimethyl butyrate (HDMB), a brain endogenous molecule, is capable of stimulating TPP1 expression and activity in mouse primary astrocytes and a neuronal cell line. HDMB activated peroxisome proliferator-activated receptor-α (PPARα), which, by forming heterodimer with Retinoid X receptor-α (RXRα), transcriptionally upregulated the Cln2 gene. Moreover, by using primary astrocytes from wild type, PPARα−/− and PPARβ−/− mice, we demonstrated that HDMB specifically required PPARα for inducing TPP1 expression. Finally, oral administration of HDMB to Cln2 heterozygous (Cln2+/−) mice led to a marked upregulation of TPP1 expression in the motor cortex and striatum in a PPARα-dependent fashion. Our study suggests that HDMB, a brain endogenous ligand of PPARα, might have therapeutic importance for LINCL treatment.
       
  • Seipin deletion in mice enhances phosphorylation and aggregation of tau
           protein through reduced neuronal PPARγ and insulin resistance
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Huanxian Chang, Tingting Di, Ya Wang, Xianying Zeng, Guoxi Li, Qi Wan, Wenfeng Yu, Ling Chen Congenital generalized lipodystrophy 2 (CGL2) is characterized by loss of adipose tissue, insulin resistance and cognitive deficits and caused by mutation of BSCL2/seipin gene. Seipin deletion in mice and rats causes severe lipodystrophy, insulin resistance, and cognitive impairment. Hippocampal neurons express seipin protein. This study aimed to investigate the influence of systemic seipin knockout (seipin-sKO), neuronal seipin knockout (seipin-nKO) or adipose seipin knockout (seipin-aKO) in hippocampal tau phosphorylation and aggregation. Levels of tau phosphorylation at Thr212/Ser214 and Ser202/Thr205 and oligomer tau protein were increased in seipin-sKO mice and seipin-nKO mice with a decrease in axonal density and expression of PPARγ. Neuronal seipin deletion increased activities of GSK3β and Akt/mTOR signaling, which were corrected by the administration of PPARγ agonist rosiglitazone for 7 days. The autophagosome formation was reduced in seipin-sKO mice and seipin-nKO mice, which was rescued by the Akt and mTOR inhibitors. The administration of rosiglitazone or Akt, mTOR and GSK3β inhibitors for 7 days could correct the hyperphosphorylation and aggregation of tau. On the other hand, seipin-sKO mice appeared insulin resistance and an increase in phosphorylation of tau at Ser396 and JNK, which were corrected by treatment with rosiglitazone for 30 days rather than 7 days. Inhibition of JNK in seipin-sKO mice corrected the hyperphosphorylated tau at Ser396. The results indicate that neuronal seipin deletion causes hyperphosphorylation and aggregation of tau protein leading to axonal atrophy through reduced PPARγ to enhance GSK3β and Akt/mTOR signaling; systemic seipin deletion-induced insulin resistance causes tau hyperphosphorylation via cascading JNK pathway.
       
  • A mouse model of adult-onset multiple system atrophy
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Kunikazu Tanji, Yasuo Miki, Fumiaki Mori, Yoshikazu Nikaido, Hidemi Narita, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder clinically characterized by autonomic failure in addition to various combinations of symptoms of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Despite extensive research, the mechanisms underlying the progression of MSA remain unknown. Animal models of human diseases that recapitulate their clinical, biochemical and pathological features are indispensable for increasing our understanding of their underlying molecular mechanisms, which allows preclinical studies to be advanced. Because the onset of MSA occurs in middle age, an animal model that first manifests abnormal protein aggregates in adulthood would be most appropriate. We therefore used the Cre-loxP system to express inducible α-synuclein (Syn), a major component of the pathological hallmark of MSA, to generate a mouse model of MSA. Beginning in adulthood, these MSA model mice express excessive levels of Syn in oligodendrocytes, resulting in abnormal Syn accumulation and modifications similar to those observed in human MSA pathology. Additionally, MSA model mice exhibit some clinical features of MSA, including decreased motor activity. These findings suggest that this new mouse model of MSA represents a useful tool for analyzing the pathophysiological alterations that underlie the progression of this disease.
       
  • Neuropathological changes and cognitive deficits in rats transgenic for
           human mutant tau recapitulate human tauopathy
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Janice C. Malcolm, Lionel Breuillaud, Sonia Do Carmo, Hélène Hall, Lindsay A. Welikovitch, Jennifer A. Macdonald, Michel Goedert, A. Claudio Cuello The assembly of tau protein into abnormal filaments and brain cell degeneration are characteristic of a number of human neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia and parkinsonism linked to chromosome 17. Several murine models have been generated to better understand the mechanisms contributing to tau assembly and neurodegeneration. Taking advantage of the more elaborate central nervous system and higher cognitive abilities of the rat, we generated a model expressing the longest human tau isoform (2N4R) with the P301S mutation. This transgenic rat line, R962-hTau, exhibits the main features of human tauopathies, such as: age-dependent increase in inclusions comprised of aggregated-tau, neuronal loss, global neurodegeneration as reflected by brain atrophy and ventricular dilation, alterations in astrocytic and microglial morphology, and myelin loss. In addition, substantial deficits across multiple memory and learning paradigms, including novel object recognition, fear conditioning and Morris water maze tasks, were observed at the time of advanced tauopathy. These results support the concept that progressive tauopathy correlates with brain atrophy and cognitive impairment.
       
  • Nucleolin reorganization and nucleolar stress in Purkinje cells of mutant
           PCD mice
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Fernando C. Baltanás, María T. Berciano, Olga Tapia, Josep Oriol Narcis, Vanesa Lafarga, David Díaz, Eduardo Weruaga, Eugenio Santos, Miguel Lafarga The Purkinje cell (PC) degeneration (pcd) mouse harbors a mutation in Agtpbp1 gene that encodes for the cytosolic carboxypeptidase, CCP1. The mutation causes degeneration and death of PCs during the postnatal life, resulting in clinical and pathological manifestation of cerebellar ataxia. Monogenic biallelic damaging variants in the Agtpbp1 gene cause infantile-onset neurodegeneration and cerebellar atrophy, linking loss of functional CCP1 with human neurodegeneration. Although CCP1 plays a key role in the regulation of tubulin stabilization, its loss of function in PCs leads to a severe nuclear phenotype with heterochromatinization and accumulation of DNA damage. Therefore, the pcd mice provides a useful neuronal model to investigate nuclear mechanisms involved in neurodegeneration, particularly the nucleolar stress. In this study, we demonstrated that the Agtpbp1 gene mutation induces a p53-dependent nucleolar stress response in PCs, which is characterized by nucleolar fragmentation, nucleoplasmic and cytoplasmic mislocalization of nucleolin, and dysfunction of both pre-rRNA processing and mRNA translation. RT-qPCR analysis revealed reduction of mature 18S rRNA, with a parallel increase of its intermediate 18S-5’-ETS precursor, that correlates with a reduced expression of Fbl mRNA, which encodes an essential factor for rRNA processing. Moreover, nucleolar alterations were accompanied by a reduction of PTEN mRNA and protein levels, which appears to be related to the chromosome instability and accumulation of DNA damage in degenerating PCs.Our results highlight the essential contribution of nucleolar stress to PC degeneration and also underscore the nucleoplasmic mislocalization of nucleolin as a potential indicator of neurodegenerative processes.
       
  • Hyperhomocysteinemia leads to exacerbation of ischemic brain damage: Role
           of GluN2A NMDA receptors
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Ankur Jindal, Sathyanarayanan Rajagopal, Lucas Winter, Joshua W. Miller, Donald W. Jacobsen, Jonathan Brigman, Andrea M. Allan, Surojit Paul, Ranjana Poddar Hyperhomocysteinemia has been implicated in several neurodegenerative disorders including ischemic stroke. However, the pathological consequences of ischemic insult in individuals predisposed to hyperhomocysteinemia and the associated etiology are unknown. In this study, we evaluated the outcome of transient ischemic stroke in a rodent model of hyperhomocysteinemia, developed by subcutaneous implantation of osmotic pumps containing L-homocysteine into male Wistar rats. Our findings show a 42.3% mortality rate in hyperhomocysteinemic rats as compared to 7.7% in control rats. Magnetic resonance imaging of the brain in the surviving rats shows that mild hyperhomocysteinemia leads to exacerbation of ischemic injury within 24 h, which remains elevated over time. Behavioral studies further demonstrate significant deficit in sensorimotor functions in hyperhomocysteinemic rats compared to control rats. Using pharmacological inhibitors targeting the NMDAR subtypes, the study further demonstrates that inhibition of GluN2A-containing NMDARs significantly reduces ischemic brain damage in hyperhomocysteinemic rats but not in control rats, indicating that hyperhomocysteinemia-mediated exacerbation of ischemic brain injury involves GluN2A-NMDAR signaling. Complementary studies in GluN2A-knockout mice show that in the absence of GluN2A-NMDARs, hyperhomocysteinemia-associated exacerbation of ischemic brain injury is blocked, confirming that GluN2A-NMDAR activation is a critical determinant of the severity of ischemic damage under hyperhomocysteinemic conditions. Furthermore, at the molecular level we observe GluN2A-NMDAR dependent sustained increase in ERK MAPK phosphorylation under hyperhomocysteinemic condition that has been shown to be involved in homocysteine-induced neurotoxicity. Taken together, the findings show that hyperhomocysteinemia triggers a unique signaling pathway that in conjunction with ischemia-induced pathways enhance the pathology of stroke under hyperhomocysteinemic conditions.
       
  • An increased rate of longitudinal cognitive decline is observed in
           Parkinson's disease patients with low CSF Aß42 and an APOE ε4 allele
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Marian Shahid, Jeehyun Kim, Katherine Leaver, Taylor Hendershott, Delphine Zhu, Brenna Cholerton, Victor W. Henderson, Lu Tian, Kathleen L. Poston ObjectiveLow concentrations of cerebrospinal fluid (CSF) amyloid-beta (Aβ-42) are associated with increased risk of cognitive decline in Parkinson's disease (PD). We sought to determine whether APOE genotype modifies the rate of cognitive decline in PD patients with low CSF Aβ-42 compared to patients with normal levels.MethodsThe Parkinson's Progression Markers Initiative is a longitudinal, ongoing study of de novo PD participants, which includes APOE genotyping, CSF Aβ-42 determinations, and neuropsychological assessments. We used linear mixed effects models in three PD groups (PD participants with low CSF Aβ at baseline, PD participants with normal CSF Aβ, and both groups combined). Having at least one copy of the APOE ɛ4 allele, time, and the interaction of APOE ɛ4 and time were predictor variables for cognitive change, adjusting for age, gender and education.Results423 de novo PD participants were followed up to 5 years with annual cognitive assessments. 103 participants had low baseline CSF Aβ-42 (39 APOE ε4+, 64 APOE ε4-). Compared to participants with normal CSF Aβ-42, those with low CSF Aβ-42 declined faster on most cognitive tests. Within the low CSF Aβ-42 group, APOE ε4+ participants had faster rates of decline on the Montreal Cognitive Assessment (primary outcome; 0.57 points annual decline, p = .005; 5-year standardized change of 1.2) and the Symbol Digit Modalities Test (1.4 points annual decline, p = .002; 5-year standardized change of 0.72).DiscussionPD patients with low CSF Aβ-42 and APOE ε4+ showed a higher rate of cognitive decline early in the disease. Tests of global cognition (Montreal Cognitive Assessment) and processing speed (Symbol Digit Modalities Test) were the most sensitive to early cognitive decline. Results suggest that CSF Aβ-42 and APOE ε4 might interact to promote early cognitive changes in PD patients.
       
  • Regional hypometabolism in the 3xTg mouse model of Alzheimer's disease
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Aida Adlimoghaddam, Wanda M. Snow, Greg Stortz, Claudia Perez, Jelena Djordjevic, Andrew L. Goertzen, Ji Hyun Ko, Benedict C. Albensi Alzheimer's disease (AD) is a progressive age-related neurodegenerative disease. Although neurofibrillary tangles and amyloid beta are classic hallmarks of AD, the earliest deficits in AD progression may be caused by unknown factors. One suspected factor has to do with brain energy metabolism. To investigate this factor, brain metabolic activity in 3xTg-AD mice and age-matched controls were measured with FDG-PET. Significant hypometabolic changes (p 
       
  • Insights into GBA Parkinson's disease pathology and therapy with induced
           pluripotent stem cell model systems
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Pascale Baden, Cong Yu, Michela Deleidi While the link between GBA and Parkinson's disease (PD) was initially unexpected, it is now well established that GBA mutations are the most frequent genetic risk for PD. GBA has also been linked to sporadic PD, dementia with Lewy bodies, and ageing. Thus, GBA represents a promising target to counteract brain disease and the age-related decline of lysosomal function. The exact mechanisms involved in the risk of developing PD in GBA mutation carriers are still unclear and research in this field has faced the major challenge of a lack of proper modeling systems. Induced pluripotent stem cells (iPSCs) as well as advances in disease modeling and genome editing have facilitated studies of human brain disease. With regard to GBA-PD, iPSCs offer several advantages including the possibility of investigating sphingolipid (SPL) biology in relevant cells, the role of dopamine metabolism as well as non-cell autonomous mechanisms that are likely involved in the disease process. This review will summarize findings that emerged from iPSC-based studies in the context of GBA-PD pathology and therapy. We also highlight current advantages and challenges of stem cell models for neurological disease modeling and drug discovery.
       
  • Cytosolic glucosylceramide regulates endolysosomal function in
           Niemann-Pick type C disease
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Simon Wheeler, Per Haberkant, Meenakshi Bhardwaj, Paige Tongue, Maria J. Ferraz, David Halter, Hein Sprong, Ralf Schmid, Johannes M.F.G. Aerts, Nikol Sullo, Dan J. Sillence Niemann-Pick type C disease (NPCD) is a neurodegenerative disease associated with increases in cellular cholesterol and glycolipids and most commonly caused by defective NPC1, a late endosomal protein. Using ratiometric probes we find that NPCD cells show increased endolysosomal pH. In addition U18666A, an inhibitor of NPC1, was found to increase endolysosomal pH, and the number, size and heterogeneity of endolysosomal vesicles. NPCD fibroblasts and cells treated with U18666A also show disrupted targeting of fluorescent lipid BODIPY-LacCer to high pH vesicles. Inhibiting non-lysosomal glucocerebrosidase (GBA2) reversed increases in endolysosomal pH and restored disrupted BODIPY-LacCer trafficking in NPCD fibroblasts. GBA2 KO cells also show decreased endolysosomal pH. NPCD fibroblasts also show increased expression of a key subunit of the lysosomal proton pump vATPase on GBA2 inhibition. The results are consistent with a model where both endolysosomal pH and Golgi targeting of BODIPY-LacCer are dependent on adequate levels of cytosolic-facing GlcCer, which are reduced in NPC disease.
       
  • Impaired development of neocortical circuits contributes to the
           neurological alterations in DYRK1A haploinsufficiency syndrome
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Juan Arranz, Elisa Balducci, Krisztina Arató, Gentzane Sánchez-Elexpuru, Sònia Najas, Alberto Parras, Elena Rebollo, Isabel Pijuan, Ionas Erb, Gaetano Verde, Ignasi Sahun, Maria J. Barallobre, José J. Lucas, Marina P. Sánchez, Susana de la Luna, Maria L. Arbonés Autism spectrum disorders are early onset neurodevelopmental disorders characterized by deficits in social communication and restricted repetitive behaviors, yet they are quite heterogeneous in terms of their genetic basis and phenotypic manifestations. Recently, de novo pathogenic mutations in DYRK1A, a chromosome 21 gene associated to neuropathological traits of Down syndrome, have been identified in patients presenting a recognizable syndrome included in the autism spectrum. These mutations produce DYRK1A kinases with partial or complete absence of the catalytic domain, or they represent missense mutations located within this domain. Here, we undertook an extensive biochemical characterization of the DYRK1A missense mutations reported to date and show that most of them, but not all, result in enzymatically dead DYRK1A proteins. We also show that haploinsufficient Dyrk1a+/− mutant mice mirror the neurological traits associated with the human pathology, such as defective social interactions, stereotypic behaviors and epileptic activity. These mutant mice present altered proportions of excitatory and inhibitory neocortical neurons and synapses. Moreover, we provide evidence that alterations in the production of cortical excitatory neurons are contributing to these defects. Indeed, by the end of the neurogenic period, the expression of developmental regulated genes involved in neuron differentiation and/or activity is altered. Therefore, our data indicate that altered neocortical neurogenesis could critically affect the formation of cortical circuits, thereby contributing to the neuropathological changes in DYRK1A haploinsufficiency syndrome.
       
  • Genetic suppression of IKK2/NF-κB in astrocytes inhibits
           neuroinflammation and reduces neuronal loss in the MPTP-Probenecid model
           of Parkinson's disease
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Kelly S. Kirkley, Katriana A. Popichak, Sean L. Hammond, Cecilia Davies, Lindsay Hunt, Ronald B. Tjalkens Neuroinflammatory activation of glia is considered a pathological hallmark of Parkinson's disease (PD) and is seen in both human PD patients and in animal models of PD; however, the relative contributions of these cell types, especially astrocytes, to the progression of disease is not fully understood. The transcription factor, nuclear factor kappa B (NFκB), is an important regulator of inflammatory gene expression in glia and is activated by multiple cellular stress signals through the kinase complex, IKK2. We sought to determine the role of NFκB in modulating inflammatory activation of astrocytes in a model of PD by generating a conditional knockout mouse (hGfapcre/Ikbk2F/F) in which IKK2 is specifically deleted in astrocytes. Measurements of IKK2 revealed a 70% deletion rate of IKK2 within astrocytes, as compared to littermate controls (Ikbk2F/F). Use of this mouse in a subacute, progressive model of PD through exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp) revealed significant protection in exposed mice to direct and progressive loss of dopaminergic neurons in the substantia nigra (SN). hGfapcre/Ikbk2F/F mice were also protected against MPTPp-induced loss in motor activity, loss of striatal proteins, and genomic alterations in nigral NFκB gene expression, but were not protected from loss of striatal catecholamines. Neuroprotection in hGfapcre/Ikbk2F/F mice was associated with inhibition of MPTPp-induced astrocytic expression of inflammatory genes and protection against nitrosative stress and apoptosis in neurons. These data indicate that deletion of IKK2 within astrocytes is neuroprotective in the MPTPp model of PD and suggests that reactive astrocytes directly contribute the potentiation of dopaminergic pathology.
       
  • DLK regulates a distinctive transcriptional regeneration program after
           peripheral nerve injury
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Jung Eun Shin, Hongseok Ha, Yoon Ki Kim, Yongcheol Cho, Aaron DiAntonio Following damage to a peripheral nerve, injury signaling pathways converge in the cell body to generate transcriptional changes that support axon regeneration. Here, we demonstrate that dual leucine zipper kinase (DLK), a central regulator of injury responses including axon regeneration and neuronal apoptosis, is required for the induction of the pro-regenerative transcriptional program in response to peripheral nerve injury. Using a sensory neuron-conditional DLK knockout mouse model, we show a time course for the dependency of gene expression changes on the DLK pathway after sciatic nerve injury. Gene ontology analysis reveals that DLK-dependent gene sets are enriched for specific functional annotations such as ion transport and immune response. A series of comparative analyses shows that the DLK-dependent transcriptional program is distinct from that promoted by the importin-dependent retrograde signaling pathway, while it is partially shared between PNS and CNS injury responses. We suggest that DLK-dependency might provide a selective filter for regeneration-associated genes among the injury-responsive transcriptome.
       
  • Systemic peptide mediated delivery of an siRNA targeting α-syn in the CNS
           ameliorates the neurodegenerative process in a transgenic model of Lewy
           body disease
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Brian Spencer, Ivy Trinh, Edward Rockenstein, Michael Mante, Jazmin Florio, Anthony Adame, Omar M.A. El-Agnaf, Changyoun Kim, Eliezer Masliah, Robert A. Rissman Neurodegenerative disorders of the aging population are characterized by progressive accumulation of neuronal proteins such as α-synuclein (α-syn) in Parkinson's Disease (PD) and Amyloid ß (Aß) and Tau in Alzheimer's disease (AD) for which no treatments are currently available. The ability to regulate the expression at the gene transcription level would be beneficial for reducing the accumulation of these proteins or regulating expression levels of other genes in the CNS. Short interfering RNA molecules can bind specifically to target RNAs and deliver them for degradation. This approach has shown promise therapeutically in vitro and in vivo in mouse models of PD and AD and other neurological disorders; however, delivery of the siRNA to the CNS in vivo has been achieved primarily through intra-cerebral or intra-thecal injections that may be less amenable for clinical translation; therefore, alternative approaches for delivery of siRNAs to the brain is needed. Recently, we described a small peptide from the envelope protein of the rabies virus (C2-9r) that was utilized to deliver an siRNA targeting α-syn across the blood brain barrier (BBB) following intravenous injection. This approach showed reduced expression of α-syn and neuroprotection in a toxic mouse model of PD. However, since receptor-mediated delivery is potentially saturable, each allowing the delivery of a limited number of molecules, we identified an alternative peptide for the transport of nucleotides across the BBB based on the apolipoprotein B (apoB) protein targeted to the family of low-density lipoprotein receptors (LDL-R). We used an 11-amino acid sequence from the apoB protein (ApoB11) that, when coupled with a 9-amino acid arginine linker, can transport siRNAs across the BBB to neuronal and glial cells. To examine the value of this peptide mediated oligonucleotide delivery system for PD, we delivered an siRNA targeting the α-syn (siα-syn) in a transgenic mouse model of PD. We found that ApoB11 was effective (comparable to C2-9r) at mediating the delivery of siα-syn into the CNS, co-localized to neurons and glial cells and reduced levels of α-syn protein translation and accumulation. Delivery of ApoB11/siα-syn was accompanied by protection from degeneration of selected neuronal populations in the neocortex, limbic system and striato-nigral system and reduced neuro-inflammation. Taken together, these results suggest that systemic delivery of oligonucleotides targeting α-syn using ApoB11 might be an interesting alternative strategy worth considering for the experimental treatment of synucleinopathies.
       
  • Assessment of APOE in atypical parkinsonism syndromes
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Marya S. Sabir, Cornelis Blauwendraat, Sarah Ahmed, Geidy E. Serrano, Thomas G. Beach, Matthew Perkins, Ann C. Rice, Eliezer Masliah, Christopher M. Morris, Lasse Pihlstrom, Alexander Pantelyat, Susan M. Resnick, Mark R. Cookson, Dena G. Hernandez, Marilyn Albert, Ted M. Dawson, Liana S. Rosenthal, Henry Houlden, Olga Pletnikova, Juan Troncoso Atypical parkinsonism syndromes are a heterogeneous group of neurodegenerative disorders that include corticobasal degeneration (CBD), Lewy body dementia (LBD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). The APOE ε4 allele is a well-established risk factor for Alzheimer's disease; however, the role of APOE in atypical parkinsonism syndromes remains controversial. To examine the associations of APOE ε4 and ε2 alleles with risk of developing these syndromes, a total of 991 pathologically-confirmed atypical parkinsonism cases were genotyped using the Illumina NeuroChip array. We also performed genotyping and logistic regression analyses to examine APOE frequency and associated risk in patients with Alzheimer's disease (n = 571) and Parkinson's disease (n = 348). APOE genotypes were compared to those from neurologically healthy controls (n = 591). We demonstrate that APOE ε4 and ε2 carriers have a significantly increased and decreased risk, respectively, of developing Alzheimer's disease (ε4: OR: 4.13, 95% CI: 3.23–5.26, p = 3.67 × 10−30; ε2: OR: 0.21, 95% CI: 0.13–0.34; p = 5.39 × 10−10) and LBD (ε4: OR: 2.94, 95% CI: 2.34–3.71, p = 6.60 × 10−20; ε2: OR = OR: 0.39, 95% CI: 0.26–0.59; p = 6.88 × 10−6). No significant associations with risk for CBD, MSA, or PSP were observed. We also show that APOE ε4 decreases survival in a dose-dependent manner in Alzheimer's disease and LBD. Taken together, this study does not provide evidence to implicate a role of APOE in the neuropathogenesis of CBD, MSA, or PSP. However, we confirm association of the APOE ε4 allele with increased risk for LBD, and importantly demonstrate that APOE ε2 reduces risk of this disease.
       
  • Genetic ablation of tau in postnatal neurons rescues decreased adult
           hippocampal neurogenesis in a tauopathy model
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Sarah Houben, Karelle Leroy, Kunie Ando, Zehra Yilmaz, Cyprien Widomski, Luc Buée, Jean-Pierre Brion Impaired adult hippocampal neurogenesis has been reported as a feature of Alzheimer's disease and other tauopathies and might contribute to defects in learning and memory in these diseases. To assess the interference of tau pathology, a common key-lesion in these diseases, with adult hippocampal neurogenesis we analyzed adult neurogenesis in the hippocampal dentate gyrus in wild-type mice, Tg30 mice expressing a FTDP-17 mutant tau and the same Tg30 mice deficient for mouse tau (Tg30/tauKO). The volume of the granular layer, the number of granule cells and of neuronal precursors expressing the immature markers DCX or 3R-tau were analyzed in the dentate gyrus (DG) using unbiased stereological methods. The co-localization of neurogenic markers with the human mutant tau was also analyzed. We observed a significant reduction of the volume of the granular layer and of granule cells number in mutant tau Tg30 mice, but not in Tg30/tauKO mice. The number of neuronal precursors expressing the immature markers DCX or 3R-tau (the latter only expressed in wild-type and Tg30 mice) and the number of cells expressing the proliferation marker Ki-67 in the neurogenic subgranular zone of the DG was reduced in Tg30 but not in Tg30/tauKO mice. The density of phosphotau positive cells in the DG and the level of soluble human phosphotau was lower in Tg30/tauKO compared to Tg30 mice. The human mutant tau was expressed in mature granule cells in Tg30 and Tg30/tauKO mice but was not expressed in Sox2 positive neural stem cells and in DCX positive neuronal precursors/immature newborn neurons. These results demonstrate an impairment of adult hippocampal neurogenesis in a FTDP-17 mutant tau mice resulting from a decrease of proliferation affecting the pool of neuronal precursors. The mutant tau was not expressed in precursors cells in these mutant tau mice, suggesting that this neurogenic defect is cell non-autonomous. Interestingly, expression of endogenous wild-type tau in mature granule cells was necessary to observe this toxic effect of human mutant tau, since this impaired adult neurogenesis was rescued by lowering tau expression in Tg30/tauKO mice. These observations suggest that development of tau pathology in granule cells of the dentate gyrus is responsible for reduction of adult hippocampal neurogenesis also in human tauopathies by impairing proliferation of neuronal precursors, and that reduction of tau expression might be an approach to rescue this impairment.
       
  • Ubiquitylome profiling of Parkin-null brain reveals dysregulation of
           calcium homeostasis factors ATP1A2, Hippocalcin and GNA11, reflected by
           altered firing of noradrenergic neurons
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): J. Key, A.K. Mueller, S. Gispert, L. Matschke, I. Wittig, O. Corti, C. Münch, N. Decher, G. Auburger Parkinson's disease (PD) is the second most frequent neurodegenerative disorder in the old population. Among its monogenic variants, a frequent cause is a mutation in the Parkin gene (Prkn). Deficient function of Parkin triggers ubiquitous mitochondrial dysfunction and inflammation in the brain, but it remains unclear how selective neural circuits become vulnerable and finally undergo atrophy.We attempted to go beyond previous work, mostly done in peripheral tumor cells, which identified protein targets of Parkin activity, an ubiquitin E3 ligase. Thus, we now used aged Parkin-knockout (KO) mouse brain for a global quantification of ubiquitylated peptides by mass spectrometry (MS). This approach confirmed the most abundant substrate to be VDAC3, a mitochondrial outer membrane porin that modulates calcium flux, while uncovering also>3-fold dysregulations for neuron-specific factors. Ubiquitylation decreases were prominent for Hippocalcin (HPCA), Calmodulin (CALM1/CALML3), Pyruvate Kinase (PKM2), sodium/potassium-transporting ATPases (ATP1A1/2/3/4), the Rab27A-GTPase activating protein alpha (TBC1D10A) and an ubiquitin ligase adapter (DDB1), while strong increases occurred for calcium transporter ATP2C1 and G-protein subunits G(i)/G(o)/G(Tr). Quantitative immunoblots validated elevated abundance for the electrogenic pump ATP1A2, for HPCA as neuron-specific calcium sensor, which stimulates guanylate cyclases and modifies axonal slow afterhyperpolarization (sAHP), and for the calcium-sensing G-protein GNA11. We assessed if compensatory molecular regulations become insufficient over time, leading to functional deficits. Patch clamp experiments in acute Parkin-KO brain slices indeed revealed alterations of the electrophysiological properties in aged noradrenergic locus coeruleus (LC) neurons. LC neurons of aged Parkin-KO brain showed an acceleration of the spontaneous pacemaker frequency, a reduction in sAHP and shortening of action potential duration, without modulation of KCNQ potassium currents.These findings indicate altered calcium-dependent excitability in a PARK2 model of PD, mediated by diminished turnover of potential Parkin targets such as ATP1A2 and HPCA. The data also identified further novel Parkin substrate candidates like SIRT2, OTUD7B and CUL5. Our elucidation of neuron-specific mechanisms of PD pathogenesis helps to explain the known exceptional susceptibility of noradrenergic and dopaminergic projections to alterations of calcium homeostasis and its mitochondrial buffering.
       
  • Synchronised spiking activity underlies phase amplitude coupling in the
           subthalamic nucleus of Parkinson's disease patients
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Anders Christian Meidahl, Christian K.E. Moll, Bernadette C.M. van Wijk, Alessandro Gulberti, Gerd Tinkhauser, Manfred Westphal, Andreas K. Engel, Wolfgang Hamel, Peter Brown, Andrew Sharott Both phase-amplitude coupling (PAC) and beta-bursts in the subthalamic nucleus have been significantly linked to symptom severity in Parkinson's disease (PD) in humans and emerged independently as competing biomarkers for closed-loop deep brain stimulation (DBS). However, the underlying nature of subthalamic PAC is poorly understood and its relationship with transient beta burst-events has not been investigated. To address this, we studied macro- and micro electrode recordings of local field potentials (LFPs) and single unit activity from 15 hemispheres in 10 PD patients undergoing DBS surgery. PAC between beta phase and high frequency oscillation (HFO) amplitude was compared to single unit firing rates, spike triggered averages, power spectral densities, inter spike intervals and phase-spike locking, and was studied in periods of beta-bursting. We found a significant synchronisation of spiking to HFOs and correlation of mean firing rates with HFO-amplitude when the latter was coupled to beta phase (i.e. in the presence of PAC). In the presence of PAC, single unit power spectra displayed peaks in the beta and HFO frequency range and the HFO frequency was correlated with that in the LFP. Furthermore, inter spike interval frequencies peaked in the same frequencies for which PAC was observed. Finally, PAC significantly increased with beta burst-duration. Our findings offer new insight in the pathology of Parkinson's disease by providing evidence that subthalamic PAC reflects the locking of spiking activity to network beta oscillations and that this coupling progressively increases with beta-burst duration. These findings suggest that beta-bursts capture periods of increased subthalamic input/output synchronisation in the beta frequency range and have important implications for therapeutic closed-loop DBS.Significance statementIdentifying biomarkers for closed-loop deep brain stimulation (DBS) has become an increasingly important issue in Parkinson's Disease (PD) research. Two such biomarkers, phase-amplitude coupling (PAC) and beta-bursts, recorded from the implanted electrodes in subthalamic nucleus in PD patients, correlate with motor impairment. However, the physiological basis of PAC, and it relationship to beta bursts, is unclear. We provide multiple lines of evidence that PAC in the human STN reflects the locking of spiking activity to network beta oscillations and that this coupling progressively increases with the duration of beta-bursts. This suggests that beta-bursts capture increased subthalamic input/output synchronisation and provides new insights in PD pathology with direct implications for closed-loop DBS therapy strategies.
       
  • Reduced disease severity following therapeutic treatment with angiotensin
           1–7 in a mouse model of multiple sclerosis
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): B.T. Lund, R. Stone, A.M. Levy, S. Lee, E. Amundson, N. Kashani, K.E. Rodgers, E.E. Kelland Multiple Sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by autoimmune and neurodegenerative pathologies for which there is no cure and no defined etiology. Although several, modestly effective, disease modifying drugs are available to treat MS, there are presently no treatments that offer neuroprotection and prevent clinical progression. Therapies are needed that control immune homeostasis, prevent disease progression, and stimulate regeneration in the CNS. Components of the renin-angiotensin-system (RAS) have recently been identified as chemical mediators in the CNS and in neurological disease.Here we show the beneficial effect of therapeutic treatment with the Mas receptor agonist and metabolite of the protective arm of RAS, angiotensin 1–7 (A(1–7)), in the experimental autoimmune encephalomyelitis (EAE) animal model of MS. Therapeutic treatment with A(1–7) caused a dose-dependent reduction both in clinical disease severity and progression, and was dependent on Mas receptor activation. Further analysis of the most optimal dose of A(1–7) treatment revealed that the reductions in clinical disease course were associated with decreased immune infiltration and demyelination, axonal loss and oxidative stress in the spinal cord. In addition A(1–7) treatment was also associated with increases in circulating alternatively activated monocytes/macrophages.
       
  • Methylglyoxal and a spinal TRPA1-AC1-Epac cascade facilitate pain in the
           db/db mouse model of type 2 diabetes
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Ryan B. Griggs, Diogo F. Santos, Don E. Laird, Suzanne Doolen, Renee R. Donahue, Caitlin R. Wessel, Weisi Fu, Ghanshyam P. Sinha, Pingyuan Wang, Jia Zhou, Sebastian Brings, Thomas Fleming, Peter P. Nawroth, Keiichiro Susuki, Bradley K. Taylor Painful diabetic neuropathy (PDN) is a devastating neurological complication of diabetes. Methylglyoxal (MG) is a reactive metabolite whose elevation in the plasma corresponds to PDN in patients and pain-like behavior in rodent models of type 1 and type 2 diabetes. Here, we addressed the MG-related spinal mechanisms of PDN in type 2 diabetes using db/db mice, an established model of type 2 diabetes, and intrathecal injection of MG in conventional C57BL/6J mice. Administration of either a MG scavenger (GERP10) or a vector overexpressing glyoxalase 1, the catabolic enzyme for MG, attenuated heat hypersensitivity in db/db mice. In C57BL/6J mice, intrathecal administration of MG produced signs of both evoked (heat and mechanical hypersensitivity) and affective (conditioned place avoidance) pain. MG-induced Ca2+ mobilization in lamina II dorsal horn neurons of C57BL/6J mice was exacerbated in db/db, suggestive of MG-evoked central sensitization. Pharmacological and/or genetic inhibition of transient receptor potential ankyrin subtype 1 (TRPA1), adenylyl cyclase type 1 (AC1), protein kinase A (PKA), or exchange protein directly activated by cyclic adenosine monophosphate (Epac) blocked MG-evoked hypersensitivity in C57BL/6J mice. Similarly, intrathecal administration of GERP10, or inhibitors of TRPA1 (HC030031), AC1 (NB001), or Epac (HJC-0197) attenuated hypersensitivity in db/db mice. We conclude that MG and sensitization of a spinal TRPA1-AC1-Epac signaling cascade facilitate PDN in db/db mice. Our results warrant clinical investigation of MG scavengers, glyoxalase inducers, and spinally-directed pharmacological inhibitors of a MG-TRPA1-AC1-Epac pathway for the treatment of PDN in type 2 diabetes.Graphical abstractSchematic illustrating our experimental approach and working hypothesis. We tested whether a spinal MG➔TRPA1➔AC1➔PKA/Epac cascade contributes to type 2 painful diabetic neuropathy (PDN) by using pharmacological and genetic approaches (as shown by Image 2) and measuring pain-like behavior and calcium imaging in the db/db and intrathecal MG models. The dashed line leading from PKA represents the possibility that PKA contributes to the initiation but not maintenance of PDN (see discussion). Our results support the conclusion that MG in type 2 diabetes leads to activation of a TRPA1-AC1-Epac signaling cascade to produce PDN.Unlabelled Image
       
  • Manipulation of microbiota reveals altered callosal myelination and white
           matter plasticity in a model of Huntington disease
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Carola I. Radulescu, Marta Garcia-Miralles, Harwin Sidik, Costanza Ferrari Bardile, Nur Amirah Binte Mohammad Yusof, Hae Ung Lee, Eliza Xin Pei Ho, Collins Wenhan Chu, Emma Layton, Donovan Low, Paola Florez De Sessions, Sven Pettersson, Florent Ginhoux, Mahmoud A. Pouladi Structural and molecular myelination deficits represent early pathological features of Huntington disease (HD). Recent evidence from germ-free (GF) animals suggests a role for microbiota-gut-brain bidirectional communication in the regulation of myelination. In this study, we aimed to investigate the impact of microbiota on myelin plasticity and oligodendroglial population dynamics in the mixed-sex BACHD mouse model of HD. Ultrastructural analysis of myelin in the corpus callosum revealed alterations of myelin thickness in BACHD GF compared to specific-pathogen free (SPF) mice, whereas no differences were observed between wild-type (WT) groups. In contrast, myelin compaction was altered in all groups when compared to WT SPF animals. Levels of myelin-related proteins were generally reduced, and the number of mature oligodendrocytes was decreased in the prefrontal cortex under GF compared to SPF conditions, regardless of genotype. Minor differences in commensal bacteria at the family and genera levels were found in the gut microbiota of BACHD and WT animals housed in standard living conditions. Our findings indicate complex effects of a germ-free status on myelin-related characteristics, and highlight the adaptive properties of myelination as a result of environmental manipulation.
       
  • Fragile X Mental Retardation Protein positively regulates PKA anchor
           Rugose and PKA activity to control actin assembly in learning/memory
           circuitry
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): James C. Sears, Woong Jae Choi, Kendal Broadie Recent work shows Fragile X Mental Retardation Protein (FMRP) drives the translation of very large proteins (>2000 aa) mediating neurodevelopment. Loss of function results in Fragile X syndrome (FXS), the leading heritable cause of intellectual disability (ID) and autism spectrum disorder (ASD). Using the Drosophila FXS disease model, we discover FMRP positively regulates the translation of the very large A-Kinase Anchor Protein (AKAP) Rugose (>3000 aa), homolog of ASD-associated human Neurobeachin (NBEA). In the central brain Mushroom Body (MB) circuit, where Protein Kinase A (PKA) signaling is necessary for learning/memory, FMRP loss reduces Rugose levels and targeted FMRP overexpression elevates Rugose levels. Using a new in vivo transgenic PKA activity reporter (PKA-SPARK), we find FMRP loss reduces PKA activity in MB Kenyon cells whereas FMRP overexpression elevates PKA activity. Consistently, loss of Rugose reduces PKA activity, but Rugose overexpression has no independent effect. A well-established PKA output is regulation of F-actin cytoskeleton dynamics. In the FXS disease model, F-actin is aberrantly accumulated in MB lobes and single MB Kenyon cells. Consistently, Rugose loss results in similar F-actin accumulation. Moreover, targeted FMRP, Rugose and PKA overexpression all result in increased F-actin accumulation in the MB circuit. These findings uncover a FMRP-Rugose-PKA mechanism regulating actin cytoskeleton. This study reveals a novel FMRP mechanism controlling neuronal PKA activity, and demonstrates a shared mechanistic connection between FXS and NBEA associated ASD disease states, with a common link to PKA and F-actin misregulation in brain neural circuits.Significance StatementAutism spectrum disorder (ASD) arises from a wide array of genetic lesions, and it is therefore critical to identify common underlying molecular mechanisms. Here, we link two ASD states; Neurobeachin (NBEA) associated ASD and Fragile X syndrome (FXS), the most common inherited ASD. Using established Drosophila disease models, we find Fragile X Mental Retardation Protein (FMRP) positively regulates translation of NBEA homolog Rugose, consistent with a recent advance showing FMRP promotes translation of very large proteins associated with ASD. FXS exhibits reduced cAMP induction, a potent activator of PKA, and Rugose/NBEA is a PKA anchor. Consistently, we find brain PKA activity strikingly reduced in both ASD models. We discover this pathway regulation controls actin cytoskeleton dynamics in brain neural circuits.
       
  • In vivo measurement of brain network connectivity reflects progression and
           intrinsic disease severity in a model of temporal lobe epilepsy
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Daniele Bertoglio, Elisabeth Jonckers, Idrish Ali, Marleen Verhoye, Annemie Van der Linden, Stefanie Dedeurwaerdere Different types of brain injury, such as status epilepticus (SE), trauma, or stroke may initiate the process of epileptogenesis and lead to the development of temporal lobe epilepsy. Epileptogenesis is characterized by an initial latent period during which impaired network communication and synaptic circuit alterations are occurring. Ultimately, these modifications result in the development of spontaneous recurrent seizures (SRS). Current knowledge on the functional connectivity network changes during epileptogenesis and how network alterations relate to seizure is very limited. To investigate these underlying network connectivity modifications, we imaged epileptic and control rats by means of resting-state functional MRI (rsfMRI) during epileptogenesis. A cohort of animals was video-electroencephalography (video-EEG) monitored continuously over 12 weeks to determine disease severity during the course of disease, with the first SRS appearing around 2 weeks post-SE for most of the animals. Epileptic animals displayed a significant wide-spread hyposynchrony at 2 weeks post-SE, followed by a significant increase in network synchronicity from 2 to 4 weeks post-SE. Interestingly, subjects with a delayed epilepsy onset demonstrated significantly lower synchronicity compared to controls and the epileptic group at 4 weeks post-SE. Finally, network connectivity at 4 weeks post-SE was found to correlate with seizure onset (r = 0.858, p 
       
  • The presence and suppressive activity of myeloid-derived suppressor cells
           are potentiated after interferon-β treatment in a murine model of
           multiple sclerosis
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Carolina Melero-Jerez, Margarita Suardíaz, Rafael Lebrón-Galán, Carmen Marín-Bañasco, Begoña Oliver-Martos, Isabel Machín-Díaz, Óscar Fernández, Fernando de Castro, Diego Clemente Multiple sclerosis (MS) is an autoimmune demyelinating disease of the human central nervous system (CNS), mainly affecting young adults. Among the immunomodulatory disease modifying treatments approved up to date to treat MS, IFN-β remains to be one of the most widely prescribed for the Relapsing-Remitting (RR) variant of the disease, although its mechanism of action is still partially understood. RR-MS variant is characterized by phases with increasing neurological symptoms (relapses) followed by periods of total or partial recovery (remissions), which implies the existence of immunomodulatory agents to promote the relapsing-to-remitting transition. Among these agents, it has been described the immunosuppressive role of a heterogeneous population of immature myeloid cells, namely the myeloid-derived suppressor cells (MDSCs) during the clinical course of the experimental autoimmune encephalomyelitis (EAE), the most used MS model to study RRMS. However, it is still unknown how the current MS disease modifying treatments, e.g. IFN- β, affects to MDSCs number or activity. Our present results show that a single injection of IFN-β at the onset of the clinical course reduces the severity of the EAE, enhancing the presence of MDSCs within the smaller demyelinated areas. Moreover, the single dose of IFN-β promotes MDSC immunosuppressive activity both in vivo and in vitro, augmenting T cell apoptosis. Finally, we show that IFN-ß preserves MDSC immaturity, preventing their differentiation to mature and less suppressive myeloid cell subsets. Taking together, all these data add new insights into the mechanism of IFN-β treatment in EAE and point to MDSCs as a putative endogenous mediator of its beneficial role in this animal model of MS.
       
  • Revisiting the role of the innate immune complement system in ALS
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Sandra E. Parker, Angela M. Hanton, Stephen N. Stefanou, Peter G. Noakes, Trent M. Woodruff, John D. Lee Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. Although the precise mechanisms leading to ALS are yet to be determined, there is now increasing evidence implicating components of the innate immune complement system in the onset and progression of its motor phenotypes. This review will survey the clinical and experimental evidence for the role of the complement system in driving neuroinflammation and contributing to ALS disease progression. Specifically, it will explore findings regarding the different complement activation pathways involved in ALS, with a focus on the terminal pathway. It will also examine potential future research directions for complement in ALS, highlighting the targeting of specific molecular components of the system.
       
  • Pathogenesis and pathophysiology of functional (psychogenic) movement
           disorders
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): José Fidel Baizabal-Carvallo, Mark Hallett, Joseph Jankovic Functional movement disorders (FMDs), known over time as “hysteria”, “dissociative”, “conversion”, “somatoform”, “non-organic” and “psychogenic” disorders, are characterized by having a voluntary quality, being modifiable by attention and distraction but perceived by the patient as involuntary. Although a high prevalence of depression and anxiety is observed in these patients, a definitive role of psychiatric disorders in FMDs has not been proven, and many patients do not endorse such manifestations. Stressful events, social influences and minor trauma may precede the onset of FMDs, but their pathogenic mechanisms are unclear. Patients with FMDs have several abnormalities in their neurobiology including strengthened connectivity between the limbic and motor networks. Additionally, there is altered top-down regulation of motor activities and increased activation of areas implicated in self-awareness, self-monitoring, and active motor inhibition such as the cingulate and insular cortex. Decreased activation of the supplementary motor area (SMA) and pre-SMA, implicated in motor control and preparation, is another finding. The sense of agency defined as the feeling of controlling external events through one's own action also seems to be impaired in individuals with FMDs. Correlating with this is a loss of intentional binding, a subjective time compression between intentional action and its sensory consequences. Organic and functional dystonia may be difficult to differentiate since they share diverse neurophysiological features including decreased cortical inhibition, and similar local field potentials in the globus pallidus and thalamus; although increased cortical plasticity is observed only in patients with organic dystonia. Advances in the pathogenesis and pathophysiology of FMDs may be helpful to understand the nature of these disorders and plan further treatment strategies.
       
  • Modeling neuronopathic storage diseases with patient-derived culture
           systems
    • Abstract: Publication date: July 2019Source: Neurobiology of Disease, Volume 127Author(s): Friederike Zunke, Joseph R. Mazzulli Lysosomes are organelles involved in the degradation and recycling of macromolecules, and play a critical role in sensing metabolic information in the cell. A class of rare metabolic diseases called lysosomal storage disorders (LSD) are characterized by lysosomal dysfunction and the accumulation of macromolecular substrates. The central nervous system appears to be particularly vulnerable to lysosomal dysfunction, since many LSDs are characterized by severe, widespread neurodegeneration with pediatric onset. Furthermore, variants in lysosomal genes are strongly associated with some common neurodegenerative disorders such as Parkinson's disease (PD). To better understand disease pathology and develop novel treatment strategies, it is critical to study the fundamental molecular disease mechanisms in the affected cell types that harbor endogenously expressed mutations. The discovery of methods for reprogramming of patient-derived somatic cells into induced pluripotent stem cells (iPSCs), and their differentiation into distinct neuronal and glial cell types, have provided novel opportunities to study mechanisms of lysosomal dysfunction within the relevant, vulnerable cell types. These models also expand our ability to develop and test novel therapeutic targets. We discuss recently developed methods for iPSC differentiation into distinct neuronal and glial cell types, while addressing the need for meticulous experimental techniques and parameters that are essential to accurately identify inherent cellular pathologies. iPSC models for neuronopathic LSDs and their relationship to sporadic age-related neurodegeneration are also discussed. These models should facilitate the discovery and development of personalized therapies in the future.
       
  • Inhibition and oscillations in the human brain tissue in vitro
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Liset Menendez de la Prida, Gilles Huberfeld Oscillations represent basic operational modes of the human brain. They reflect local field potential activity generated by the laminar arrangement of cell-type specific microcircuits interacting brain-wide under the influence of neuromodulators, endogenous processes and cognitive demands. Under neuropathological conditions, the spatiotemporal structure of physiological brain oscillations is disrupted as recorded by electroencephalography and event-relate potentials. Such rhythmopathies can be used to track microcircuit alterations leading not only to transient pathological activities such as interictal discharges and seizures but also to a range of cognitive co-morbidities. Here we review how basic oscillatory modes induced in human brain slices prepared after surgical treatment can help us to understand basic aspects of brain function and dysfunction. We propose to overcome the traditional view of examining human brain slices merely as generators of epileptiform activities and to integrate them in a more physiologically-oriented oscillatory framework to better understand mechanisms of the diseased human brain.
       
  • GABAA receptor-mediated networks during focal seizure onset and
           progression in vitro
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Marco de Curtis, Laura Librizzi, Laura Uva, Vadym Gnatkovsky Focal seizures are triggered by the pathological synchronization of a functionally altered group of neurons. In vivo and in vitro results in rodents and single unit studies in humans suggest that seizure can be initiated by increased activity in interneuronal networks. We review here the data derived from in vitro perparations to describe the function of GABAergic network in different phases of focal seizures. The data demonstrate that GABA-mediated synchronization of interneuronal activity has an active role in shaping focal seizure dynamics.
       
  • Differential accumulation of Tau phosphorylated at residues Thr231, Ser262
           and Thr205 in hippocampal interneurons and its modulation by Tau mutations
           (VLW) and amyloid-β peptide
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Eva Dávila-Bouziguet, Georgina Targa-Fabra, Jesús Ávila, Eduardo Soriano, Marta Pascual Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β peptide (Aβ) and hyperphosphorylated Tau protein (P-Tau). Our recent data showed a differential accumulation of Tau protein phosphorylated at residue Thr231 (pThr231) in distinct hippocampal neurons in VLW mice—a model that overexpresses mutated human Tau. Here we demonstrate that, in VLW mice, the accumulation of human P-Tau in pyramidal cells induces the phosphorylation of murine Tau at residue Thr231 in hippocampal interneurons.In addition, we show that pSer262 and pThr205 Tau are present specifically in the soma of some hippocampal interneurons in control mice. Analysis of J20 mice—a model that accumulates Aβ—and of VLW animals showed that the density of hippocampal interneurons accumulating pThr205 Tau is lower in VLW mice than in controls. In contrast, the density of interneurons accumulating pThr205 Tau in J20 mice was increased compared to controls in hippocampal regions with a higher Aβ plaque load, thereby suggesting that pThr205 Tau is induced by Aβ. No significant differences were found between the density of hippocampal interneurons positive for pSer262 Tau in VLW or J20 mice compared to control animals.We also show that pSer262 and pThr205 Tau are present in the soma of some hippocampal interneurons containing Parvalbumin, Calbindin or Calretinin in control, VLW, and J20 mice. Moreover, our results reveal that some interneurons in human hippocampi of cases of AD and control cases accumulate pSer262 and pThr205 Tau. Taken together, these data point to a specific role of pSer262 and pThr205 Tau in the soma of hippocampal interneurons in control and pathological conditions.Graphical Unlabelled Image
       
  • Olfactory bulb atrophy and caspase activation observed in the BACHD rat
           models of Huntington disease
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): M. Lessard-Beaudoin, L. Yu-Taeger, M. Laroche, E. Singer, O. Riess, H.H.P. Nguyen, R.K. Graham Olfactory dysfunction is observed in several neurological disorders, including Huntington disease (HD), and correlates with global cognitive performance, depression and degeneration of olfactory regions in the brain. Despite clear evidence demonstrating olfactory dysfunction in HD patients, only limited details are available in murine models and the underlying mechanisms are unknown. In order to determine if alterations in the olfactory bulb (OB) are observed in HD we assessed OB weight or area from 3 to 12 months of age in the BACHD transgenic lines (TG5 and TG9). A significant decrease in the OB was observed at 6 and 12 months of age compared to WT. We also detected increased mRNA and protein expression of mutant huntingtin (mHTT) in the OB of TG5 compared to TG9 at specific ages. Despite the higher expression of mHTT in the TG5 OBs, there was increased nuclear accumulation of mHTT in the OB of TG9 compared to WT and TG5 rats. As we observed atrophy of the OB in the BACHD rats we assessed for caspase activation, a known mechanism underlying the cell death observed in HD. We characterized caspase-3, −6, −8 and − 9 mRNA and protein expression levels in the OB of the BACHD transgenic lines at 3, 6 and 12 months of age. Alterations in caspase mRNA and protein expression were detected in the TG5 and TG9 lines. However, the changes observed in the mRNA and protein levels are in some cases discordant, suggesting that the caspase protein modifications detected may be more attributable to post-translational modifications. The caspase activation studies support that cell death may be increased in the rodent HD OB and further our understanding of the olfactory dysfunction and the role of caspases in the pathogenesis of HD.
       
  • Maternal immune activation impairs cognitive flexibility and alters
           transcription in frontal cortex
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Dionisio A. Amodeo, Chi-Yu Lai, Omron Hassan, Eran A. Mukamel, M. Margarita Behrens, Susan B. Powell BackgroundEpidemiological studies suggest that the risk of neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia is increased by prenatal exposure to viral or bacterial infection during pregnancy. It is still unclear how activation of the maternal immune response interacts with underlying genetic factors to influence observed ASD phenotypes.MethodsThe current study investigated how maternal immune activation (MIA) in mice impacts gene expression in the frontal cortex in adulthood, and how these molecular changes relate to deficits in cognitive flexibility and social behavior, and increases in repetitive behavior that are prevalent in ASD. Poly(I:C) (20 mg/kg) was administered to dams on E12.5 and offspring were tested for social approach behavior, repetitive grooming, and probabilistic reversal learning in adulthood (n = 8 vehicle; n = 9 Poly(I:C)). We employed next-generation high-throughput mRNA sequencing (RNA-seq) to comprehensively investigate the transcriptome profile in frontal cortex of adult offspring of Poly(I:C)-exposed dams.ResultsExposure to poly(I:C) during gestation impaired probabilistic reversal learning and decreased social approach in MIA offspring compared to controls. We found long-term effects of MIA on expression of 24 genes, including genes involved in glutamatergic neurotransmission, mTOR signaling and potassium ion channel activity. Correlations between gene expression and specific behavioral measures provided insight into genes that may be responsible for ASD-like behavioral alterations.ConclusionsThese findings suggest that MIA can lead to impairments in cognitive flexibility in mice similar to those exhibited in ASD individuals, and that these impairments are associated with altered gene expression in frontal cortex.
       
  • Loss of biliverdin reductase-A favors Tau hyper-phosphorylation in
           Alzheimer's disease
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Nidhi Sharma, Antonella Tramutola, Chiara Lanzillotta, Andrea Arena, Carla Blarzino, Tommaso Cassano, D. Allan Butterfield, Fabio Di Domenico, Marzia Perluigi, Eugenio Barone Hyper-active GSK-3β favors Tau phosphorylation during the progression of Alzheimer's disease (AD). Akt is one of the main kinases inhibiting GSK-3β and its activation occurs in response to neurotoxic stimuli including, i.e., oxidative stress. Biliverdin reductase-A (BVR-A) is a scaffold protein favoring the Akt-mediated inhibition of GSK-3β. Reduced BVR-A levels along with increased oxidative stress were observed early in the hippocampus of 3xTg-AD mice (at 6 months), thus suggesting that loss of BVR-A could be a limiting factor in the oxidative stress-induced Akt-mediated inhibition of GSK-3β in AD.We evaluated changes of BVR-A, Akt, GSK-3β, oxidative stress and Tau phosphorylation levels: (a) in brain from young (6-months) and old (12-months) 3xTg-AD mice; and (b) in post-mortem inferior parietal lobule (IPL) samples from amnestic mild cognitive impairment (MCI), from AD and from age-matched controls. Furthermore, similar analyses were performed in vitro in cells lacking BVR-A and treated with H2O2.Reduced BVR-A levels along with: (a) increased oxidative stress; (b) reduced GSK-3β inhibition; and (c) increased Tau Ser404 phosphorylation (target of GSK-3β activity) without changes of Akt activation in young mice, were observed. Similar findings were obtained in MCI, consistent with the notion that this is a molecular mechanism disrupted in humans. Interestingly, cells lacking BVR-A and treated with H2O2 showed reduced GSK-3β inhibition and increased Tau Ser404 phosphorylation, which resulted from a defect of Akt and GSK-3β physical interaction. Reduced levels of Akt/GSK-3β complex were confirmed in both young 3xTg-AD and MCI brain.We demonstrated that loss of BVR-A impairs the neuroprotective Akt-mediated inhibition of GSK-3β in response to oxidative stress, thus contributing to Tau hyper-phosphorylation in early stage AD. Such changes potential provide promising therapeutic targets for this devastating disorder.Graphical abstractUnlabelled Image
       
  • Mannitol decreases neocortical epileptiform activity during early brain
           development via cotransport of chloride and water
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): J. Glykys, E. Duquette, N. Rahmati, K. Duquette, K.J. Staley Seizures and brain injury lead to water and Cl− accumulation in neurons. The increase in intraneuronal Cl− concentration ([Cl−]i) depolarizes the GABAA reversal potential (EGABA) and worsens seizure activity. Neocortical neuronal membranes have a low water permeability due to the lack of aquaporins necessary to move free water. Instead, neurons use cotransport of ions including Cl− to move water. Thus, increasing the extracellular osmolarity during seizures should result in an outward movement of water and salt, reducing [Cl−]i and improving GABAA receptor-mediated inhibition. We tested the effects of hyperosmotic therapy with a clinically relevant dose of mannitol (20 mM) on epileptiform activity, spontaneous multiunit activity, spontaneous inhibitory post-synaptic currents (sIPSCs), [Cl−]i, and neuronal volume in layer IV/V of the developing neocortex of C57BL/6 and Clomeleon mice. Using electrophysiological techniques and multiphoton imaging in acute brain slices (post-natal day 7–12) and organotypic neocortical slice cultures (post-natal day 14), we observed that mannitol: 1) decreased epileptiform activity, 2) decreased neuronal volume and [Cl−]i through CCCs, 3) decreased spontaneous multi-unit activity frequency but not amplitude, and 4) restored the anticonvulsant efficacy of the GABAA receptor modulator diazepam. Increasing extracellular osmolarity by 20 mOsm with hypertonic saline did not decrease epileptiform activity. We conclude that an increase in extracellular osmolarity by mannitol mediates the efflux of [Cl−]i and water through CCCs, which results in a decrease in epileptiform activity and enhances benzodiazepine actions in the developing neocortex in vitro. Novel treatments aimed to decrease neuronal volume may concomitantly decrease [Cl−]i and improve seizure control.Graphical abstractUnlabelled Image
       
  • MiR-146a promotes oligodendrocyte progenitor cell differentiation and
           enhances remyelination in a model of experimental autoimmune
           encephalomyelitis
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Jing Zhang, Zheng Gang Zhang, Mei Lu, Yi Zhang, Xia Shang, Michael Chopp The death of mature oligodendrocytes (OLs) leads to demyelination in the central nervous system (CNS) and subsequently to functional deficits. Remyelination requires the differentiation of oligodendrocyte progenitor cells (OPCs) into myelinating OLs, which in the CNS with neurodegenerative diseases such as multiple sclerosis (MS), is often inhibited. Among the inhibitors of OPC differentiation are toll-like receptor 2 (TLR2) and interleukin-1 receptor-associated kinase 1 (IRAK1) signaling, and both are negatively regulated by microRNA-146a (miR-146a). Therefore, we hypothesized that increase of miR-146a level in the CNS would foster OPC differentiation and remyelination by inhibiting the TLR2/IRAK1 signaling pathway. Here, we tested this hypothesis using exogenous miR-146a mimics and a mouse model of MS, experimental autoimmune encephalomyelitis (EAE) induced by immunization with myelin proteolipid protein peptide (PLP139–151). EAE mice were treated by miR-146a mimics or miR-146a mimic negative controls, respectively, which initiated at day 14 post immunization, once a week for 6 consecutive weeks. Neurological function was monitored daily. Immunofluorescent staining, qRT-PCR and Western blot were used to measure the differentiation of OPCs and myelination, and to investigate the underlying mechanisms of action of miR-146a. Using a fluorescence tracing approach, we found that miR-146a mimics crossed the blood brain barrier and targeted OPCs and microglia/macrophages after systemic administration. MiR-146a mimic treatment substantially improved neurological functional outcome, increased the number of newly generated OLs which may facilitate remyelination in the CNS. The cell number, cytokine level and protein levels of M2 phonotype of microglia/macrophages significantly increased, while cytokine and protein levels of the M1 phenotype significantly decreased after miR-146a mimic treatment. Increased OPC differentiation and remyelination were associated with reduction of TLR2/IRAK1 signaling pathway activity by miR-146a mimic treatment. This study provides insight into the cellular and molecular bases for the therapeutic effects of miR-146a on OPC differentiation and remyelination, and suggests the potential of enhancing miR-146a as a treatment of demyelinating disorders.
       
  • Long-term RNAi knockdown of α-synuclein in the adult rat substantia nigra
           without neurodegeneration
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Alevtina Zharikov, Qing Bai, Briana R. De Miranda, Amber Van Laar, J. Timothy Greenamyre, Edward A. Burton α-Synuclein plays a central role in the pathogenesis of Parkinson's disease (PD); interventions that decrease its expression appear neuroprotective in PD models. Successful translation of these observations into effective therapies will be dependent on the safety of suppressing α-synuclein expression in the adult brain. We investigated long-term α-synuclein knockdown in the adult rat CNS. 8-month old animals received either AAV-sh[Snca] (an RNA interference vector targeting the Snca mRNA transcript) or AAV-sh[Ctrl] (a control vector) unilaterally into the substantia nigra. No signs of systemic toxicity or motor dysfunction were observed in either experimental group over 12 months. Viral transgene expression persisted to 12 months post-inoculation, at which point Snca mRNA expression in substantia nigra dopaminergic neurons of animals that received AAV-sh[Snca] was decreased by ≈90%, and α-synuclein immunoreactivity by>70% relative to the control side. Stereological quantification of Nissl-labeled neurons showed no evidence of neurodegeneration in the substantia nigra 12 months after inoculation with either vector, and we observed abundant dopaminergic neurons with minimal α-synuclein immunoreactivity that appeared otherwise unremarkable in the AAV-sh[Snca] group. Despite the absence of neurodegeneration, some loss of TH expression was evident in nigral neurons after transduction with either vector, presumably a non-specific consequence of vector delivery, cellular transduction, or expression of shRNA or GFP. We conclude that long-term α-synuclein knockdown in the substantia nigra does not cause significant functional deficits in the ascending dopaminergic projection, or neurodegeneration. These findings are encouraging that it may be feasible to target α-synuclein expression therapeutically in PD.
       
  • Synergistic action of CB1 and 5-HT2B receptors in preventing
           pilocarpine-induced status epilepticus in rats
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Roberto Colangeli, Roberto Di Maio, Massimo Pierucci, Gabriele Deidda, Maurizio Casarrubea, Giuseppe Di Giovanni Endocannabinoids (eCBs) and serotonin (5-HT) play a neuromodulatory role in the central nervous system. Both eCBs and 5-HT regulate neuronal excitability and their pharmacological potentiation has been shown to control seizures in pre-clinical and human studies. Compelling evidence indicates that eCB and 5-HT systems interact to modulate several physiological and pathological brain functions, such as food intake, pain, drug addiction, depression, and anxiety. Nevertheless, there is no evidence of an eCB/5-HT interaction in experimental and human epilepsies, including status epilepticus (SE). Here, we performed video-EEG recording in behaving rats treated with the pro-convulsant agent pilocarpine (PILO), in order to study the effect of the activation of CB1/5-HT2 receptors and their interaction on SE. Synthetic cannabinoid agonist WIN55,212–2 (WIN) decreased behavioral seizure severity of PILO-induced SE at 2 mg/kg (but not at 1 and 5 mg/kg, i.p.), while 5-HT2B/2C receptor agonist RO60–0175 (RO; 1, 3, 10 mg/kg, i.p.) was devoid of any effect. RO 3 mg/kg was instead capable of potentiating the effect of WIN 2 mg/kg on the Racine scale score. Surprisingly, neither WIN 2 mg/kg nor RO 3 mg/kg had any effect on the incidence and the intensity of EEG seizures when administered alone. However, WIN+RO co-administration reduced the incidence and the severity of EEG SE and increased the latency to SE onset after PILO injection. WIN+RO effects were blocked by the selective CB1R antagonist AM251 and the 5-HT2BR antagonist RS127445, but not by the 5-HT2CR antagonist SB242084 or the 5-HT2AR antagonist MDL11,939.These data revealed a synergistic interaction between CB1R/5-HT2BR in the expression of PILO-induced SE.
       
  • Multi-faceted therapeutic strategy for treatment of Alzheimer's disease by
           concurrent administration of etodolac and α-tocopherol
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Khaled H. Elfakhri, Ihab M. Abdallah, Andrew D. Brannen, Amal Kaddoumi Alzheimer's disease (AD) is a complex neurodegenerative disorder with multiple dysfunctional pathways. Therefore, a sophisticated treatment strategy that simultaneously targets multiple brain cell types and disease pathways could be advantageous for effective intervention. To elucidate an effective treatment, we developed an in vitro high-throughput screening (HTS) assay to evaluate candidate drugs for their ability to enhance the integrity of the blood-brain barrier (BBB) and improve clearance of amyloid-β (Aβ) using a cell-based BBB model. Results from HTS identified etodolac and α-tocopherol as promising drugs for further investigation. Both drugs were tested separately and in combination for the purpose of targeting multiple pathways including neuroinflammation and oxidative stress. In vitro studies assessed the effects of etodolac and α-tocopherol individually and collectively for BBB integrity and Aβ transport, synaptic markers and Aβ production in APP-transfected neuronal cells, as well as effects on inflammation and oxidative stress in astrocytes. Transgenic 5XFAD mice were used to translate in vitro results of etodolac and α-tocopherol independently and with concurrent administration. Compared to either drug alone, the combination significantly enhanced the BBB function, decreased total Aβ load correlated with increased expression of major transport proteins, promoted APP processing towards the neuroprotective and non-amyloidogenic pathway, induced synaptic markers expression, and significantly reduced neuroinflammation and oxidative stress both in vitro and in vivo. Collective findings demonstrated the combination produced mixed interaction showing additive, less than additive or synergistic effects on the evaluated markers. In conclusion, this study highlights the significance of combination therapy to simultaneously target multiple disease pathways, and suggest the repurposing and combination of etodolac and α-tocopherol as a novel therapeutic strategy against AD.
       
  • Trihexyphenidyl rescues the deficit in dopamine neurotransmission in a
           mouse model of DYT1 dystonia
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Anthony M. Downs, Xueliang Fan, Christine Donsante, H.A. Jinnah, Ellen J. Hess Trihexyphenidyl, a nonselective muscarinic receptor antagonist, is the small molecule drug of choice for the treatment of DYT1 dystonia, but it is poorly tolerated due to significant side effects. A better understanding of the mechanism of action of trihexyphenidyl is needed for the development of improved treatments. Because DTY1 dystonia is associated with both abnormal cholinergic neurotransmission and abnormal dopamine regulation, we tested the hypothesis that trihexyphenidyl normalizes striatal dopamine release in a mouse model of DYT1 dystonia using ex vivo fast scan cyclic voltammetry and in vivo microdialysis. Trihexyphenidyl increased striatal dopamine release and efflux as assessed by ex vivo voltammetry and in vivo microdialysis respectively. In contrast, ʟ-DOPA, which is not usually effective for the treatment of DYT1 dystonia, did not increase dopamine release in either Dyt1 or control mice. Trihexyphenidyl was less effective at enhancing dopamine release in Dyt1 mice relative to controls ex vivo (mean increase WT: 65% vs Dyt1: 35%). Trihexyphenidyl required nicotinic receptors but not glutamate receptors to increase dopamine release. Dyt1 mice were more sensitive to the dopamine release decreasing effects of nicotinic acetylcholine receptor antagonism (IC50: WT = 29.46 nM, Dyt1 = 12.26 nM) and less sensitive to acetylcholinesterase inhibitors suggesting that nicotinic acetylcholine receptor neurotransmission is altered in Dyt1 mice, that nicotinic receptors indirectly mediate the differential effects of trihexyphenidyl in Dyt1 mice, and that nicotinic receptors may be suitable therapeutic targets for DYT1 dystonia.Graphical abstractUnlabelled Image
       
  • Neuronal overexpression of Alzheimer's disease and Down's syndrome
           associated DYRK1A/minibrain gene alters motor decline, neurodegeneration
           and synaptic plasticity in Drosophila
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Simon A. Lowe, Maria M. Usowicz, James J.L. Hodge Down syndrome (DS) is characterised by abnormal cognitive and motor development, and later in life by progressive Alzheimer's disease (AD)-like dementia, neuropathology, declining motor function and shorter life expectancy. It is caused by trisomy of chromosome 21 (Hsa21), but how individual Hsa21 genes contribute to various aspects of the disorder is incompletely understood. Previous work has demonstrated a role for triplication of the Hsa21 gene DYRK1A in cognitive and motor deficits, as well as in altered neurogenesis and neurofibrillary degeneration in the DS brain, but its contribution to other DS phenotypes is unclear. Here we demonstrate that overexpression of minibrain (mnb), the Drosophila ortholog of DYRK1A, in the Drosophila nervous system accelerated age-dependent decline in motor performance and shortened lifespan. Overexpression of mnb in the eye was neurotoxic and overexpression in ellipsoid body neurons in the brain caused age-dependent neurodegeneration. At the larval neuromuscular junction, an established model for mammalian central glutamatergic synapses, neuronal mnb overexpression enhanced spontaneous vesicular transmitter release. It also slowed recovery from short-term depression of evoked transmitter release induced by high-frequency nerve stimulation and increased the number of boutons in one of the two glutamatergic motor neurons innervating the muscle. These results provide further insight into the roles of DYRK1A triplication in abnormal aging and synaptic dysfunction in DS.
       
  • Cannabinoid type-1 receptor blockade restores neurological phenotypes in
           two models for Down syndrome
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Alba Navarro-Romero, Anna Vázquez-Oliver, Maria Gomis-González, Carlos Garzón-Montesinos, Rafael Falcón-Moya, Antoni Pastor, Elena Martín-García, Nieves Pizarro, Arnau Busquets-Garcia, Jean-Michel Revest, Pier-Vincenzo Piazza, Fátima Bosch, Mara Dierssen, Rafael de la Torre, Antonio Rodríguez-Moreno, Rafael Maldonado, Andrés Ozaita Intellectual disability is the most limiting hallmark of Down syndrome, for which there is no gold-standard clinical treatment yet. The endocannabinoid system is a widespread neuromodulatory system involved in multiple functions including learning and memory processes. Alterations of this system contribute to the pathogenesis of several neurological and neurodevelopmental disorders. However, the involvement of the endocannabinoid system in the pathogenesis of Down syndrome has not been explored before. We used the best-characterized preclinical model of Down syndrome, the segmentally trisomic Ts65Dn model. In male Ts65Dn mice, cannabinoid type-1 receptor (CB1R) expression was enhanced and its function increased in hippocampal excitatory terminals. Knockdown of CB1R in the hippocampus of male Ts65Dn mice restored hippocampal-dependent memory. Concomitant with this result, pharmacological inhibition of CB1R restored memory deficits, hippocampal synaptic plasticity and adult neurogenesis in the subgranular zone of the dentate gyrus. Notably, the blockade of CB1R also normalized hippocampal-dependent memory in female Ts65Dn mice. To further investigate the mechanisms involved, we used a second transgenic mouse model overexpressing a single gene candidate for Down syndrome cognitive phenotypes, the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). CB1R pharmacological blockade similarly improved cognitive performance, synaptic plasticity and neurogenesis in transgenic male Dyrk1A mice. Our results identify CB1R as a novel druggable target potentially relevant for the improvement of cognitive deficits associated with Down syndrome.
       
  • N-Palmitoylethanolamine-oxazoline (PEA-OXA): A new therapeutic strategy to
           reduce neuroinflammation, oxidative stress associated to vascular dementia
           in an experimental model of repeated bilateral common carotid arteries
           occlusion
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Daniela Impellizzeri, Rosalba Siracusa, Marika Cordaro, Rosalia Crupi, Alessio Filippo Peritore, Enrico Gugliandolo, Ramona D'Amico, Stefania Petrosino, Maurizio Evangelista, Rosanna Di Paola, Salvatore Cuzzocrea AimRecent studies revealed that pharmacological modulation of NAE-hydrolyzing acid amidase (NAAA) can be achieved with PEA oxazoline (PEA-OXA). Hence, the aim of the present work was to thoroughly evaluate the anti-inflammatory and neuroprotective effects of PEA-OXA in an experimental model of vascular dementia (VaD) induced by bilateral carotid arteries occlusion. At 24 h after VaD induction, animals were orally administered with 10 mg/kg of PEA-OXA daily for 15 days.ResultsBrain tissues were handled for histological, immunohistochemical, western blot, and immunofluorescence analysis. PEA-OXA treatment evidently reduced the histological alterations and neuronal death induced by VaD and additionally improved behavioral deficits. Further, PEA-OXA decreased GFAP and Iba-1, markers of astrocytes, and microglia activation, as well as increased MAP-2, a marker of neuron development. Moreover, PEA-OXA reduced oxidative stress, modulated Nrf2-mediated antioxidant response, and inhibited the apoptotic process.InnovationSome drugs may demonstrate their healing potential by regulating neuroinflammation, rather than by their habitually attributed actions only. Palmitoylethanolamide (PEA) is a prototype ALIAmide, well-known for its analgesic, anti-inflammatory, and neuroprotective properties. The inhibition of PEA degradation by targeting NAAA, its catabolic enzyme, is a different approach for treating neuroinflammation. This research offers new insight into the mechanism of PEA-OXA-induced neuroprotection.ConclusionThus, the modulation of intracellular NAAA by PEA-OXA could offer a novel means of controlling neuroinflammatory conditions associated with VaD.
       
  • TDP-43 proteinopathy in aging: Associations with risk-associated gene
           variants and with brain parenchymal thyroid hormone levels
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Peter T. Nelson, Zsombor Gal, Wang-Xia Wang, Dana M. Niedowicz, Sergey C. Artiushin, Samuel Wycoff, Angela Wei, Gregory A. Jicha, David W. Fardo TDP-43 proteinopathy is very prevalent among the elderly (affecting at least 25% of individuals over 85 years of age) and is associated with substantial cognitive impairment. Risk factors implicated in age-related TDP-43 proteinopathy include commonly inherited gene variants, comorbid Alzheimer's disease pathology, and thyroid hormone dysfunction. To test parameters that are associated with aging-related TDP-43 pathology, we performed exploratory analyses of pathologic, genetic, and biochemical data derived from research volunteers in the University of Kentucky Alzheimer's Disease Center autopsy cohort (n = 136 subjects). Digital pathologic methods were used to discriminate and quantify both neuritic and intracytoplasmic TDP-43 pathology in the hippocampal formation. Overall, 46.4% of the cases were positive for TDP-43 intracellular inclusions, which is consistent with results in other prior community-based cohorts. The pathologies were correlated with hippocampal sclerosis of aging (HS-Aging) linked genotypes. We also assayed brain parenchymal thyroid hormone (triiodothyronine [T3] and thyroxine [T4]) levels. In cases with SLCO1A2/IAPP or ABCC9 risk associated genotypes, the T3/T4 ratio tended to be reduced (p = .051 using 2-tailed statistical test), and in cases with low T3/T4 ratios (bottom quintile), there was a higher likelihood of HS-Aging pathology (p = .025 using 2-tailed statistical test). This is intriguing because the SLCO1A2/IAPP and ABCC9 risk associated genotypes have been associated with altered expression of the astrocytic thyroid hormone receptor (protein product of the nearby gene SLCO1C1). These data indicate that dysregulation of thyroid hormone signaling may play a role in age-related TDP-43 proteinopathy.
       
  • Increased anxiety-like behavior following circuit-specific catecholamine
           denervation in mice
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Sara Ferrazzo, Ozge Gunduz-Cinar, Nadia Stefanova, Gabrielle A. Pollack, Andrew Holmes, Claudia Schmuckermair, Francesco Ferraguti Parkinson's disease (PD) presents with a constellation of non-motor symptoms, notably increased anxiety, which are currently poorly treated and underrepresented in animal models of the disease. Human post-mortem studies report loss of catecholaminergic neurons in the pre-symptomatic phases of PD when anxiety symptoms emerge, and a large literature from rodent and human studies indicate that catecholamines are important mediators of anxiety via their modulatory effects on limbic regions such as the amygdala. On the basis of these observations, we hypothesized that anxiety in PD could result from an early loss of catecholaminergic inputs to the amygdala and/or other limbic structures. To interrogate this hypothesis, we bilaterally injected the neurotoxin 6-OHDA in the mouse basolateral amygdala (BL). This produced a restricted pattern of catecholaminergic (tyrosine-hydroxylase-labeled) denervation in the BL, intercalated cell masses and ventral hippocampus, but not the central amygdala or prefrontal cortex. We found that this circuit-specific lesion did not compromise performance on multiple measures of motor function (home cage, accelerating rotarod, beam balance, pole climbing), but did increase anxiety-like behavior in the elevated plus-maze and light-dark exploration tests. Fear behavior in the pavlovian cued conditioning and passive avoidance assays was, by contrast, unaffected; possibly due to preservation of catecholamine innervation of the central amygdala from the periaqueductal gray. These data provide some of the first evidence implicating loss of catecholaminergic neurotransmission in midbrain-amygdala circuits to increased anxiety-like behavior. Our findings offer an initial step towards identifying the neural substrates for pre-motor anxiety symptoms in PD.
       
  • The role of pallidum in the neural integrator model of cervical dystonia
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Alexey Sedov, Svetlana Usova, Ulia Semenova, Anna Gamaleya, Alexey Tomskiy, J. Douglas Crawford, Brian Corneil, H.A. Jinnah, Aasef G. Shaikh Dystonia is the third most common movement disorder affecting three million people worldwide. Cervical dystonia is the most common form of dystonia. Despite common prevalence the pathophysiology of cervical dystonia is unclear. Traditional view is that basal ganglia is involved in pathophysiology of cervical dystonia, while contemporary theories suggested the role of cerebellum and proprioception in the pathophysiology of cervical dystonia. It was recently proposed that the cervical dystonia is due to malfunctioning of the head neural integrator – the neuron network that normally converts head velocity to position. Most importantly the neural integrator model was inclusive of traditional proposal emphasizing the role of basal ganglia while also accommodating the contemporary view suggesting the involvement of cerebellum and proprioception. It was hypothesized that the head neural integrator malfunction is the result of impairment in cerebellar, basal ganglia, or proprioceptive feedback that converge onto the integrator. The concept of converging input from the basal ganglia, cerebellum, and proprioception to the network participating in head neural integrator explains that abnormality originating anywhere in the network can lead to the identical motor deficits – drifts followed by rapid corrective movements – a signature of neural integrator dysfunction. We tested this hypothesis in an experiment examining simultaneously recorded globus pallidal single-unit activity, synchronized neural activity (local field potential), and electromyography (EMG) measured from the neck muscles during the standard-of-care deep brain stimulation surgery in 12 cervical dystonia patients (24 hemispheres). Physiological data were collected spontaneously or during voluntary shoulder shrug activating the contralateral trapezius muscle. The activity of pallidal neurons during shoulder shrug exponentially decayed with time constants that were comparable to one measured from the pretectal neural integrator and the trapezius electromyography. These results show that evidence of abnormal neural integration is also seen in globus pallidum, and that latter is connected with the neural integrator. Pretectal single neuron responses consistently preceded the muscle activity; while the globus pallidum internus response always lagged behind the muscle activity. Globus pallidum externa had equal proportion of lag and lead neurons. These results suggest globus pallidum receive feedback from the muscles or the efference copy from the integrator or the other source of the feedback. There was bi-hemispheric asymmetry in the pallidal single-unit activity and local field potentials. The asymmetry correlated with degree of lateral head turning in cervical dystonia patients. These results suggest that bihemispheric asymmetry in the feedback leads to asymmetric dysfunction in the neural integrator causing head turning.
       
  • A two-hit story: Seizures and genetic mutation interaction sets phenotype
           severity in SCN1A epilepsies
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Ana Rita Salgueiro-Pereira, Fabrice Duprat, Paula A. Pousinha, Alexandre Loucif, Vincent Douchamps, Cristina Regondi, Marion Ayrault, Martine Eugie, Marion I. Stunault, Andrew Escayg, Romain Goutagny, Vadym Gnatkovsky, Carolina Frassoni, Hélène Marie, Ingrid Bethus, Massimo Mantegazza SCN1A (NaV1.1 sodium channel) mutations cause Dravet syndrome (DS) and GEFS+ (which is in general milder), and are risk factors in other epilepsies. Phenotypic variability limits precision medicine in epilepsy, and it is important to identify factors that set phenotype severity and their mechanisms. It is not yet clear whether SCN1A mutations are necessary for the development of severe phenotypes or just for promoting seizures. A relevant example is the pleiotropic R1648H mutation that can cause either mild GEFS+ or severe DS.We used a R1648H knock-in mouse model (Scn1aRH/+) with mild/asymptomatic phenotype to dissociate the effects of seizures and of the mutation per se. The induction of short repeated seizures, at the age of disease onset for Scn1a mouse models (P21), had no effect in WT mice, but transformed the mild/asymptomatic phenotype of Scn1aRH/+ mice into a severe DS-like phenotype, including frequent spontaneous seizures and cognitive/behavioral deficits. In these mice, we found no major modifications in cytoarchitecture or neuronal death, but increased excitability of hippocampal granule cells, consistent with a pathological remodeling.Therefore, we demonstrate for our model that an SCN1A mutation is a prerequisite for a long term deleterious effect of seizures on the brain, indicating a clear interaction between seizures and the mutation for the development of a severe phenotype generated by pathological remodeling. Applied to humans, this result suggests that genetic alterations, even if mild per se, may increase the risk of second hits to develop severe phenotypes.
       
  • The α3 and α4 nicotinic acetylcholine receptor (nAChR) subunits in the
           brainstem medulla of sudden infant death syndrome (SIDS)
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Atqiya Aishah, Tina Hinton, Karen A. Waters, Rita Machaalani SIDS occurs in early infancy and predominantly during a sleep period. Abnormalities in nicotine receptor binding and in the expression of the nicotinic acetylcholine receptor (nAChR) subunits α7 and β2 have been reported in the brainstem of SIDS infants. This study focuses on the α3 and α4 nAChR subunits as α3 is important for early postnatal survival while α4 is crucial for nicotine-elicited antinociception and sleep-wake cycle regulation. Tissue from the rostral medulla of infants who died with a known cause of death (eSUDI, n = 7), and from SIDS classified as SIDS I (n = 8) and SIDS II (n = 27), was immunohistochemically stained for the α3 and α4 nAChR subunits and quantified in 9 nuclei comparing amongst these groups. The association with risk factors of sex, cigarette smoke exposure, upper respiratory tract infection (URTI), prone sleeping and bedsharing was also evaluated. Results showed that only α4 changes (increase) were evident in SIDS, occurring in the hypoglossal and cuneate nuclei of SIDS II infants and the nucleus of the spinal trigeminal tract of SIDS I infants. Amongst the SIDS infants, cigarette smoke exposure was only associated with decreased α4 in cribriform fibre tracts, while sex and bedsharing were associated with increases in α3 in the dorsal motor nucleus of the vagus and solitary nucleus, respectively. Combined, these findings suggest that abnormalities in endogenous acetylcholine synthesis and regulation may underlie the altered α3 and α4 nAChR subunit expressions in the SIDS brainstem medulla since the changes were not related to cigarette smoke exposure.
       
  • Brain insulin response and peripheral metabolic changes in a Tau
           transgenic mouse model
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Antoine Leboucher, Tariq Ahmed, Emilie Caron, Anne Tailleux, Sylvie Raison, Aurélie Joly-Amado, Elodie Marciniak, Kevin Carvalho, Malika Hamdane, Kadiombo Bantubungi, Steve Lancel, Sabiha Eddarkaoui, Raphaelle Caillierez, Emmanuelle Vallez, Bart Staels, Didier Vieau, Detlef Balschun, Luc Buee, David Blum Accumulation of hyper-phosphorylated and aggregated Tau proteins is a neuropathological hallmark of Alzheimer's Disease (AD) and Tauopathies. AD patient brains also exhibit insulin resistance. Whereas, under normal physiological conditions insulin signaling in the brain mediates plasticity and memory formation, it can also regulate peripheral energy homeostasis. Thus, in AD, brain insulin resistance affects both cognitive and metabolic changes described in these patients. While a role of Aβ oligomers and APOE4 towards the development of brain insulin resistance emerged, contribution of Tau pathology has been largely overlooked. Our recent data demonstrated that one of the physiological function of Tau is to sustain brain insulin signaling. We postulated that under pathological conditions, hyper-phosphorylated/aggregated Tau is likely to lose this function and to favor the development of brain insulin resistance. This hypothesis was substantiated by observations from patient brains with pure Tauopathies. To address the potential link between Tau pathology and brain insulin resistance, we have evaluated the brain response to insulin in a transgenic mouse model of AD-like Tau pathology (THY-Tau22). Using electrophysiological and biochemical evaluations, we surprisingly observed that, at a time when Tau pathology and cognitive deficits are overt and obvious, the hippocampus of THY-Tau22 mice exhibits enhanced response to insulin. In addition, we demonstrated that the ability of i.c.v. insulin to promote body weight loss is enhanced in THY-Tau22 mice. In line with this, THY-Tau22 mice exhibited a lower body weight gain, hypoleptinemia and hypoinsulinemia and finally a metabolic resistance to high-fat diet. The present data highlight that the brain of transgenic Tau mice exhibit enhanced brain response to insulin. Whether these observations are ascribed to the development of Tau pathology, and therefore relevant to human Tauopathies, or unexpectedly results from the Tau transgene overexpression is debatable and discussed.
       
  • Maternal immune activation-induced PPARγ-dependent dysfunction of
           microglia associated with neurogenic impairment and aberrant postnatal
           behaviors in offspring
    • Abstract: Publication date: May 2019Source: Neurobiology of Disease, Volume 125Author(s): Qiuying Zhao, Qiaozhi Wang, Jiutai Wang, Minmin Tang, Shugui Huang, Ke Peng, Yue Han, Jinqiang Zhang, Guangyi Liu, Qi Fang, Zili You Maternal infection during pregnancy is an important factor involved in the pathogenesis of brain disorders in the offspring. Mounting evidence from maternal immune activation (MIA) animals indicates that microglial priming may contribute to neurodevelopmental abnormalities in the offspring. Because peroxisome proliferator-activated receptor gamma (PPARγ) activation exerts neuroprotective effects by regulating neuroinflammatory response, it is a pharmacological target for treating neurogenic disorders. We investigated the effect of PPARγ-dependent microglial activation on neurogenesis and consequent behavioral outcomes in male MIA-offspring. Pregnant dams on gestation day 18 received Poly(I:C) (1, 5, or 10 mg/kg; i.p.) or the vehicle. The MIA model that received 10 mg/kg Poly(I:C) showed significantly increased inflammatory responses in the maternal serum and fetal hippocampus, followed by cognitive deficits, which were highly correlated with hippocampal neurogenesis impairment in prepubertal male offspring. The microglial population in hippocampus increased, displayed decreased processes and larger soma, and had a higher expression of the CD11b, which is indicative of the M1 phenotype (classical activation). Activation of the PPARγ pathway by pioglitazone in the MIA offspring rescued the imbalance of the microglial activation and ameliorated the MIA-induced suppressed neurogenesis and cognitive impairments and anxiety behaviors. In an in vitro experiment, PPARγ-induced M2 microglia (alternative activation) promoted the proliferation and differentiation of neural precursor cells. These results indicated that the MIA-induced long-term changes in microglia phenotypes were associated with hippocampal neurogenesis and neurobehavioral abnormalities in offspring. Modulation of the microglial phenotypes was associated with a PPARγ-mediated neuroprotective mechanism in the MIA offspring and may serve as a potential therapeutic approach for prenatal immune activation-induced neuropsychiatric disorders.Graphical abstractUnlabelled Image
       
  • An integrated transcriptomics and proteomics analysis reveals functional
           endocytic dysregulation caused by mutations in LRRK2
    • Abstract: Publication date: Available online 5 April 2019Source: Neurobiology of DiseaseAuthor(s): Natalie Connor-Robson, Heather Booth, Jeffrey G. Martin, Benbo Gao, Kejie Li, Natalie Doig, Jane Vowles, Cathy Browne, Laura Klinger, Peter Juhasz, Christine Klein, Sally A. Cowley, Paul Bolam, Warren Hirst, Richard Wade-Martins BackgroundMutations in LRRK2 are the most common cause of autosomal dominant Parkinson's disease, and the relevance of LRRK2 to the sporadic form of the disease is becoming ever more apparent. It is therefore essential that studies are conducted to improve our understanding of the cellular role of this protein. Here we use multiple models and techniques to identify the pathways through which LRRK2 mutations may lead to the development of Parkinson's disease.MethodsA novel integrated transcriptomics and proteomics approach was used to identify pathways that were significantly altered in iPSC-derived dopaminergic neurons carrying the LRRK2-G2019S mutation. Western blotting, immunostaining and functional assays including FM1-43 analysis of synaptic vesicle endocytosis were performed to confirm these findings in iPSC-derived dopaminergic neuronal cultures carrying either the LRRK2-G2019S or the LRRK2-R1441C mutation, and LRRK2 BAC transgenic rats, and post-mortem human brain tissue from LRRK2-G2019S patients.ResultsOur integrated -omics analysis revealed highly significant dysregulation of the endocytic pathway in iPSC-derived dopaminergic neurons carrying the LRRK2-G2019S mutation. Western blot analysis confirmed that key endocytic proteins including endophilin I-III, dynamin-1, and various RAB proteins were downregulated in these cultures and in cultures carrying the LRRK2-R1441C mutation, compared with controls. We also found changes in expression of 25 RAB proteins. Changes in endocytic protein expression led to a functional impairment in clathrin-mediated synaptic vesicle endocytosis. Further to this, we found that the endocytic pathway was also perturbed in striatal tissue of aged LRRK2 BAC transgenic rats overexpressing either the LRRK2 wildtype, LRRK2-R1441C or LRRK2-G2019S transgenes. Finally, we found that clathrin heavy chain and endophilin I-III levels are increased in human post-mortem tissue from LRRK2-G2019S patients compared with controls.ConclusionsOur study demonstrates extensive alterations across the endocytic pathway associated with LRRK2 mutations in iPSC-derived dopaminergic neurons and BAC transgenic rats, as well as in post-mortem brain tissue from PD patients carrying a LRRK2 mutation. In particular, we find evidence of disrupted clathrin-mediated endocytosis and suggest that LRRK2-mediated PD pathogenesis may arise through dysregulation of this process.
       
  • A Parkinson's disease gene, DJ-1, regulates anti-inflammatory roles of
           astrocytes through prostaglandin D2 synthase expression
    • Abstract: Publication date: Available online 4 April 2019Source: Neurobiology of DiseaseAuthor(s): Dong-Joo Choi, Jiawei An, Ilo Jou, Sang Myun Park, Eun-Hye Joe Dysfunctional regulation of inflammation may contribute to the progression of neurodegenerative diseases. The results of this study revealed that DJ-1, a Parkinson's disease (PD) gene, regulated expression of prostaglandin D2 synthase (PTGDS) and production of prostaglandin D2 (PGD2), by which DJ-1 enhanced anti-inflammatory function of astrocytes. In injured DJ-1 knockout (KO) brain, expression of tumor necrosis factor-alpha (TNF-α) was more increased, but that of anti-inflammatory heme oxygenase-1 (HO-1) was less increased compared with that in injured wild-type (WT) brain. Similarly, astrocyte-conditioned media (ACM) prepared from DJ-1-KO astrocytes less induced HO-1 expression and less inhibited expression of inflammatory mediators in microglia. With respect to the underlying mechanism, we found that PTGDS that induced expression of HO-1 was lower in DJ-1 KO astrocytes and brains compared with their WT counterparts. In addition, PTGDS levels increased in the injured brain of WT mice, but barely in that of KO mice. We also found that DJ-1 regulated PTGDS expression through Sox9. Thus, Sox9 siRNAs reduced PTGDS expression in WT astrocytes, and Sox9 overexpression rescued PTGDS expression in DJ-1 KO astrocytes. In agreement with these results, ACM from Sox9 siRNA-treated astrocytes and that from Sox9-overexpression astrocytes exerted opposite effects on HO-1 expression and anti-inflammation. These findings suggest that DJ-1 positively regulates anti-inflammatory functions of astrocytes, and that DJ-1 dysfunction contributes to the excessive inflammatory response in PD development.Graphical abstractUnlabelled Image
       
  • Heritability and genetic variance of dementia with Lewy bodies
    • Abstract: Publication date: Available online 3 April 2019Source: Neurobiology of DiseaseAuthor(s): Rita Guerreiro, Valentina Escott-Price, Dena G. Hernandez, Celia Kun-Rodrigues, Owen A. Ross, Tatiana Orme, Joao Luis Neto, Susana Carmona, Nadia Dehghani, John D. Eicher, Claire Shepherd, Laura Parkkinen, Lee Darwent, Michael G. Heckman, Sonja W. Scholz, Juan C. Troncoso, Olga Pletnikova, Ted Dawson, Liana Rosenthal, Olaf Ansorge Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.
       
  • Quantitative ultrasound and apoptotic death in the neonatal primate brain
    • Abstract: Publication date: Available online 2 April 2019Source: Neurobiology of DiseaseAuthor(s): Ivan M. Rosado-Mendez, Kevin K. Noguchi, Laura Castañeda-Martinez, George Kirvassilis, Sophie H. Wang, Francesca Manzella, Brant S. Swiney, Kobe Masuoka, Saverio Capuano, Kevin G. Brunner, Kristin Crosno, Quinton W. Guerrero, Hayley Whitson, Ansgar Brambrink, Heather S. Simmons, Andres F. Mejia, James A. Zagzebski, Timothy J. Hall, Chrysanthy Ikonomidou Apoptosis is triggered in the developing mammalian brain by sedative, anesthetic or antiepileptic drugs during late gestation and early life. Whether human children are vulnerable to this toxicity mechanism remains unknown, as there are no imaging techniques to capture it. Apoptosis is characterized by distinct structural features, which affect the way damaged tissue scatters ultrasound compared to healthy tissue. We evaluated whether apoptosis, triggered by the anesthetic sevoflurane in the brains of neonatal rhesus macaques, can be detected using quantitative ultrasound (QUS).Neonatal (n = 15) rhesus macaques underwent 5 h of sevoflurane anesthesia. QUS images were obtained through the sagittal suture at 0.5 and 6 h. Brains were collected at 8 h and examined immunohistochemically to analyze apoptotic neuronal and oligodendroglial death.Significant apoptosis was detected in white and gray matter throughout the brain, including the thalamus. We measured a change in the effective scatterer size (ESS), a QUS biomarker derived from ultrasound echo signals obtained with clinical scanners, after sevoflurane-anesthesia in the thalamus. Although initial inclusion of all measurements did not reveal a significant correlation, when outliers were excluded, the change in the ESS between the pre- and post-anesthesia measurements correlated strongly and proportionally with the severity of apoptotic death.We report for the first time in vivo changes in QUS parameters, which may reflect severity of apoptosis in the brains of infant nonhuman primates. These findings suggest that QUS may enable in vivo studies of apoptosis in the brains of human infants following exposure to anesthetics, antiepileptics and other brain injury mechanisms.
       
  • Inducible nitric oxide synthase inhibitor, 1400W, mitigates DFP-induced
           long-term neurotoxicity in the rat model
    • Abstract: Publication date: Available online 30 March 2019Source: Neurobiology of DiseaseAuthor(s): Marson Putra, Shaunik Sharma, Meghan Gage, Grace Gasser, Andy Hinojo-Perez, Ashley Olson, Adriana Gregory-Flores, Sreekanth Puttachary, Chong Wang, Vellareddy Anantharam, Thimmasettappa Thippeswamy Chemical nerve agents (CNA) are increasingly becoming a threat to both civilians and military personnel. CNA-induced acute effects on the nervous system have been known for some time and the long-term consequences are beginning to emerge. In this study, we used diisopropylfluorophosphate (DFP), a seizurogenic CNA to investigate the long-term impact of its acute exposure on the brain and its mitigation by an inducible nitric oxide synthase (iNOS) inhibitor, 1400W as a neuroprotectant in the rat model. Several experimental studies have demonstrated that DFP-induced seizures and/or status epilepticus (SE) causes permanent brain injury, even after the countermeasure medication (atropine, oxime, and diazepam). In the present study, DFP-induced SE caused a significant increase in iNOS and 3-nitrotyrosine (3-NT) at 24 h, 48 h, 7d, and persisted for a long-term (12 weeks post-exposure), which led to the hypothesis that iNOS is a potential therapeutic target in DFP-induced brain injury. To test the hypothesis, we administered 1400W (20 mg/kg, i.m.) or the vehicle twice daily for the first three days of post-exposure. 1400W significantly reduced DFP-induced iNOS and 3-NT upregulation in the hippocampus and piriform cortex, and the serum nitrite levels at 24 h post-exposure. 1400W also prevented DFP-induced mortality in
       
  • New piperazine multi-effect drugs prevent neurofibrillary degeneration and
           amyloid deposition, and preserve memory in animal models of Alzheimer's
           disease
    • Abstract: Publication date: Available online 27 March 2019Source: Neurobiology of DiseaseAuthor(s): Nicolas Sergeant, Valérie Vingtdeux, Sabiha Eddarkaoui, Marion Gay, Caroline Evrard, Nicolas Le Fur, Cyril Laurent, Raphaelle Caillierez, Hélène Obriot, Paul-Emmanuel Larchanché, Amaury Farce, Mathilde Coevoet, Pascal Carato, Mostafa Kouach, Amandine Descat, Patrick Dallemagne, Valérie Buée-Scherrer, David Blum, Malika Hamdane, Luc Buée Alzheimer's Disease is a devastating dementing disease involving amyloid deposits, neurofibrillary tangles, progressive and irreversible cognitive impairment. Today, only symptomatic drugs are available and therapeutic treatments, possibly acting at a multiscale level, are thus urgently needed. To that purpose, we designed multi-effects compounds by synthesizing drug candidates derived by substituting a novel N,N′-disubstituted piperazine anti-amyloid scaffold and adding acetylcholinesterase inhibition property. Two compounds were synthesized and evaluated. The most promising hybrid molecule reduces both the amyloid pathology and the Tau pathology as well as the memory impairments in a preclinical model of Alzheimer's disease. In vitro also, the compound reduces the phosphorylation of Tau and inhibits the release of Aβ peptides while preserving the processing of other metabolites of the amyloid precursor protein.We synthetized and tested the first drug capable of ameliorating both the amyloid and Tau pathology in animal models of AD as well as preventing the major brain lesions and associated memory impairments. This work paves the way for future compound medicines against both Alzheimer's-related brain lesions development and the associated cognitive impairments.
       
  • The UPR-PERK pathway is not a promising therapeutic target for mutant
           SOD1-induced ALS
    • Abstract: Publication date: Available online 26 March 2019Source: Neurobiology of DiseaseAuthor(s): Yulia Dzhashiashvili, Chase P. Monckton, Harini S. Shah, Rejani B. Kunjamma, Brian Popko Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, characterized by motor neuron death in the brain and spinal cord. Mutations in the Cu/Zn superoxide dismutase (SOD1) gene account for ~20% of all familial ALS forms, corresponding to 1%–2% of all ALS cases. One of the suggested mechanisms by which mutant SOD1 (mtSOD1) exerts its toxic effects involves intracellular accumulation of abnormal mtSOD1 aggregates, which trigger endoplasmic reticulum (ER) stress and activate its adaptive signal transduction pathways, including the unfolded protein response (UPR). PERK, an eIF2α kinase, is central to the UPR and is the most rapidly activated pathway in response to ER stress. Previous reports using mtSOD1 transgenic mice indicated that genetic or pharmacological enhancement of the UPR-PERK pathway may be effective in treating ALS. We investigated the response to PERK haploinsufficiency, and the response to deficiency of its downstream effectors GADD34 and CHOP, in five distinct lines of mtSOD1 mice. We demonstrate that, in contrast to a previously published study, PERK haploinsufficiency has no effect on disease in all mtSOD1 strains examined. We also show that deficiency of GADD34, which enhances the UPR by prolonging the phosphorylation of eIF2α,does not ameliorate disease in these mtSOD1 mouse strains. Finally, we demonstrate that genetic ablation of CHOP transcription factor, which is known to be pro-apoptotic, does not ameliorate disease in mtSOD1 mice. Cumulatively, our studies reveal that neither genetic inhibition of the UPR via ablation of PERK, nor genetic UPR enhancement via ablation of GADD34, is beneficial for mtSOD1-induced motor neuron disease. Therefore, the PERK pathway is not a likely target for therapeutic intervention in ALS.
       
  • Soluble tau aggregates inhibit synaptic long-term depression and amyloid
           β-facilitated LTD in vivo
    • Abstract: Publication date: Available online 22 March 2019Source: Neurobiology of DiseaseAuthor(s): Tomas Ondrejcak, Neng-Wei Hu, Yingjie Qi, Igor Klyubin, Grant T. Corbett, Graham Fraser, Michael S. Perkinton, Dominic M. Walsh, Andrew Billinton, Michael J. Rowan Soluble synaptotoxic aggregates of the main pathological proteins of Alzheimer's disease, amyloid β-protein (Aß) and tau, have rapid and potent inhibitory effects on long-term potentiation (LTP). Although the promotion of synaptic weakening mechanisms, including long-term depression (LTD), is posited to mediate LTP inhibition by Aß, little is known regarding the action of exogenous tau on LTD. The present study examined the ability of different assemblies of full-length human tau to affect LTD in the dorsal hippocampus of the anaesthetized rat. Unlike Aß, intracerebroventricular injection of soluble aggregates of tau (SτAs), but not monomers or fibrils, potently increased the threshold for LTD induction in a manner that required cellular prion protein. However, MTEP, an antagonist of the putative prion protein coreceptor metabotropic glutamate receptor 5, did not prevent the disruption of synaptic plasticity by SτAs. In contrast, systemic treatment with Ro 25–6981, a selective antagonist at GluN2B subunit-containing NMDA receptors, reduced SτA-mediated inhibition of LTD, but not LTP. Intriguingly, SτAs completely blocked Aß-facilitated LTD, whereas a subthreshold dose of SτAs facilitated Aß-mediated inhibition of LTP. Overall, these findings support the importance of cellular prion protein in mediating a range of, sometimes opposing, actions of soluble Aß and tau aggregates with different effector mechanisms on synaptic plasticity.
       
  • Persistent behavior deficits, neuroinflammation, and oxidative stress in a
           rat model of acute organophosphate intoxication
    • Abstract: Publication date: Available online 21 March 2019Source: Neurobiology of DiseaseAuthor(s): Michelle Guignet, Kiran Dhakal, Brenna M. Flannery, Brad A. Hobson, Dorota Zolkowska, Ashish Dhir, Donald A. Bruun, Shuyang Li, Abdul Wahab, Danielle J. Harvey, Jill L. Silverman, Michael A. Rogawski, Pamela J. Lein Current medical countermeasures for organophosphate (OP)-induced status epilepticus (SE) are not effective in preventing long-term morbidity and there is an urgent need for improved therapies. Rat models of acute intoxication with the OP, diisopropylfluorophosphate (DFP), are increasingly being used to evaluate therapeutic candidates for efficacy in mitigating the long-term neurologic effects associated with OP-induced SE. Many of these therapeutic candidates target neuroinflammation and oxidative stress because of their implication in the pathogenesis of persistent neurologic deficits associated with OP-induced SE. Critical to these efforts is the rigorous characterization of the rat DFP model with respect to outcomes associated with acute OP intoxication in humans, which include long-term electroencephalographic, neurobehavioral, and neuropathologic effects, and their temporal relationship to neuroinflammation and oxidative stress. To address these needs, we examined a range of outcomes at later times post-exposure than have previously been reported for this model. Adult male Sprague-Dawley rats were given pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to administration of DFP (4 mg/kg, sc), which was immediately followed by atropine sulfate (2 mg/kg, im) and pralidoxime (25 mg/kg, im). This exposure paradigm triggered robust electroencephalographic and behavioral seizures that rapidly progressed to SE lasting several hours in 90% of exposed animals. Animals that survived DFP-induced SE (~70%) exhibited spontaneous recurrent seizures and hyperreactive responses to tactile stimuli over the first 2 months post-exposure. Performance in the elevated plus maze, open field, and Pavlovian fear conditioning tests indicated that acute DFP intoxication reduced anxiety-like behavior and impaired learning and memory at 1 and 2 months post-exposure in the absence of effects on general locomotor behavior. Immunohistochemical analyses revealed significantly increased expression of biomarkers of reactive astrogliosis, microglial activation and oxidative stress in multiple brain regions at 1 and 2 months post-DFP, although there was significant spatiotemporal heterogeneity across these endpoints. Collectively, these data largely support the relevance of the rat model of acute DFP intoxication as a model for acute OP intoxication in the human, and support the hypothesis that neuroinflammation and/or oxidative stress represent potential therapeutic targets for mitigating the long-term neurologic sequelae of acute OP intoxication.
       
  • Opportunities in precision psychiatry using PET neuroimaging in psychosis
    • Abstract: Publication date: Available online 20 March 2019Source: Neurobiology of DiseaseAuthor(s): Jennifer M. Coughlin, Andrew G. Horti, Martin G. Pomper With the movement toward precision medicine in healthcare, recent studies of individuals with psychosis have begun to explore positron emission tomography (PET) as a tool to test for biochemical signatures that may distinguish subtypes of psychosis that guide subtype-specific therapeutic interventions. This review presents selected PET findings that exemplify early promise in using molecular imaging to predict treatment response, provide rationale for new therapeutic targets, and monitor target engagement in biomarker-defined subtypes of psychosis. PET data, among other data types, may prove useful in the scientific pursuit of identifying precision strategies to improve clinical outcomes for individuals with psychosis.
       
  • Beta bursts during continuous movements accompany the velocity decrement
           in Parkinson's disease patients
    • Abstract: Publication date: Available online 18 March 2019Source: Neurobiology of DiseaseAuthor(s): Roxanne Lofredi, Huiling Tan, Wolf-Julian Neumann, Chien-Hung Yeh, Gerd-Helge Schneider, Andrea A. Kühn, Peter Brown Bradykinesia is reported to correlate with subthalamic beta power (13–35 Hz) recorded at rest in Parkinson's disease (PD). Pilot studies suggest adaptive deep brain stimulation triggered by amplitude threshold crossings of beta activity defined at rest is effective. This is puzzling, given that beta is suppressed during repetitive movements when bradykinesia becomes apparent. Recently, increased beta power in PD has been linked to beta bursts. Here we investigate whether beta bursts also occur during repetitive movements and relate to progressive decrement in movement velocity. Therefore, subthalamic local field potentials were recorded in 12 PD patients off medication while performing 30s blocks of rotatory movements alternating with rest periods. Bursts were defined separately for the low (13–20 Hz) and high (20–35 Hz) beta band using thresholds defined at rest. As expected, velocity significantly decreased within movement blocks. Despite the sustained suppression of both beta sub-bands, bursts could still be detected during movement. Beta bursts were reduced in amplitude, duration and rate during movement with beta rate correlating best with beta power. A mixed-effects linear model revealed that percentage time spent in beta bursts predicted velocity decreases better than averaged power. This correlation was specific for the low beta band. Our results link beta bursts during movement to bradykinesia. This helps explain how beta activity may contribute to bradykinetic movement decrement even though mean beta power is reduced during movement. Moreover, our findings help explain the effectiveness of adaptive DBS triggered off beta bursts, even though these may be defined with respect to beta levels at rest.
       
  • PPN-DBS: A utopic vision or a realistic perspective'
    • Abstract: Publication date: Available online 16 March 2019Source: Neurobiology of DiseaseAuthor(s): Alessandro Stefani, Salvatore Galati
       
  • The impact of indigenous microbes on Parkinson's disease
    • Abstract: Publication date: Available online 15 March 2019Source: Neurobiology of DiseaseAuthor(s): Timothy Sampson The gastrointestinal tract is inhabited by trillions of individual microbes, representing hundreds to thousands of distinct species. These indigenous organisms are not simply spectators to host activity, but instead actively modulate critical aspects of host physiology. From digestion and the production of small molecules, to the maturation and tuning of immune responses, the gastrointestinal microbiome influences every organ system in the body. Growing experimental evidence demonstrates microbial influence on neurological function in both health and disease. Furthermore, sequencing of the intestinal microbe population reveals altered community structures in various neurological conditions. Here, we provide a perspective on the potential roles for the intestinal microbiome in modulating Parkinson's disease. While Parkinson's disease has been historically studied as a disease of the central nervous system, there is growing appreciation for the roles of both gastrointestinal function and its resident microbes within this disease state. Recent studies focused on the microbiome during Parkinson's disease may advance our understanding of disease etiology and provide perspective for previously unrecognized therapeutic avenues through modulation of intestinal microbes.
       
  • Novel therapeutics for treating organophosphate-induced status epilepticus
           co-morbidities, based on changes in calcium homeostasis
    • Abstract: Publication date: Available online 12 March 2019Source: Neurobiology of DiseaseAuthor(s): Laxmikant S. Deshpande, Robert J. DeLorenzo Organophosphate (OP) chemicals include pesticides such as parathion, and nerve gases such as sarin and soman and are considered major chemical threat agents. Acute OP exposure is associated with a cholinergic crisis and status epilepticus (SE). It is also known that the survivors of OP toxicity exhibit neurobehavioral deficits such as mood changes, depression, and memory impairment, and acquired epilepsy. Our research has focused on addressing the need to develop effective therapeutic agents that could be administered even after prolonged seizures and would prevent or lessen the chronic morbidity associated with OP-SE survival. We have developed rat survival models of OP pesticide metabolite paraoxon (POX) and nerve agent sarin surrogate diisopropyl fluorophosphate (DFP) induced SE that are being used to screen for medical countermeasures against an OP attack. Our research has focused on studying neuronal calcium (Ca2+) homeostatic mechanisms for identifying mechanisms and therapeutics for the expression of neurological morbidities associated with OP-SE survival. We have observed development of a “Ca2+ plateau” characterized by sustained elevations in neuronal Ca2+ levels in OP-SE surviving rats that coincided with the appearance of OP-SE chronic morbidities. These Ca2+ elevations had their origin in Ca2+ release from the intracellular stores such that blockade with antagonists like dantrolene, carisbamate, and levetiracetam lowered OP-SE mediated Ca2+ plateau and afforded significant neuroprotection. Since the Ca2+ plateau lasts for a prolonged period, our studies suggest that blocking it after the control of SE may represent a unique target for development of novel countermeasures to prevent long term Ca2+ mediated OP-SE neuropsychiatric comorbidities such as depression, anxiety, and acquired epilepsy (AE).
       
  • Toward integrated understanding of salience in psychosis
    • Abstract: Publication date: Available online 6 March 2019Source: Neurobiology of DiseaseAuthor(s): Jun Miyata Attribution of abnormally heightened salience to daily-life stimuli is considered to underlie psychosis. Dopaminergic hyperactivity in the midbrain-striatum is thought to cause such aberrant salience attribution. A “salience network” comprising the bilateral insula and anterior cingulate cortex is related to the processing of stimulus salience. In addition, visual and auditory attention is well described by a “saliency map”. However, so far there has been no attempt to clarify these different domains of salience in an integrated way. This article provides an overview of the literature related to four domains of salience, tries to unite them, and attempts to extend the understanding of the relationship between aberrant salience and psychosis.
       
  • Neonatal general anesthesia causes lasting alterations in excitatory and
           inhibitory synaptic transmission in the ventrobasal thalamus of adolescent
           female rats
    • Abstract: Publication date: Available online 28 February 2019Source: Neurobiology of DiseaseAuthor(s): Taylor J. Woodward, Tamara Timic Stamenic, Slobodan M. Todorovic Ample evidence has surfaced documenting the neurotoxic effects of various general anesthetic (GA) agents in the mammalian brain when administered at critical periods of synaptogenesis. However, little is known about how this neurotoxic insult affects persisting neuronal excitability after the initial exposure. Here we investigated synaptic activity and intrinsic excitability of the ventrobasal nucleus (VB) of the thalamus caused by neonatal GA administration. We used patch-clamp recordings from acute thalamic slices in young rats up to two weeks after neurotoxic GA exposure of isoflurane and nitrous oxide for 6 h at postnatal age of 7 (P7) days. We found that GA exposure at P7 increases evoked excitatory postsynaptic currents (eEPSCs) two fold by means through AMPA mediated mechanisms, while NMDA component was spared. In addition, miniature EPSCs showed a faster decay rate in neurons from GA treated animals when compared to sham controls. Likewise, we discovered that the amplitudes of evoked inhibitory postsynaptic currents (eIPSCs) were increased in VB neurons from GA animals about two-fold. Interestingly, these results were observed in female but not male rats. In contrast, intrinsic excitability and properties of T-type voltage gated calcium currents were minimally affected by GA exposure. Together, these data further the idea that GAs cause lasting alterations in synaptic transmission and neuronal excitability depending upon the placing and connectivity of neurons in the thalamus. Given that function of thalamocortical circuits critically depends on the delicate balance between excitation and inhibition, future development of therapies aimed at addressing consequences of altered excitability in the developing brain by GAs may be an attractive possibility.
       
  • A rat model of organophosphate-induced status epilepticus and the
           beneficial effects of EP2 receptor inhibition
    • Abstract: Publication date: Available online 25 February 2019Source: Neurobiology of DiseaseAuthor(s): Asheebo Rojas, Thota Ganesh, Wenyi Wang, Jennifer Wang, Raymond Dingledine This review describes an adult rat model of status epilepticus (SE) induced by diisopropyl fluorophosphate (DFP), and the beneficial outcomes of transient inhibition of the prostaglandin-E2 receptor EP2 with a small molecule antagonist, delayed by 2–4 h after SE onset. Administration of six doses of the selective EP2 antagonist TG6-10-1 over a 2–3 day period accelerates functional recovery, attenuates hippocampal neurodegeneration, neuroinflammation, gliosis and blood-brain barrier leakage, and prevents long-term cognitive deficits without blocking SE itself or altering acute seizure characteristics. This work has provided important information regarding organophosphate-induced seizure related pathologies in adults and revealed the effectiveness of delayed EP2 inhibition to combat these pathologies.Graphical abstractUnlabelled Image
       
  • From adagio to allegretto: The changing tempo of theta frequencies in
           epilepsy and its relation to interneuron function
    • Abstract: Publication date: Available online 21 February 2019Source: Neurobiology of DiseaseAuthor(s): Karen A. Moxon, Kiarash Shahlaie, Fady Girgis, Ignacio Saez, Jeffrey Kennedy, Gene G. Gurkoff Despite decades of research, our understanding of epilepsy, including how seizures are generated and propagate, is incomplete. However, there is growing recognition that epilepsy is more than just the occurrence of seizures, with patients often experiencing comorbid deficits in cognition that are poorly understood. In addition, the available therapies for treatment of epilepsy, from pharmaceutical treatment to surgical resection and seizure prevention devices, often exacerbate deficits in cognitive function. In this review, we discuss the hypothesis that seizure generation and cognitive deficits have a similar pathological source characterized by, but not limited to, deficits in theta oscillations and their influence on interneurons. We present a new framework that describes oscillatory states in epilepsy as alternating between hyper- and hypo-synchrony rather than solely the spontaneous transition to hyper-excitability characterized by the seizures. This framework suggests that as neural oscillations, specifically in the theta range, vary their tempo from a slowed almost adagio tempo during interictal periods to faster, more rhythmic allegretto tempo preictally, they impact the function of interneurons, modulating their ability to control seizures and their role in cognitive processing. This slow wave oscillatory framework may help explain why current therapies that work to reduce hyper-excitability do not completely eliminate seizures and often lead to exacerbated cognitive deficits.
       
  • Targeting the glutamatergic system to counteract organophosphate
           poisoning: A novel therapeutic strategy
    • Abstract: Publication date: Available online 21 February 2019Source: Neurobiology of DiseaseAuthor(s): Vassiliki Aroniadou-Anderjaska, Taiza H. Figueiredo, James P. Apland, Maria F. Braga One of the devastating effects of acute exposure to organophosphates, like nerve agents, is the induction of severe and prolonged status epilepticus (SE), which can cause death, or brain damage if death is prevented. Seizures after exposure are initiated by muscarinic receptor hyperstimulation—after inhibition of acetylcholinesterase by the organophosphorus agent and subsequent elevation of acetylcholine—but they are reinforced and sustained by glutamatergic hyperexcitation, which is the primary cause of brain damage. Diazepam is the FDA-approved anticonvulsant for the treatment of nerve agent-induced SE, and its replacement by midazolam is currently under consideration. However, clinical data derived from the treatment of SE of any etiology, as well as studies on the control of nerve agent-induced SE in animal models, have indicated that diazepam and midazolam control seizures only temporarily, their antiseizure efficacy is reduced as the latency of treatment from the onset of SE increases, and their neuroprotective efficacy is limited or absent. Here, we review data on the discovery of a novel anticonvulsant and neuroprotectant, LY293558, an AMPA/GluK1 receptor antagonist. Treatment of soman-exposed immature, young-adult, and aged rats with LY293558, terminates SE with limited recurrence of seizures, significantly protects from brain damage, and prevents long-term behavioral deficits, even when LY293558 is administered 1 h post-exposure. More beneficial effects and complete neuroprotection is obtained when LY293558 administration is combined with caramiphen, which antagonizes NMDA receptors. Further efficacy studies may bring the LY293558 + caramiphen combination therapy on the pathway to approval for human use.Graphical abstractUnlabelled Image
       
  • Role of pedunculopontine nucleus in sleep-wake cycle and cognition in
           humans: A systematic review of DBS studies
    • Abstract: Publication date: Available online 30 January 2019Source: Neurobiology of DiseaseAuthor(s): Lucia Ricciardi, Marianna Sarchioto, Francesca Morgante BackgroundAnimal studies have demonstrated that the pedunculopontine nucleus (PPN) is involved in the control of posture and gait, and that it is also a key structure in controlling basic non-motor functions such as sleep, attention and arousal. In this systematic review we aimed to evaluate all available studies assessing the role of PPN on cognition, nocturnal sleep and alertness in humans. Finally, we attempted to define a model in which PPN acts as an interface structure between motor control and behavior.MethodsA systematic search of the computerized databases MEDLINE and PubMed was conducted to identify papers on PPN and cognitive functions, sleep and alertness. Key search terms included: ‘PPN’, ‘arousal’, ‘sleep’, ‘cognition’, ‘memory’, ‘language’, ‘attention’, ‘alertness’, ‘PPN-DBS’, ‘Parkinson's and PPN’, ‘Parkinson's and PPN-DBS’.ResultsTwelve studies met our inclusion criteria and were included. All of them involved PD patients implanted with unilateral or bilateral PPN-DBS, most patients had concomitant DBS of another anatomical structure (subthalamic nucleus or Zona incerta). There is a lack of consistent evidences confirming the effect of PPN-DBS on specific cognitive functions, alertness or sleep in PD. There is heterogeneity between and within surgical centres of study protocols especially regarding DBS targeting, parameters of stimulation and experimental methods. Moreover, the available studies are limited by the small sample size and the short follow-up time. It has been suggested that low frequency stimulation (25 Hz) has a better effect compared to the high frequency one (60–80 Hz) on alertness, however this needs to be confirmed in further studies.ConclusionsPPN-DBS is a promising but yet an experimental procedure. PD represents an encouraging pathological model for future studies aiming to shade light on the role of PPN in cognition, attention and alertness in humans.
       
  • Child maltreatment and psychosis
    • Abstract: Publication date: Available online 24 January 2019Source: Neurobiology of DiseaseAuthor(s): Joan Kaufman, Souraya Torbey This paper reviews the literature on the association between experiences of child abuse and neglect and the development of psychoses. It then explores the premise that psychotic patients with a history of maltreatment may comprise a clinically and biological distinct subgroup. The review demonstrates that there is a growing consensus in the field that experiences of child maltreatment contribute to the onset of psychotic symptoms and psychotic disorders. There is also strong support for the premise that patients with psychotic disorders and histories of child maltreatment have distinct clinical characteristics and unique treatment needs, and emerging preliminary data to suggest psychotic patients with a history of maltreatment may comprise a distinct neurobiological subgroup. The mechanisms by which experiences of child maltreatment confers risk for psychotic disorders remains unknown, and the review highlights the value of incorporating translational research perspectives to advance knowledge in this area.
       
  • Neural correlates of cognitive deficits across developmental phases of
           schizophrenia
    • Abstract: Publication date: Available online 22 December 2018Source: Neurobiology of DiseaseAuthor(s): Sinead Kelly, Synthia Guimond, Amanda Lyall, William S. Stone, Martha E. Shenton, Matcheri Keshavan, Larry J. Seidman Schizophrenia is associated with cognitive deficits across all stages of the illness (i.e., high risk, first episode, early and chronic phases). Identifying the underlying neurobiological mechanisms of these deficits is an important area of scientific inquiry. Here, we selectively review evidence regarding the pattern of deficits across the developmental trajectory of schizophrenia using the five cognitive domains identified by the Research Domain Criteria (RDoC) initiative. We also report associated findings from neuroimaging studies. We suggest that most cognitive domains are affected across the developmental trajectory, with corresponding brain structural and/or functional differences. The idea of a common mechanism driving these deficits is discussed, along with implications for cognitive treatment in schizophrenia.
       
  • Chronic stress-induced gut dysfunction exacerbates Parkinson's disease
           phenotype and pathology in a rotenone-induced mouse model of Parkinson's
           disease
    • Abstract: Publication date: Available online 21 December 2018Source: Neurobiology of DiseaseAuthor(s): Hemraj B. Dodiya, Christopher B. Forsyth, Robin M. Voigt, Phillip A. Engen, Jinal Patel, Maliha Shaikh, Stefan J. Green, Ankur Naqib, Avik Roy, Jeffrey H. Kordower, Kalipada Pahan, Kathleen M. Shannon, Ali Keshavarzian Recent evidence provides support for involvement of the microbiota-gut-brain axis in Parkinson's disease (PD) pathogenesis. We propose that a pro-inflammatory intestinal milieu, due to intestinal hyper-permeability and/or microbial dysbiosis, initiates or exacerbates PD pathogenesis. One factor that can cause intestinal hyper-permeability and dysbiosis is chronic stress which has been shown to accelerate neuronal degeneration and motor deficits in Parkinsonism rodent models. We hypothesized that stress-induced intestinal barrier dysfunction and microbial dysbiosis lead to a pro-inflammatory milieu that exacerbates the PD phenotype in the low-dose oral rotenone PD mice model. To test this hypothesis, mice received unpredictable restraint stress (RS) for 12 weeks, and during the last six weeks mice also received a daily administration of low-dose rotenone (10 mg/kg/day) orally. The initial six weeks of RS caused significantly higher urinary cortisol, intestinal hyperpermeability, and decreased abundance of putative “anti-inflammatory” bacteria (Lactobacillus) compared to non-stressed mice. Rotenone alone (i.e., without RS) disrupted the colonic expression of the tight junction protein ZO-1, increased oxidative stress (N-tyrosine), increased myenteric plexus enteric glial cell GFAP expression and increased α-synuclein (α-syn) protein levels in the colon compared to controls. Restraint stress exacerbated these rotenone-induced changes. Specifically, RS potentiated rotenone-induced effects in the colon including: 1) intestinal hyper-permeability, 2) disruption of tight junction proteins (ZO-1, Occludin, Claudin1), 3) oxidative stress (N-tyrosine), 4) inflammation in glial cells (GFAP + enteric glia cells), 5) α-syn, 6) increased relative abundance of fecal Akkermansia (mucin-degrading Gram-negative bacteria), and 7) endotoxemia. In addition, RS promoted a number of rotenone-induced effects in the brain including: 1) reduced number of resting microglia and a higher number of dystrophic/phagocytic microglia as well as (FJ-C+) dying cells in the substantia nigra (SN), 2) increased lipopolysaccharide (LPS) reactivity in the SN, and 3) reduced dopamine (DA) and DA metabolites (DOPAC, HVA) in the striatum compared to control mice. Our findings support a model in which chronic stress-induced, gut-derived, pro-inflammatory milieu exacerbates the PD phenotype via a dysfunctional microbiota-gut-brain axis.
       
  • Deciphering microbiome and neuroactive immune gene interactions in
           schizophrenia
    • Abstract: Publication date: Available online 22 November 2018Source: Neurobiology of DiseaseAuthor(s): Emily G. Severance, Robert H. Yolken The body's microbiome represents an actively regulated network of novel mechanisms that potentially underlie the etiology and pathophysiology of a wide range of diseases. For complex brain disorders such as schizophrenia, understanding the cellular and molecular pathways that intersect the bidirectional gut-brain axis is anticipated to lead to new methods of treatment. The means by which the microbiome might differ across neuropsychiatric and neurological disorders are not known. Brain disorders as diverse as schizophrenia, major depression, Parkinson's disease and multiple sclerosis appear to share a common pathology of an imbalanced community of commensal microbiota, often measured in terms of a leaky gut phenotype accompanied by low level systemic inflammation. While environmental factors associated with these disease states might contribute to intestinal pathologies, products from a perturbed microbiome may also directly promote specific signs, symptoms and etiologies of individual disorders. We hypothesize that in schizophrenia, it is the putatively unique susceptibility related to genes that modulate the immune system and the gut-brain pleiotropy of these genes which leads to a particularly neuropathological response when challenged by a microbiome in dysbiosis. Consequences from exposure to this dysbiosis may occur during pre- or post-natal time periods and thus may interfere with normal neurodevelopment in those who are genetically predisposed. Here, we review the evidence from the literature which supports the idea that the intersection of the microbiome and immune gene susceptibility in schizophrenia is relevant etiologically and for disease progression. Figuring prominently at both ends of the gut-brain axis and at points in between are proteins encoded by genes found in the major histocompatibility complex (MHC), including select MHC as well as non-MHC complement pathway genes.
       
  • Translational research on chemical nerve agents
    • Abstract: Publication date: Available online 20 November 2018Source: Neurobiology of DiseaseAuthor(s): David A. Jett, Shardell M. Spriggs This special issue will describe cutting-edge translational research on the development of safe and effective therapeutics for treating exposure to toxic chemical threat agents that target the nervous system. These studies are supported by the National Institutes of Health (NIH) Countermeasures Against Chemical Threats (CounterACT) program. Chemical threats include chemical warfare agents, pesticides and other toxic chemicals whose primary mode of action is targeted within the nervous system. Depending on the dose, the effects of these toxic chemicals can be lethal or cause serious morbidity including neuropathology and neurological deficits. Current topics in research on organophosphorus pesticides and chemical warfare agents include developing alternatives to currently approve acetylcholinesterase reactivators, control of seizures that are refractory to benzodiazepine drugs, and treatments for serious morbidity caused by non-lethal exposures. There is also an effort to understand the mechanisms of toxicity and treatments for other neuro-active agents such as tetramine and hydrogen sulfide. A robust translational research effort on nerve agents is essential for being better prepared with an effective medical response capability during chemical emergencies.
       
  • Cognitive functions associated with developing prefrontal cortex during
           adolescence and developmental neuropsychiatric disorders
    • Abstract: Publication date: Available online 10 November 2018Source: Neurobiology of DiseaseAuthor(s): Takeshi Sakurai, Nao J. Gamo Cognitive functions including social cognition improve significantly during adolescence, the time period during which the brain typically handles a large volume of incoming information from the outside environment. Processing information and responding to environmental challenges allow the prefrontal cortex, a brain region important for cognition, to mature further and establish self-identity, social skills, and other cognitive abilities, thus helping individuals to function in society. People with vulnerable circuitries predisposed by either genetic or early environmental insults, may not be able to deal with social situations appropriately, and develop network dysfunction that may lead to the onset of schizophrenia, which often occurs during this period. Populations with higher risk for developing schizophrenia present “prodromal” phenotypes, including cognitive deficits, even before the onset of the disorder. Modulating circuit plasticity when the prefrontal cortex is particularly vulnerable allows us to support the development of cognitive functions in such populations and prevent them from transitioning into full-blown schizophrenia. For this approach to be successful, we need to conduct both human and animal studies side by side to better understand the neurobiology underlying the disorder, especially changes that occur over the disease trajectory that may be clinically relevant. By taking a multidisciplinary approach, there is a hope for precision medicine for schizophrenia in the future.
       
  • Deep brain stimulation of the pedunculopontine nucleus modulates
           subthalamic pathological oscillations
    • Abstract: Publication date: Available online 10 November 2018Source: Neurobiology of DiseaseAuthor(s): Alessandro Stefani, Laura Clara Grandi, Salvatore Galati Low frequency deep brain stimulation (DBS) of the pedunculopontine nucleus area (PPNa) has been proposed as a novel surgical target for gait dysfunction in the late stage of Parkinson's disease (PD). Since the mid-2000s, we have shown that intrasurgical delivery of stimulation in the pontine tegmentum affects the firing activity in the subthalamic nucleus (STN), but its effect on STN oscillatory rhythms has not been studied. Neuronal oscillations detected by local field potential (LFPs) have great importance, since they express complex movement-related behavior such as locomotion. Therefore, we examined the effect of three PPNa-DBS stimulation protocols (at 10, 25 and 80 Hz) on the STN oscillatory activity of PD patients. We focused on the anti-kinetic beta (β, 15–30 Hz), the pro-kinetic gamma (γ, 60–90 Hz) and “gait-related” alpha (α, 7–12 Hz) bands. We hypothesized that modulation of STN oscillations might have clinical relevance in the PPNa-mediated effects.PPNa stimulation at 25 and 80 Hz decreased the power of the STN β band by 33.94 and 40.22%, respectively. PPNa-DBS did not affect the other two bands with a tendency to suppress α power, while γ oscillation increased.Our results suggest that the anti-kinetic β band is the oscillation most sensitive to PPNa-DBS despite the negligible clinical efficacy on bradykinesia. However, how these changes interact reciprocally with the cortex or are counterbalanced by lower brainstem/spinal pathways remain to be elucidated.Our observation might turn out to be helpful in new protocols designed with adaptive DBS supporting the addition of PPN implantation in PD patients experiencing declining efficacy of STN-DBS.
       
  • Neurobiology and treatment of social cognition in schizophrenia: Bridging
           the bed-bench gap
    • Abstract: Publication date: Available online 2 November 2018Source: Neurobiology of DiseaseAuthor(s): Sohei Kimoto, Manabu Makinodan, Toshifumi Kishimoto Social cognition refers to the psychological processes involved in the perception, encoding, storage, retrieval, and regulation of information about others and ourselves. This process is essential for survival and reproduction in complex social environments. Recent evidence suggests that impairments in social cognition frequently occur in schizophrenia, mainly contributing to poor functional outcomes, including the inability to engage in meaningful work and maintain satisfying interpersonal relationships. With the ambiguous definition of social cognition, the neurobiology underlying impaired social cognition remains unknown, and the effectiveness of currently available intervention strategies in schizophrenia remain limited. Considering the advances and challenges of translational research for schizophrenia, social cognition has been considered a high-priority domain for treatment development. Here, we describe the current state of the framework, clinical concerns, and intervention approaches for social cognition in schizophrenia. Next, we introduce translatable rodent models associated with schizophrenia that allow the evaluation of different components of social behaviors, providing deeper insights into the neural substrates of social cognition in schizophrenia. Our review presents a valuable perspective that indicates the necessity of building bridges between basic and clinical science researchers for the development of novel therapeutic approaches in impaired social cognition in schizophrenia.
       
  • The gut microbiome and neuroinflammation in amyotrophic lateral
           sclerosis' Emerging clinical evidence
    • Abstract: Publication date: Available online 12 October 2018Source: Neurobiology of DiseaseAuthor(s): Christina N. Fournier, Madelyn Houser, Malú G. Tansey, Jonathan D. Glass, Vicki Stover Hertzberg
       
  • Stem cell therapy for neurological disorders: A focus on aging
    • Abstract: Publication date: Available online 13 September 2018Source: Neurobiology of DiseaseAuthor(s): Hung Nguyen, Sydney Zarriello, Alexandreya Coats, Cannon Nelson, Chase Kingsbury, Anna Gorsky, Mira Rajani, Elliot G. Neal, Cesar V. Borlongan Age-related neurological disorders continue to pose a significant societal and economic burden. Aging is a complex phenomenon that affects many aspects of the human body. Specifically, aging can have detrimental effects on the progression of brain diseases and endogenous stem cells. Stem cell therapies possess promising potential to mitigate the neurological symptoms of such diseases. However, aging presents a major obstacle for maximum efficacy of these treatments. In this review, we discuss current preclinical and clinical literature to highlight the interactions between aging, stem cell therapy, and the progression of major neurological disease states such as Parkinson’s disease, Huntington’s disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and multiple system atrophy. We raise important questions to guide future research and advance novel treatment options.
       
  • Post-stroke administration of omega-3 polyunsaturated fatty acids promotes
           neurovascular restoration after ischemic stroke in mice: Efficacy declines
           with aging
    • Abstract: Publication date: Available online 12 September 2018Source: Neurobiology of DiseaseAuthor(s): Xiaoyan Jiang, Jun Suenaga, Hongjian Pu, Zhishuo Wei, Amanda D. Smith, Xiaoming Hu, Yejie Shi, Jun Chen Post-stroke treatment with omega-3 polyunsaturated fatty acids (n-3 PUFAs) may be a promising therapy in young animals but this has not been tested in aged subjects, a population at most risk of ischemic stroke. Herein we examined the therapeutic efficacy of n-3 PUFAs after distal middle cerebral artery occlusion (dMCAO) in young (10–12 weeks old) and aged (18 months old) mice. Post-ischemic mice were randomly assigned to 4 groups that received: 1) regular food with low content of n-3 PUFAs, 2) intraperitoneal docosahexaenoic acid (DHA, a major component of n-3 PUFAs) injections, 3) Fish oil (FO, containing high concentration of n-3 PUFAs) dietary supplement, or 4) combined treatment with DHA and FO dietary supplement. Long-term neurorestoration induced by n-3 PUFA post-stroke administration and its underlying mechanism(s) were analyzed up to 35 days after dMCAO. Aged mice showed more severe neurological deficits than young mice after dMCAO with histological lesions extended to the striatum. Notably, post-stroke treatment with combined DHA injections and FO dietary supplementation was more effective in reducing brain injury and improving sensorimotor function in aged mice than either treatment alone, albeit to a lesser extent than in the young mice. Unlike the improvement in spatial cognitive function observed in young mice, the combined treatment regimen failed to improve cognitive function in aged mice. The reduction in stroke-induced neurological deficits with n-3 PUFA post-treatment was associated with enhanced angiogenesis, oligodendrogenesis, neuron survival and white matter restoration. Together, these results indicate that the neurological benefits of n-3 PUFA administration after stroke extend to older animals and are associated with improved neuronal survival and brain remodeling, therefore suggesting that post-stroke administration of n-3 PUFAs is a viable clinically relevant treatment option against stroke.
       
  • Dichotomy between motor and cognitive functions of midbrain cholinergic
           neurons
    • Abstract: Publication date: Available online 10 September 2018Source: Neurobiology of DiseaseAuthor(s): Nadine K. Gut, Juan Mena-Segovia Cholinergic neurons of the pedunculopontine nucleus (PPN) are interconnected with all the basal ganglia structures, as well as with motor centers in the brainstem and medulla. Recent theories put into question whether PPN cholinergic neurons form part of a locomotor region that directly regulates the motor output, and rather suggest a modulatory role in adaptive behavior involving both motor and cognitive functions. In support of this, experimental studies in animals suggest that cholinergic neurons reinforce actions by signaling reward prediction and shape adaptations in behavior during changes of environmental contingencies. This is further supported by clinical studies proposing that decreased cholinergic transmission originated in the PPN is associated with impaired sensorimotor integration and perseverant behavior, giving rise to some of the symptoms observed in Parkinson’s disease and progressive supranuclear palsy. Altogether, the evidence suggests that cholinergic neurons of the PPN, mainly through their interactions with the basal ganglia, have a leading role in action control.
       
  • Decline in Sirtuin-1 expression and activity plays a critical role in
           blood-brain barrier permeability in aging
    • Abstract: Publication date: Available online 6 September 2018Source: Neurobiology of DiseaseAuthor(s): Svetlana M. Stamatovic, Gabriela Martinez-Revollar, Anna Hu, Jennifer Choi, Richard F. Keep, Anuska V. Andjelkovic Accumulating evidence suggest that cerebral microvascular disease increases with advancing age and is associated with lacunar stroke, leukoaraiosis, vascular dementia and Alzheimer disease. Increased blood brain barrier (BBB) permeability/leakage takes “center stage” in ongoing age-related vascular/brain parenchymal injury. Although significant effort has been made in defining the gene mutations and risk factors involved in microvascular alterations in vascular dementia and Alzheimer disease, the intra- and intercellular pathogenic mechanisms responsible for vascular hyperpermeability are still largely unknown. The present study aimed to reveal the ongoing senescence process in brain endothelial cells and its effect on BBB integrity in healthy/non-disease conditions. An analysis of BBB integrity during the life span of C56Bl6 mice (young, 2–6 months; middle-aged, 6–12, months; old, 16–22 months) showed increased BBB permeability for different molecular sized tracers (sodium fluorescein, inulin and 20 kDa dextran) in aged mice which was accompanied by modifications in tight junction (TJ) complex organization, manifested as altered TJ protein expression (particularly claudin-5). A gene screening analysis of aging associated markers in brain microvessels isolated from “aged” mice (C56Bl6, 18-20 months) and human brain samples showed a significant decline in sirtuin-1 expression (Sirt1; ~2.8-fold) confirmed at mRNA and protein levels and by activation assay. Experiments in Sirt1 transgenic mice and brain endothelial cell-specific Sirt1 knockout mice indicated that Sirt1 affects BBB integrity, with loss increasing permeability. Similarly, in vitro, overexpressing Sirt1 or increasing Sirt1 activity with an agonist (Sirt1720) protected against senescence-induced brain endothelial barrier hyperpermeability, stabilized claudin-5/ZO-1 interactions and rescued claudin-5 expression. These findings reveal a novel role of Sirt1 in modulating aging-associated BBB persistent leakage.
       
  • Microbiome profiling reveals gut dysbiosis in a transgenic mouse model of
           Huntington's disease
    • Abstract: Publication date: Available online 5 September 2018Source: Neurobiology of DiseaseAuthor(s): Geraldine Kong, Kim-Anh Lê Cao, Louise M. Judd, ShanShan Li, Thibault Renoir, Anthony J. Hannan Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a trinucleotide repeat expansion in the huntingtin (HTT) gene, which is expressed ubiquitously throughout the brain and peripheral tissues. Whilst the focus of much research has been on the cognitive, psychiatric and motor symptoms of HD, the extent of peripheral pathology and its potential impact on central symptoms has been less intensely explored. Disruption of the gastrointestinal microbiome (gut dysbiosis) has been recently reported in a number of neurological and psychiatric disorders, and therefore we hypothesized that it might also occur in HD. We have used 16S rRNA amplicon sequencing to characterize the gut microbiome in the R6/1 transgenic mouse model of HD, relative to littermate wild-type controls. We report that there is a significant difference in microbiota composition in HD mice at 12 weeks of age. Specifically, we observed an increase in Bacteriodetes and a proportional decrease in Firmicutes in the HD gut microbiome. In addition, we observed an increase in microbial diversity in male HD mice, compared to wild-type controls, but no differences in diversity were observed in female HD mice. The gut dysbiosis observed coincided with impairment in body weight gain despite higher food intake as well as motor deficits at 12 weeks of age. Gut dysbiosis was also associated with a change in the gut microenvironment, as we observed higher fecal water content in HD mice at 12 weeks of age. This study provides the first evidence of gut dysbiosis in HD.
       
  • Pedunculopontine nucleus: An integrative view with implications on Deep
           Brain Stimulation
    • Abstract: Publication date: Available online 3 September 2018Source: Neurobiology of DiseaseAuthor(s): Andreas Nowacki, Salvatore Galati, Janine Ai-Schlaeppi, Claudio Bassetti, Alain Kaelin, Claudio Pollo The pedunculopontine nucleus (PPN) is a reticular nucleus located in the mesencephalic and upper pontine tegmentum. Initially, characterized by its predominant cholinergic projection neurons, it was associated with the “mesencephalic locomotor region” and “reticular activating system”. Furthermore, based on histopathological studies, the PPN was hypothesized to play a role in the manifestation of symptoms in movement disorders such as Parkinson's disease (PD). Since axial symptoms represent unmet needs of PD treatments, a series of pioneering experiments in Parkinsonian monkeys promoted the idea of a potential new target for deep brain stimulation (DBS) and much clinical interest was generated in the following years leading to a number of trials analysing the role of PPN for gait disorders. This review summarizes the historical background and more recent findings about the anatomy and function of the PPN and its implications in the basal ganglia network of the normal as well as diseased brain. Classical views on PPN function shall be challenged by more recent findings. Additionally, the current role and future perspectives of PPN DBS in PD patients shall be outlined.
       
  • The pedunclopontine nucleus and Parkinson's disease
    • Abstract: Publication date: Available online 29 August 2018Source: Neurobiology of DiseaseAuthor(s): Cecilia Tubert, Daniel Galtieri, D. James Surmeier In the last decade, scientific and clinical interest in the pedunculopontine nucleus (PPN) has grown dramatically. This growth is largely a consequence of experimental work demonstrating its connection to the control of gait and of clinical work implicating PPN pathology in levodopa-insensitive gait symptoms of Parkinson's disease (PD). In addition, the development of optogenetic and chemogenetic approaches has made experimental analysis of PPN circuitry and function more tractable. In this brief review, recent findings in the field linking PPN to the basal ganglia and PD are summarized; in addition, an attempt is made to identify key gaps in our understanding and challenges this field faces in moving forward.
       
  • Treatment resistant schizophrenia: Clinical, biological, and therapeutic
           perspectives
    • Abstract: Publication date: Available online 29 August 2018Source: Neurobiology of DiseaseAuthor(s): Frederick C. Nucifora, Edgar Woznica, Brian J. Lee, Nicola Cascella, Akira Sawa Treatment resistant schizophrenia (TRS) refers to the significant proportion of schizophrenia patients who continue to have symptoms and poor outcomes despite treatment. While many definitions of TRS include failure of two different antipsychotics as a minimum criterion, the wide variability in inclusion criteria has challenged the consistency and reproducibility of results from studies of TRS. We begin by reviewing the clinical, neuroimaging, and neurobiological characteristics of TRS. We further review the current treatment strategies available, addressing clozapine, the first-line pharmacological agent for TRS, as well as pharmacological and non-pharmacological augmentation of clozapine including medication combinations, electroconvulsive therapy, repetitive transcranial magnetic stimulation, deep brain stimulation, and psychotherapies. We conclude by highlighting the most recent consensus for defining TRS proposed by the Treatment Response and Resistance in Psychosis Working Group, and provide our overview of future perspectives and directions that could help advance the field of TRS research, including the concept of TRS as a potential subtype of schizophrenia.
       
  • Reciprocal interaction between monoaminergic systems and the
           pedunculopontine nucleus: Implication in the mechanism of L-DOPA
    • Abstract: Publication date: Available online 24 August 2018Source: Neurobiology of DiseaseAuthor(s): Giuseppe Di Giovanni, Abdeslam Chagraoui, Emilie Puginier, Salvatore Galati, Philippe De Deurwaerdère The pedunculopontine nucleus (PPN) is part of the mesencephalic locomotor region (MLR) and has been involved in the control of gait, posture, locomotion, sleep, and arousal. It likely participates in some motor and non-motor symptoms of Parkinson's disease and is regularly proposed as a surgical target to ameliorate gait, posture and sleep disorders in Parkinsonian patients. The PPN overlaps with the monoaminergic systems including dopamine, serotonin and noradrenaline in the modulation of the above-mentioned functions. All these systems are involved in Parkinson's disease and the mechanism of the anti-Parkinsonian agents, mostly L-DOPA. This suggests that PPN interacts with monoaminergic neurons and vice versa. Some evidence indicates that the PPN sends cholinergic, glutamatergic and even gabaergic inputs to mesencephalic dopaminergic cells, with the data regarding serotonergic or noradrenergic cells being less well known. Similarly, the control exerted by the PPN on dopaminergic neurons, is multiple and complex, and more extensively explored than the other monoaminergic systems. The data on the influence of monoaminergic systems on PPN neuron activity are rather scarce. While there is evidence that the PPN influences the therapeutic response of L-DOPA, it is still difficult to discerne the reciprocal action of the PPN and monoaminergic systems in this action. Additional data are required to better understand the functional organization of monoaminergic inputs to the MLR including the PPN to get a clearer picture of their interaction.
       
  • Genetics of stroke recovery: BDNF val66met polymorphism in stroke recovery
           and its interaction with aging
    • Abstract: Publication date: Available online 15 August 2018Source: Neurobiology of DiseaseAuthor(s): Mustafa Balkaya, Sunghee Cho Stroke leads to long term sensory, motor and cognitive impairments. Most patients experience some degree of spontaneous recovery which is mostly incomplete and varying greatly among individuals. The variation in recovery outcomes has been attributed to numerous factors including lesion size, corticospinal tract integrity, age, gender and race. It is well accepted that genetics play a crucial role in stroke incidence and accumulating evidence suggests that it is also a significant determinant in recovery. Among the number of genes and variations implicated in stroke recovery the val66met single nucleotide polymorphism (SNP) in the BDNF gene influences post-stroke plasticity in the most significant ways. Val66met is the most well characterized BDNF SNP and is common (40–50 % in Asian and 25–32% in Caucasian populations) in humans. It reduces activity-dependent BDNF release, dampens cortical plasticity and is implicated in numerous diseases. Earlier studies on the effects of val66met on stroke outcome and recovery presented primarily a maladaptive role. Novel findings however indicate a much more intricate interaction between val66met and stroke recovery which appears to be influenced by lesion location, post-stroke stage and age. This review will focus on the role of BDNF and val66met SNP in relation to stroke recovery and try to identify potential pathophysiologic mechanisms involved. The effects of age on val66met associated alterations in plasticity and potential consequences in terms of stroke are also discussed.
       
 
 
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