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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: 424, 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: 285, 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: 170, 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: 360, 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: 195, 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: 206, 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
Journal Prestige (SJR): 10.654
Citation Impact (citeScore): 11
Number of Followers: 240  
  Full-text available via subscription Subscription journal
ISSN (Print) 0896-6273 - ISSN (Online) 1097-4199
Published by Elsevier Homepage  [3158 journals]
  • A Common Neuroendocrine Substrate for Diverse General Anesthetics and
    • Abstract: Publication date: Available online 18 April 2019Source: NeuronAuthor(s): Li-Feng Jiang-Xie, Luping Yin, Shengli Zhao, Vincent Prevosto, Bao-Xia Han, Kafui Dzirasa, Fan WangSummaryHow general anesthesia (GA) induces loss of consciousness remains unclear, and whether diverse anesthetic drugs and sleep share a common neural pathway is unknown. Previous studies have revealed that many GA drugs inhibit neural activity through targeting GABA receptors. Here, using Fos staining, ex vivo brain slice recording, and in vivo multi-channel electrophysiology, we discovered a core ensemble of hypothalamic neurons in and near the supraoptic nucleus, consisting primarily of neuroendocrine cells, which are persistently and commonly activated by multiple classes of GA drugs. Remarkably, chemogenetic or brief optogenetic activations of these anesthesia-activated neurons (AANs) strongly promote slow-wave sleep and potentiates GA, whereas conditional ablation or inhibition of AANs led to diminished slow-wave oscillation, significant loss of sleep, and shortened durations of GA. These findings identify a common neural substrate underlying diverse GA drugs and natural sleep and reveal a crucial role of the neuroendocrine system in regulating global brain states.
  • Sister, Sister: Ependymal Cells and Adult Neural Stem Cells Are Separated
           at Birth by Geminin Family Members
    • Abstract: Publication date: 17 April 2019Source: Neuron, Volume 102, Issue 2Author(s): Ryann M. Fame, Maria K. LehtinenThe adult subventricular zone (SVZ) stem cell niche is comprised of multi-ciliated ependymal cells that line the brain ventricular system and adult stem cells. Papers in Neuron (Ortiz-Álvarez et al., 2019) and Cell Reports (Redmond et al., 2019) report that these cell types share a common precursor. Ortiz-Álvarez et al. further show that Geminin family members modulate the fate of daughter cells.
  • Disruption of RNA Metabolism in Neurological Diseases and Emerging
           Therapeutic Interventions
    • Abstract: Publication date: 17 April 2019Source: Neuron, Volume 102, Issue 2Author(s): Julia K. Nussbacher, Ricardos Tabet, Gene W. Yeo, Clotilde Lagier-TourenneRNA binding proteins are critical to the maintenance of the transcriptome via controlled regulation of RNA processing and transport. Alterations of these proteins impact multiple steps of the RNA life cycle resulting in various molecular phenotypes such as aberrant RNA splicing, transport, and stability. Disruption of RNA binding proteins and widespread RNA processing defects are increasingly recognized as critical determinants of neurological diseases. Here, we describe distinct mechanisms by which the homeostasis of RNA binding proteins is compromised in neurological disorders through their reduced expression level, increased propensity to aggregate or sequestration by abnormal RNAs. These mechanisms all converge toward altered neuronal function highlighting the susceptibility of neurons to deleterious changes in RNA expression and the central role of RNA binding proteins in preserving neuronal integrity. Emerging therapeutic approaches to mitigate or reverse alterations of RNA binding proteins in neurological diseases are discussed.
  • Filters: When, Why, and How (Not) to Use Them
    • Abstract: Publication date: 17 April 2019Source: Neuron, Volume 102, Issue 2Author(s): Alain de Cheveigné, Israel NelkenFilters are commonly used to reduce noise and improve data quality. Filter theory is part of a scientist’s training, yet the impact of filters on interpreting data is not always fully appreciated. This paper reviews the issue and explains what a filter is, what problems are to be expected when using them, how to choose the right filter, and how to avoid filtering by using alternative tools. Time-frequency analysis shares some of the same problems that filters have, particularly in the case of wavelet transforms. We recommend reporting filter characteristics with sufficient details, including a plot of the impulse or step response as an inset.
  • Microglia Sculpt Sex Differences in Social Behavior
    • Abstract: Publication date: 17 April 2019Source: Neuron, Volume 102, Issue 2Author(s): Caroline J. Smith, Staci D. BilboMicroglia are increasingly recognized as developmental sculptors of neural circuits. In this issue of Neuron, VanRyzin et al. (2019) demonstrate a novel mechanism by which endocannabinoids drive microglia to phagocytose newborn astrocytes in the medial amygdala of male rats, promoting sex differences in social play behavior.
  • Switching Gears, Structuring the Right Search Strategy
    • Abstract: Publication date: 17 April 2019Source: Neuron, Volume 102, Issue 2Author(s): Johannes Felsenberg, Scott WaddellNematodes can use local and global search strategies to find food. In this issue of Neuron, López-Cruz et al. (2019) unravel a neural circuit mechanism that allows worms to select and switch between these search modes depending on recent experience of food.
  • The Yin and Yang of Arnt2 in Activity-Dependent Transcription
    • Abstract: Publication date: 17 April 2019Source: Neuron, Volume 102, Issue 2Author(s): Zeynep Okur, Peter ScheiffeleSpatiotemporal regulation of neuronal gene expression is essential for proper functioning of neuronal circuits. In this issue of Neuron, Sharma et al. (2019) discover a dual role for Arnt2-NcoR2 protein complexes in the activity-dependent regulation of neuronal transcriptomes.
  • Chandelier Cells Swipe Right for L1CAM
    • Abstract: Publication date: 17 April 2019Source: Neuron, Volume 102, Issue 2Author(s): Ryan Hamnett, Julia A. KaltschmidtEstablishing a functional neuronal circuit requires not only synapsing with the right cell type, but also targeting the right subcellular compartment. In this issue of Neuron, Tai et al. (2019) identify the cell adhesion molecule L1CAM as integral to the mechanism by which chandelier cells establish subcellular compartment-specific innervation of pyramidal neurons in the mammalian cerebral cortex.
  • The Evolution of Phase-Separated TDP-43 in Stress
    • Abstract: Publication date: 17 April 2019Source: Neuron, Volume 102, Issue 2Author(s): Benjamin WolozinIn this issue of Neuron, Gasset-Rosa et al. (2019) and Mann et al. (2019) demonstrate that cytoplasmic inclusions containing aggregated phosphorylated TDP-43 can evolve through three pathways: direct aggregation or phase-separated intermediates involving ejection from stress granules or seeding with exogenous fibrils. Interestingly, seeding with exogenous fibrils also induces cytoplasmic aggregates of nuclear pore proteins.
  • Alternative Splicing of Presynaptic Neurexins Differentially Controls
           Postsynaptic NMDA and AMPA Receptor Responses
    • Abstract: Publication date: Available online 17 April 2019Source: NeuronAuthor(s): Jinye Dai, Jason Aoto, Thomas C. SüdhofSummaryAMPA- and NMDA-type glutamate receptors mediate distinct postsynaptic signals that differ characteristically among synapses. How postsynaptic AMPA- and NMDA-receptor levels are regulated, however, remains unclear. Using newly generated conditional knockin mice that enable genetic control of neurexin alternative splicing, we show that in hippocampal synapses, alternative splicing of presynaptic neurexin-1 at splice site 4 (SS4) dramatically enhanced postsynaptic NMDA-receptor-mediated, but not AMPA-receptor-mediated, synaptic responses without altering synapse density. In contrast, alternative splicing of neurexin-3 at SS4 suppressed AMPA-receptor-mediated, but not NMDA-receptor-mediated, synaptic responses, while alternative splicing of neurexin-2 at SS4 had no effect on NMDA- or AMPA-receptor-mediated responses. Presynaptic overexpression of the neurexin-1β and neurexin-3β SS4+ splice variants, but not of their SS4− splice variants, replicated the respective SS4+ knockin phenotypes. Thus, different neurexins perform distinct nonoverlapping functions at hippocampal synapses that are independently regulated by alternative splicing. These functions transsynaptically control NMDA and AMPA receptors, thereby mediating presynaptic control of postsynaptic responses.
  • Synaptic Vesicle Recycling Pathway Determines Neurotransmitter Content and
           Release Properties
    • Abstract: Publication date: Available online 16 April 2019Source: NeuronAuthor(s): Kätlin Silm, Jing Yang, Pamela F. Marcott, Cedric S. Asensio, Jacob Eriksen, Daryl A. Guthrie, Amy H. Newman, Christopher P. Ford, Robert H. EdwardsSummaryIn contrast to temporal coding by synaptically acting neurotransmitters such as glutamate, neuromodulators such as monoamines signal changes in firing rate. The two modes of signaling have been thought to reflect differences in release by different cells. We now find that midbrain dopamine neurons release glutamate and dopamine with different properties that reflect storage in different synaptic vesicles. The vesicles differ in release probability, coupling to presynaptic Ca2+ channels and frequency dependence. Although previous work has attributed variation in these properties to differences in location or cytoskeletal association of synaptic vesicles, the release of different transmitters shows that intrinsic differences in vesicle identity drive different modes of release. Indeed, dopamine but not glutamate vesicles depend on the adaptor protein AP-3, revealing an unrecognized linkage between the pathway of synaptic vesicle recycling and the properties of exocytosis. Storage of the two transmitters in different vesicles enables the transmission of distinct signals.
  • Central Processing of Itch in the Midbrain Reward Center
    • Abstract: Publication date: Available online 15 April 2019Source: NeuronAuthor(s): Xin-Yu Su, Ming Chen, Yuan Yuan, Ying Li, Su-Shan Guo, Huo-Qing Luo, Chen Huang, Wenzhi Sun, Yong Li, Michael X. Zhu, Ming-Gang Liu, Ji Hu, Tian-Le XuSummaryItch is an aversive sensation that evokes a desire to scratch. Paradoxically, scratching the itch also produces a hedonic experience. The specific brain circuits processing these different aspects of itch, however, remain elusive. Here, we report that GABAergic (GABA) and dopaminergic (DA) neurons in the ventral tegmental area (VTA) are activated with different temporal patterns during acute and chronic itch. DA neuron activation lags behind GABA neurons and is dependent on scratching of the itchy site. Optogenetic manipulations of VTA GABA neurons rapidly modulated scratching behaviors through encoding itch-associated aversion. In contrast, optogenetic manipulations of VTA DA neurons revealed their roles in sustaining recurrent scratching episodes through signaling scratching-induced reward. A similar dichotomy exists for the role of VTA in chronic itch. These findings advance understanding of circuit mechanisms of the unstoppable itch-scratch cycles and shed important insights into chronic itch therapy.
  • Glutamate-Releasing SWELL1 Channel in Astrocytes Modulates Synaptic
           Transmission and Promotes Brain Damage in Stroke
    • Abstract: Publication date: Available online 11 April 2019Source: NeuronAuthor(s): Junhua Yang, Maria del Carmen Vitery, Jianan Chen, James Osei-Owusu, Jiachen Chu, Zhaozhu QiuSummaryBy releasing glutamate, astrocytes actively regulate synaptic transmission and contribute to excitotoxicity in neurological diseases. However, the mechanisms of astrocytic glutamate release have been debated. Here, we report non-vesicular release of glutamate through the glutamate-permeable volume-regulated anion channel (VRAC). Both cell swelling and receptor stimulation activated astrocytic VRAC, which requires its only obligatory subunit, Swell1. Astrocyte-specific Swell1 knockout mice exhibited impaired glutamatergic transmission due to the decreases in presynaptic release probability and ambient glutamate level. Consistently, the mutant mice displayed hippocampal-dependent learning and memory deficits. During pathological cell swelling, deletion of astrocytic Swell1 attenuated glutamate-dependent neuronal excitability and protected mice from brain damage after ischemic stroke. Our identification of a new molecular mechanism for channel-mediated glutamate release establishes a role for astrocyte-neuron interactions in both synaptic transmission and brain ischemia. It provides a rationale for targeting VRAC for the treatment of stroke and other neurological diseases associated with excitotoxicity.Graphical Graphical abstract for this article
  • Morning and Evening Circadian Pacemakers Independently Drive Premotor
           Centers via a Specific Dopamine Relay
    • Abstract: Publication date: Available online 10 April 2019Source: NeuronAuthor(s): Xitong Liang, Margaret C.W. Ho, Yajun Zhang, Yulong Li, Mark N. Wu, Timothy E. Holy, Paul H. TaghertSummaryMany animals exhibit morning and evening peaks of locomotor behavior. In Drosophila, two corresponding circadian neural oscillators—M (morning) cells and E (evening) cells—exhibit a corresponding morning or evening neural activity peak. Yet we know little of the neural circuitry by which distinct circadian oscillators produce specific outputs to precisely control behavioral episodes. Here, we show that ring neurons of the ellipsoid body (EB-RNs) display spontaneous morning and evening neural activity peaks in vivo: these peaks coincide with the bouts of locomotor activity and result from independent activation by M and E pacemakers. Further, M and E cells regulate EB-RNs via identified PPM3 dopaminergic neurons, which project to the EB and are normally co-active with EB-RNs. These in vivo findings establish the fundamental elements of a circadian neuronal output pathway: distinct circadian oscillators independently drive a common pre-motor center through the agency of specific dopaminergic interneurons.
  • Multiplexing of Theta and Alpha Rhythms in the Amygdala-Hippocampal
           Circuit Supports Pattern Separation of Emotional Information
    • Abstract: Publication date: Available online 9 April 2019Source: NeuronAuthor(s): Jie Zheng, Rebecca F. Stevenson, Bryce A. Mander, Lilit Mnatsakanyan, Frank P.K. Hsu, Sumeet Vadera, Robert T. Knight, Michael A. Yassa, Jack J. LinSummaryHow do we remember emotional events' While emotion often leads to vivid recollection, the precision of emotional memories can be degraded, especially when discriminating among overlapping experiences in memory (i.e., pattern separation). Communication between the amygdala and the hippocampus has been proposed to support emotional memory, but the exact neural mechanisms remain unclear. Here, we used intracranial recordings in pre-surgical epilepsy patients to show that successful pattern separation of emotional stimuli is associated with theta band (3–7 Hz)-coordinated bidirectional interactions between the amygdala and the hippocampus. In contrast, discrimination errors (i.e., failure to discriminate similar stimuli) were associated with alpha band (7–13 Hz)-coordinated unidirectional influence from the amygdala to the hippocampus. These findings imply that alpha band synchrony may impair discrimination of similar emotional events via the amygdala-hippocampal directional coupling, which suggests a target for treatments of psychiatric conditions such as post-traumatic stress disorder, in which aversive experiences are often overgeneralized.
  • Obsessive-Compulsive Disorder: Puzzles and Prospects
    • Abstract: Publication date: 3 April 2019Source: Neuron, Volume 102, Issue 1Author(s): Trevor W. Robbins, Matilde M. Vaghi, Paula BancaObsessive-compulsive disorder is a severe and disabling psychiatric disorder that presents several challenges for neuroscience. Recent advances in its genetic and developmental causation, as well as its neuropsychological basis, are reviewed. Hypotheses concerning an imbalance between goal-directed and habitual behavior together with neural correlates in cortico-striatal circuitry are evaluated and contrasted with metacognitive theories. Treatments for obsessive-compulsive disorder (OCD) tend to be of mixed efficacy but include psychological, pharmacological, and surgical approaches, the underlying mechanisms of which are still under debate. Overall, the prospects for new animal models and an integrated understanding of the pathophysiology of OCD are considered in the context of dimensional psychiatry.
  • Therapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality
    • Abstract: Publication date: 3 April 2019Source: Neuron, Volume 102, Issue 1Author(s): Eloise Hudry, Luk H. Vandenberghe
  • Uncovering the Genetic Architecture of Major Depression
    • Abstract: Publication date: 3 April 2019Source: Neuron, Volume 102, Issue 1Author(s): Andrew M. McIntosh, Patrick F. Sullivan, Cathryn M. LewisThere have been several recent studies addressing the genetic architecture of depression. This review serves to take stock of what is known now about the genetics of depression, how it has increased our knowledge and understanding of its mechanisms, and how the information and knowledge can be leveraged to improve the care of people affected. We identify four priorities for how the field of MD genetics research may move forward in future years, namely by increasing the sample sizes available for genome-wide association studies (GWASs), greater inclusion of diverse ancestries and low-income countries, the closer integration of psychiatric genetics with electronic medical records, and the development of the neuroscience toolkit for polygenic disorders.
  • Altered Connectivity in Depression: GABA and Glutamate Neurotransmitter
           Deficits and Reversal by Novel Treatments
    • Abstract: Publication date: 3 April 2019Source: Neuron, Volume 102, Issue 1Author(s): Ronald S. Duman, Gerard Sanacora, John H. KrystalSummaryThe mechanisms underlying the pathophysiology and treatment of depression and stress-related disorders remain unclear, but studies in depressed patients and rodent models are beginning to yield promising insights. These studies demonstrate that depression and chronic stress exposure cause atrophy of neurons in cortical and limbic brain regions implicated in depression, and brain imaging studies demonstrate altered connectivity and network function in the brains of depressed patients. Studies of the neurobiological basis of the these alterations have focused on both the principle, excitatory glutamate neurons, as well as inhibitory GABA interneurons. They demonstrate structural, functional, and neurochemical deficits in both major neuronal types that could lead to degradation of signal integrity in cortical and hippocampal regions. The molecular mechanisms underlying these changes have not been identified but are thought to be related to stress induced excitotoxic effects in combination with elevated adrenal glucocorticoids and inflammatory cytokines as well as other environmental factors. Transcriptomic studies are beginning to demonstrate important sex differences and, together with genomic studies, are starting to reveal mechanistic domains of overlap and uniqueness with regards to risk and pathophysiological mechanisms with schizophrenia and bipolar disorder. These studies also implicate GABA and glutamate dysfunction as well as immunologic mechanisms. While current antidepressants have significant time lag and efficacy limitations, new rapid-acting agents that target the glutamate and GABA systems address these issues and offer superior therapeutic interventions for this widespread and debilitating disorder.
  • Deconstructing the Gestalt: Mechanisms of Fear, Threat, and Trauma Memory
    • Abstract: Publication date: 3 April 2019Source: Neuron, Volume 102, Issue 1Author(s): Stephanie A. Maddox, Jakob Hartmann, Rachel A. Ross, Kerry J. ResslerThreat processing is central to understanding debilitating fear- and trauma-related disorders such as posttraumatic stress disorder (PTSD). Progress has been made in understanding the neural circuits underlying the “engram” of threat or fear memory formation that complements a decades-old appreciation of the neurobiology of fear and threat involving hub structures such as the amygdala. In this review, we examine key recent findings, as well as integrate the importance of hormonal and physiological approaches, to provide a broader perspective of how bodily systems engaged in threat responses may interact with amygdala-based circuits in the encoding and updating of threat-related memory. Understanding how trauma-related memories are encoded and updated throughout the brain and the body will ultimately lead to novel biologically-driven approaches for treatment and prevention.
  • The Molecular Basis of Drug Addiction: Linking Epigenetic to Synaptic and
           Circuit Mechanisms
    • Abstract: Publication date: 3 April 2019Source: Neuron, Volume 102, Issue 1Author(s): Eric J. Nestler, Christian LüscherSummaryAddiction is a disease in which, after a period of recreational use, a subset of individuals develops compulsive use that does not stop even in light of major negative consequences. Here, we review the evidence for underlying epigenetic remodeling in brain in two settings. First, excessive dopamine signaling during drug use may modulate gene expression, altering synaptic function and circuit activity and leading over time to maladaptive behaviors in vulnerable individuals. Second, on a longer timescale, life experience can shape the epigenetic landscape in brain and thereby may contribute to an individual’s vulnerability by amplifying drug-induced changes in gene expression that drive the transition to addiction. We conclude by exploring how epigenetic mechanisms might serve as therapeutic targets for addiction treatments.
  • Learning How Neurons Fail Inside of Networks: Nonhuman Primates Provide
           Critical Data for Psychiatry
    • Abstract: Publication date: 3 April 2019Source: Neuron, Volume 102, Issue 1Author(s): Sarah R. Heilbronner, Matthew V. ChafeeAdvancing psychiatry requires understanding brain malfunction at a microscopic scale, where neurons and synapses operate under constraints imposed by behavior, cognition, and neural architecture. Nonhuman primates are unmatched in approximating the structural and computational environment of the human brain.
  • The Emerging Importance of the Cerebellum in Broad Risk for
    • Abstract: Publication date: 3 April 2019Source: Neuron, Volume 102, Issue 1Author(s): Ahmad R. HaririRecent research has identified a single factor accounting for broad risk to experience common forms of psychopathology. Structural alterations of cerebellar circuitry have emerged as a neural nexus of this broad risk, highlighting the cerebellum’s importance for executive control.
  • Perinatal Depression: Embracing Variability toward Better Treatment and
    • Abstract: Publication date: 3 April 2019Source: Neuron, Volume 102, Issue 1Author(s): Liisa A.M. Galea, Vibe G. FrokjaerPerinatal depression (PND) is a heterogeneous disorder with differences in timing of onset of depression, which influences symptomology, severity, and treatment efficacy. Researchers must embrace the heterogeneity to bring fruition to a precision medicine approach for women in reproductive mental health care.
  • Special Issue on Disease: New Advances in Psychiatry
    • Abstract: Publication date: 3 April 2019Source: Neuron, Volume 102, Issue 1Author(s): Christina Konen, Emily Niederst
  • The Shifting Sands of Cortical Divisions
    • Abstract: Publication date: 3 April 2019Source: Neuron, Volume 102, Issue 1Author(s): Kiah Hardcastle, Lisa M. GiocomoIn this issue of Neuron, a new study by Minderer et al. (2019) examines the activity of thousands of cortical neurons during a navigation task and reveals that features of the task encoded by neurons vary smoothly across cortex rather than falling into functionally discrete cortical regions.
  • Managing Neuronal Ensembles: Somatostatin Interneuron Subpopulations Shape
           and Protect Cortical Neuronal Ensembles for Learning
    • Abstract: Publication date: 3 April 2019Source: Neuron, Volume 102, Issue 1Author(s): Melissa Serrano, Pico CaroniLearning is accompanied by temporal compression and sharpening of neuronal firing sequences. In this issue of Neuron, Adler et al. (2019), using a motor skill paradigm and its variant, uncover a dual role for somatostatin interneuron regulation to support ensemble compaction and protection in learning.
  • Taming the “Black Dog” by Light: A Retina-Habenula Circuit
           Mechanism Unveiled
    • Abstract: Publication date: 3 April 2019Source: Neuron, Volume 102, Issue 1Author(s): Yiyan Dong, Hailan HuLight exerts powerful effects on mood and has been used for the therapeutic treatment of depression. In this issue of Neuron, Huang et al. (2019) identify a visual pathway linked to the lateral habenula mediating the antidepressant effects of light.
  • Transient Input-Specific Neural Plasticity in the Lateral Habenula
           Facilitates Learning
    • Abstract: Publication date: 3 April 2019Source: Neuron, Volume 102, Issue 1Author(s): Phillip M. Baker, Yingxue Rao, Sheri J.Y. MizumoriIn this issue of Neuron, Trusel et al. (2019) demonstrate that circuit-specific plasticity in the lateral habenula is dynamically involved in translating CS-US contingencies into cue-driven avoidance behavior. Disruption of this plasticity prevents learning about CS-US relationships when they are uncertain.
  • Input-Timing-Dependent Plasticity in the Hippocampal CA2 Region and Its
           Potential Role in Social Memory
    • Abstract: Publication date: 3 April 2019Source: Neuron, Volume 102, Issue 1Author(s): Felix Leroy, David H. Brann, Torcato Meira, Steven A. Siegelbaum
  • Encoding of Wind Direction by Central Neurons in Drosophila
    • Abstract: Publication date: Available online 1 April 2019Source: NeuronAuthor(s): Marie P. Suver, Andrew M.M. Matheson, Sinekdha Sarkar, Matthew Damiata, David Schoppik, Katherine I. NagelSummaryWind is a major navigational cue for insects, but how wind direction is decoded by central neurons in the insect brain is unknown. Here we find that walking flies combine signals from both antennae to orient to wind during olfactory search behavior. Movements of single antennae are ambiguous with respect to wind direction, but the difference between left and right antennal displacements yields a linear code for wind direction in azimuth. Second-order mechanosensory neurons share the ambiguous responses of a single antenna and receive input primarily from the ipsilateral antenna. Finally, we identify novel “wedge projection neurons” that integrate signals across the two antennae and receive input from at least three classes of second-order neurons to produce a more linear representation of wind direction. This study establishes how a feature of the sensory environment—wind direction—is decoded by neurons that compare information across two sensors.Graphical Graphical abstract for this article
  • A Role of Drd2 Hippocampal Neurons in Context-Dependent Food Intake
    • Abstract: Publication date: Available online 28 March 2019Source: NeuronAuthor(s): Estefania P. Azevedo, Lisa Pomeranz, Jia Cheng, Marc Schneeberger, Roger Vaughan, Sarah A. Stern, Bowen Tan, Katherine Doerig, Paul Greengard, Jeffrey M. FriedmanSummaryAssociative learning of food cues that link location in space to food availability guides feeding behavior in mammals. However, the function of specific neurons that are elements of the higher-order, cognitive circuitry controlling feeding behavior is largely unexplored. Here, we report that hippocampal dopamine 2 receptor (hD2R) neurons are specifically activated by food and that both acute and chronic modulation of their activity reduces food intake in mice. Upstream projections from the lateral entorhinal cortex (LEC) to the hippocampus activate hD2R cells and can also decrease food intake. Finally, activation of hD2R neurons interferes with the encoding of a spatial memory linking food to a specific location via projections from the hippocampus to the septal area. Altogether these data describe a previously unidentified LEC> hippocampus> septal higher-order circuit that regulates feeding behavior.Graphical Graphical abstract for this article
  • Conversion of Graded Presynaptic Climbing Fiber Activity into Graded
           Postsynaptic Ca2+ Signals by Purkinje Cell Dendrites
    • Abstract: Publication date: Available online 27 March 2019Source: NeuronAuthor(s): Michael A. Gaffield, Audrey Bonnan, Jason M. ChristieSummaryThe brain must make sense of external stimuli to generate relevant behavior. We used a combination of in vivo approaches to investigate how the cerebellum processes sensory-related information. We found that the inferior olive encodes contexts of sensory-associated external cues in a graded manner, apparent in the presynaptic activity of their axonal projections (climbing fibers) in the cerebellar cortex. Individual climbing fibers were broadly responsive to different sensory modalities but relayed sensory-related information to the cortex in a lobule-dependent manner. Purkinje cell dendrites faithfully transformed this climbing fiber activity into dendrite-wide Ca2+ signals without a direct contribution from the mossy fiber pathway. These results demonstrate that the size of climbing-fiber-evoked Ca2+ signals in Purkinje cell dendrites is largely determined by the firing level of climbing fibers. This coding scheme emphasizes the overwhelming role of the inferior olive in generating salient signals useful for instructing plasticity and learning.
  • Location and Plasticity of the Sodium Spike Initiation Zone in Nociceptive
           Terminals In Vivo
    • Abstract: Publication date: Available online 26 March 2019Source: NeuronAuthor(s): Robert H. Goldstein, Omer Barkai, Almudena Íñigo-Portugués, Ben Katz, Shaya Lev, Alexander M. BinshtokSummaryNociceptive terminals possess the elements for detecting, transmitting, and modulating noxious signals, thus being pivotal for pain sensation. Despite this, a functional description of the transduction process by the terminals, in physiological conditions, has not been fully achieved. Here, we studied how nociceptive terminals in vivo convert noxious stimuli into propagating signals. By monitoring noxious-stimulus-induced Ca2+ dynamics from mouse corneal terminals, we found that initiation of Na+ channel (Nav)-dependent propagating signals takes place away from the terminal and that the starting point for Nav-mediated propagation depends on Nav functional availability. Acute treatment with the proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) resulted in a shift of the location of Nav involvement toward the terminal, thus increasing nociceptive excitability. Moreover, a shift of Nav involvement toward the terminal occurs in corneal hyperalgesia resulting from acute photokeratitis. This dynamic change in the location of Nav-mediated propagation initiation could underlie pathological pain hypersensitivity.
  • A Genetically Encoded Fluorescent Sensor for Rapid and Specific In Vivo
           Detection of Norepinephrine
    • Abstract: Publication date: Available online 25 March 2019Source: NeuronAuthor(s): Jiesi Feng, Changmei Zhang, Julieta E. Lischinsky, Miao Jing, Jingheng Zhou, Huan Wang, Yajun Zhang, Ao Dong, Zhaofa Wu, Hao Wu, Weiyu Chen, Peng Zhang, Jing Zou, S. Andrew Hires, J. Julius Zhu, Guohong Cui, Dayu Lin, Jiulin Du, Yulong LiSummaryNorepinephrine (NE) is a key biogenic monoamine neurotransmitter involved in a wide range of physiological processes. However, its precise dynamics and regulation remain poorly characterized, in part due to limitations of available techniques for measuring NE in vivo. Here, we developed a family of GPCR activation-based NE (GRABNE) sensors with a 230% peak ΔF/F0 response to NE, good photostability, nanomolar-to-micromolar sensitivities, sub-second kinetics, and high specificity. Viral- or transgenic-mediated expression of GRABNE sensors was able to detect electrical-stimulation-evoked NE release in the locus coeruleus (LC) of mouse brain slices, looming-evoked NE release in the midbrain of live zebrafish, as well as optogenetically and behaviorally triggered NE release in the LC and hypothalamus of freely moving mice. Thus, GRABNE sensors are robust tools for rapid and specific monitoring of in vivo NE transmission in both physiological and pathological processes.Graphical Graphical abstract for this article
  • α1ACT Is Essential for Survival and Early Cerebellar Programming in a
           Critical Neonatal Window
    • Abstract: Publication date: Available online 25 March 2019Source: NeuronAuthor(s): Xiaofei Du, Cenfu Wei, Daniel Parviz Hejazi Pastor, Eshaan R. Rao, Yan Li, Giorgio Grasselli, Jack Godfrey, Ann C. Palmenberg, Jorge Andrade, Christian Hansel, Christopher M. GomezSummaryPostnatal cerebellar development is a precisely regulated process involving well-orchestrated expression of neural genes. Neurological phenotypes associated with CACNA1A gene defects have been increasingly recognized, yet the molecular principles underlying this association remain elusive. By characterizing a dose-dependent CACNA1A gene deficiency mouse model, we discovered that α1ACT, as a transcription factor and secondary protein of CACNA1A mRNA, drives dynamic gene expression networks within cerebellar Purkinje cells and is indispensable for neonatal survival. Perinatal loss of α1ACT leads to motor dysfunction through disruption of neurogenesis and synaptic regulatory networks. However, its elimination in adulthood has minimal effect on the cerebellum. These findings shed light on the critical role of α1ACT in facilitating neuronal development in both mice and humans and support a rationale for gene therapies for calcium-channel-associated cerebellar disorders. Finally, we show that bicistronic expression may be common to the voltage-gated calcium channel (VGCC) gene family and may help explain complex genetic syndromes.Graphical Graphical abstract for this article
  • Distinct Cortical-Thalamic-Striatal Circuits through the Parafascicular
    • Abstract: Publication date: Available online 21 March 2019Source: NeuronAuthor(s): Gil Mandelbaum, Julian Taranda, Trevor M. Haynes, Daniel R. Hochbaum, Kee Wui Huang, Minsuk Hyun, Kannan Umadevi Venkataraju, Christoph Straub, Wengang Wang, Keiramarie Robertson, Pavel Osten, Bernardo L. SabatiniSummaryThe thalamic parafascicular nucleus (PF), an excitatory input to the basal ganglia, is targeted with deep-brain stimulation to alleviate a range of neuropsychiatric symptoms. Furthermore, PF lesions disrupt the execution of correct motor actions in uncertain environments. Nevertheless, the circuitry of the PF and its contribution to action selection are poorly understood. We find that, in mice, PF has the highest density of striatum-projecting neurons among all sub-cortical structures. This projection arises from transcriptionally and physiologically distinct classes of PF neurons that are also reciprocally connected with functionally distinct cortical regions, differentially innervate striatal neurons, and are not synaptically connected in PF. Thus, mouse PF contains heterogeneous neurons that are organized into parallel and independent associative, limbic, and somatosensory circuits. Furthermore, these subcircuits share motifs of cortical-PF-cortical and cortical-PF-striatum organization that allow each PF subregion, via its precise connectivity with cortex, to coordinate diverse inputs to striatum.Graphical Graphical abstract for this article
  • p190RhoGAP Filters Competing Signals to Resolve Axon Guidance Conflicts
    • Abstract: Publication date: Available online 19 March 2019Source: NeuronAuthor(s): Dario Bonanomi, Fabiola Valenza, Onanong Chivatakarn, Matthew J. Sternfeld, Shawn P. Driscoll, Aaron Aslanian, Karen Lettieri, Miriam Gullo, Aurora Badaloni, Joseph W. Lewcock, Tony Hunter, Samuel L. PfaffSummaryThe rich functional diversity of the nervous system is founded in the specific connectivity of the underlying neural circuitry. Neurons are often preprogrammed to respond to multiple axon guidance signals because they use sequential guideposts along their pathways, but this necessitates a strict spatiotemporal regulation of intracellular signaling to ensure the cues are detected in the correct order. We performed a mouse mutagenesis screen and identified the Rho GTPase antagonist p190RhoGAP as a critical regulator of motor axon guidance. Rather than acting as a compulsory signal relay, p190RhoGAP uses a non-conventional GAP-independent mode to transiently suppress attraction to Netrin-1 while motor axons exit the spinal cord. Once in the periphery, a subset of axons requires p190RhoGAP-mediated inhibition of Rho signaling to target specific muscles. Thus, the multifunctional activity of p190RhoGAP emerges from its modular design. Our findings reveal a cell-intrinsic gate that filters conflicting signals, establishing temporal windows of signal detection.Graphical Graphical abstract for this article
  • A Disinhibitory Microcircuit Mediates Conditioned Social Fear in the
           Prefrontal Cortex
    • Abstract: Publication date: Available online 18 March 2019Source: NeuronAuthor(s): Haifeng Xu, Ling Liu, Yuanyuan Tian, Jun Wang, Jie Li, Junqiang Zheng, Hongfei Zhao, Miao He, Tian-Le Xu, Shumin Duan, Han XuSummaryFear behavior is under tight control of the prefrontal cortex, but the underlying microcircuit mechanism remains elusive. In particular, it is unclear how distinct subtypes of inhibitory interneurons (INs) within prefrontal cortex interact and contribute to fear expression. We employed a social fear conditioning paradigm and induced robust social fear in mice. We found that social fear is characterized by activation of dorsal medial prefrontal cortex (dmPFC) and is largely diminished by dmPFC inactivation. With a combination of in vivo electrophysiological recordings and fiber photometry together with cell-type-specific pharmacogenetics, we further demonstrated that somatostatin (SST) INs suppressed parvalbumin (PV) INs and disinhibited pyramidal cells and consequently enhanced dmPFC output to mediate social fear responses. These results reveal a previously unknown disinhibitory microcircuit in prefrontal cortex through interactions between IN subtypes and suggest that SST INs-mediated disinhibition represents an important circuit mechanism in gating social fear behavior.Graphical Graphical abstract for this article
  • The Paraventricular Hypothalamus Regulates Satiety and Prevents Obesity
           via Two Genetically Distinct Circuits
    • Abstract: Publication date: Available online 14 March 2019Source: NeuronAuthor(s): Monica M. Li, Joseph C. Madara, Jennifer S. Steger, Michael J. Krashes, Nina Balthasar, John N. Campbell, Jon M. Resch, Nicholas J. Conley, Alastair S. Garfield, Bradford B. LowellSummarySIM1-expressing paraventricular hypothalamus (PVH) neurons are key regulators of energy balance. Within the PVHSIM1 population, melanocortin-4 receptor-expressing (PVHMC4R) neurons are known to regulate satiety and bodyweight, yet they account for only half of PVHSIM1 neuron-mediated regulation. Here we report that PVH prodynorphin-expressing (PVHPDYN) neurons, which notably lack MC4Rs, function independently and additively with PVHMC4R neurons to account for the totality of PVHSIM1 neuron-mediated satiety. Moreover, PVHPDYN neurons are necessary for prevention of obesity in an independent but equipotent manner to PVHMC4R neurons. While PVHPDYN and PVHMC4R neurons both project to the parabrachial complex (PB), they synaptically engage distinct efferent nodes, the pre-locus coeruleus (pLC), and central lateral parabrachial nucleus (cLPBN), respectively. PB-projecting PVHPDYN neurons, like PVHMC4R neurons, receive input from interoceptive ARCAgRP neurons, respond to caloric state, and are sufficient and necessary to control food intake. This expands the CNS satiety circuitry to include two non-overlapping PVH to hindbrain circuits.Graphical Graphical abstract for this article
  • Pain-Induced Negative Affect Is Mediated via Recruitment of The Nucleus
           Accumbens Kappa Opioid System
    • Abstract: Publication date: Available online 13 March 2019Source: NeuronAuthor(s): Nicolas Massaly, Bryan A. Copits, Adrianne R. Wilson-Poe, Lucia Hipólito, Tamara Markovic, Hye Jean Yoon, Shiwei Liu, Marie C. Walicki, Dionnet L. Bhatti, Sunil Sirohi, Amanda Klaas, Brendan M. Walker, Rachael Neve, Catherine M. Cahill, Kooresh I. Shoghi, Robert W. Gereau, Jordan G. McCall, Ream Al-Hasani, Michael R. Bruchas, Jose A. MorónSummaryNegative affective states affect quality of life for patients suffering from pain. These maladaptive emotional states can lead to involuntary opioid overdose and many neuropsychiatric comorbidities. Uncovering the mechanisms responsible for pain-induced negative affect is critical in addressing these comorbid outcomes. The nucleus accumbens (NAc) shell, which integrates the aversive and rewarding valence of stimuli, exhibits plastic adaptations in the presence of pain. In discrete regions of the NAc, activation of the kappa opioid receptor (KOR) decreases the reinforcing properties of rewards and induces aversive behaviors. Using complementary techniques, we report that in vivo recruitment of NAc shell dynorphin neurons, acting through KOR, is necessary and sufficient to drive pain-induced negative affect. Taken together, our results provide evidence that pain-induced adaptations in the kappa opioid system within the NAc shell represent a functional target for therapeutic intervention that could circumvent pain-induced affective disorders.Graphical Graphical abstract for this article
  • Reversible Inactivation of Different Millimeter-Scale Regions of Primate
           IT Results in Different Patterns of Core Object Recognition Deficits
    • Abstract: Publication date: Available online 13 March 2019Source: NeuronAuthor(s): Rishi Rajalingham, James J. DiCarloSummaryExtensive research suggests that the inferior temporal (IT) population supports visual object recognition behavior. However, causal evidence for this hypothesis has been equivocal, particularly beyond the specific case of face-selective subregions of IT. Here, we directly tested this hypothesis by pharmacologically inactivating individual, millimeter-scale subregions of IT while monkeys performed several core object recognition subtasks, interleaved trial-by trial. First, we observed that IT inactivation resulted in reliable contralateral-biased subtask-selective behavioral deficits. Moreover, inactivating different IT subregions resulted in different patterns of subtask deficits, predicted by each subregion’s neuronal object discriminability. Finally, the similarity between different inactivation effects was tightly related to the anatomical distance between corresponding inactivation sites. Taken together, these results provide direct evidence that the IT cortex causally supports general core object recognition and that the underlying IT coding dimensions are topographically organized.
  • Nucleoporin Seh1 Interacts with Olig2/Brd7 to Promote Oligodendrocyte
           Differentiation and Myelination
    • Abstract: Publication date: Available online 12 March 2019Source: NeuronAuthor(s): Zhixiong Liu, Minbiao Yan, Yaoji Liang, Min Liu, Kun Zhang, Dandan Shao, Rencai Jiang, Li Li, Chaomeng Wang, Daniel R. Nussenzveig, Kunkun Zhang, Shaoxuan Chen, Chuanqi Zhong, Wei Mo, Beatriz M.A. Fontoura, Liang ZhangSummaryNucleoporins (Nups) are involved in neural development, and alterations in Nup genes are linked to human neurological diseases. However, physiological functions of specific Nups and the underlying mechanisms involved in these processes remain elusive. Here, we show that tissue-specific depletion of the nucleoporin Seh1 causes dramatic myelination defects in the CNS. Although proliferation is not altered in Seh1-deficient oligodendrocyte progenitor cells (OPCs), they fail to differentiate into mature oligodendrocytes, which impairs myelin production and remyelination after demyelinating injury. Genome-wide analyses show that Seh1 regulates a core myelinogenic regulatory network and establishes an accessible chromatin landscape. Mechanistically, Seh1 regulates OPCs differentiation by assembling Olig2 and Brd7 into a transcription complex at nuclear periphery. Together, our results reveal that Seh1 is required for oligodendrocyte differentiation and myelination by promoting assembly of an Olig2-dependent transcription complex and define a nucleoporin as a key player in the CNS.Graphical Graphical abstract for this article
  • Retinoic Acid Induces Hyperactivity, and Blocking Its Receptor Unmasks
           Light Responses and Augments Vision in Retinal Degeneration
    • Abstract: Publication date: Available online 12 March 2019Source: NeuronAuthor(s): Michael Telias, Bristol Denlinger, Zachary Helft, Casey Thornton, Billie Beckwith-Cohen, Richard H. KramerSummaryLight responses are initiated in photoreceptors, processed by interneurons, and synaptically transmitted to retinal ganglion cells (RGCs), which send information to the brain. Retinitis pigmentosa (RP) is a blinding disease caused by photoreceptor degeneration, depriving downstream neurons of light-sensitive input. Photoreceptor degeneration also triggers hyperactive firing of RGCs, obscuring light responses initiated by surviving photoreceptors. Here we show that retinoic acid (RA), signaling through its receptor (RAR), is the trigger for hyperactivity. A genetically encoded reporter shows elevated RAR signaling in degenerated retinas from murine RP models. Enhancing RAR signaling in healthy retinas mimics the pathophysiology of degenerating retinas. Drug inhibition of RAR reduces hyperactivity in degenerating retinas and unmasks light responses in RGCs. Gene therapy inhibition of RAR increases innate and learned light-elicited behaviors in vision-impaired mice. Identification of RAR as the trigger for hyperactivity presents a degeneration-dependent therapeutic target for enhancing low vision in RP and other blinding disorders.
  • Hippocampal Contributions to Model-Based Planning and Spatial Memory
    • Abstract: Publication date: Available online 11 March 2019Source: NeuronAuthor(s): Oliver M. Vikbladh, Michael R. Meager, John King, Karen Blackmon, Orrin Devinsky, Daphna Shohamy, Neil Burgess, Nathaniel D. DawSummaryLittle is known about the neural mechanisms that allow humans and animals to plan actions using knowledge of task contingencies. Emerging theories hypothesize that it involves the same hippocampal mechanisms that support self-localization and memory for locations. Yet limited direct evidence supports the link between planning and the hippocampal place map. We addressed this by investigating model-based planning and place memory in healthy controls and epilepsy patients treated using unilateral anterior temporal lobectomy with hippocampal resection. Both functions were impaired in the patient group. Specifically, the planning impairment was related to right hippocampal lesion size, controlling for overall lesion size. Furthermore, although planning and boundary-driven place memory covaried in the control group, this relationship was attenuated in patients, consistent with both functions relying on the same structure in the healthy brain. These findings clarify both the neural mechanism of model-based planning and the scope of hippocampal contributions to behavior.
  • Neuroligin-1 Signaling Controls LTP and NMDA Receptors by Distinct
           Molecular Pathways
    • Abstract: Publication date: Available online 11 March 2019Source: NeuronAuthor(s): Xiaoting Wu, Wade K. Morishita, Ashley M. Riley, William D. Hale, Thomas C. Südhof, Robert C. MalenkaSummaryNeuroligins, postsynaptic cell adhesion molecules that are linked to neuropsychiatric disorders, are extensively studied, but fundamental questions about their functions remain. Using in vivo replacement strategies in quadruple conditional knockout mice of all neuroligins to avoid heterodimerization artifacts, we show, in hippocampal CA1 pyramidal neurons, that neuroligin-1 performs two key functions in excitatory synapses by distinct molecular mechanisms. N-methyl-D-aspartate (NMDA) receptor-dependent LTP requires trans-synaptic binding of postsynaptic neuroligin-1 to presynaptic β-neurexins but not the cytoplasmic sequences of neuroligins. In contrast, postsynaptic NMDA receptor (NMDAR)-mediated responses involve a neurexin-independent mechanism that requires the neuroligin-1 cytoplasmic sequences. Strikingly, deletion of neuroligins blocked the spine expansion associated with LTP, as monitored by two-photon imaging; this block involved a mechanism identical to that of the role of neuroligin-1 in NMDAR-dependent LTP. Our data suggest that neuroligin-1 performs two mechanistically distinct signaling functions and that neurolign-1-mediated trans-synaptic cell adhesion signaling critically regulates LTP.
  • Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives
           Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death
    • Abstract: Publication date: Available online 7 March 2019Source: NeuronAuthor(s): Fatima Gasset-Rosa, Shan Lu, Haiyang Yu, Cong Chen, Ze’ev Melamed, Lin Guo, James Shorter, Sandrine Da Cruz, Don W. ClevelandSummaryWhile cytoplasmic aggregation of TDP-43 is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia, how aggregates form and what drives its nuclear clearance have not been determined. Here we show that TDP-43 at its endogenous level undergoes liquid-liquid phase separation (LLPS) within nuclei in multiple cell types. Increased concentration of TDP-43 in the cytoplasm or transient exposure to sonicated amyloid-like fibrils is shown to provoke long-lived liquid droplets of cytosolic TDP-43 whose assembly and maintenance are independent of conventional stress granules. Cytosolic liquid droplets of TDP-43 accumulate phosphorylated TDP-43 and rapidly convert into gels/solids in response to transient, arsenite-mediated stress. Cytoplasmic TDP-43 droplets slowly recruit importin-α and Nup62 and induce mislocalization of RanGap1, Ran, and Nup107, thereby provoking inhibition of nucleocytoplasmic transport, clearance of nuclear TDP-43, and cell death. These findings identify a neuronal cell death mechanism that can be initiated by transient-stress-induced cytosolic de-mixing of TDP-43.Graphical Graphical abstract for this article
  • Regulation of NGF Signaling by an Axonal Untranslated mRNA
    • Abstract: Publication date: Available online 7 March 2019Source: NeuronAuthor(s): Hamish Crerar, Emily Scott-Solomon, Chantal Bodkin-Clarke, Catia Andreassi, Maria Hazbon, Emilie Logie, Marifé Cano-Jaimez, Marco Gaspari, Rejji Kuruvilla, Antonella RiccioSummaryNeurons are extraordinarily large and highly polarized cells that require rapid and efficient communication between cell bodies and axons over long distances. In peripheral neurons, transcripts are transported along axons to growth cones, where they are rapidly translated in response to extrinsic signals. While studying Tp53inp2, a transcript highly expressed and enriched in sympathetic neuron axons, we unexpectedly discovered that Tp53inp2 is not translated. Instead, the transcript supports axon growth in a coding-independent manner. Increasing evidence indicates that mRNAs may function independently of their coding capacity; for example, acting as a scaffold for functionally related proteins. The Tp53inp2 transcript interacts with the nerve growth factor (NGF) receptor TrkA, regulating TrkA endocytosis and signaling. Deletion of Tp53inp2 inhibits axon growth in vivo, and the defects are rescued by a non-translatable form of the transcript. Tp53inp2 is an atypical mRNA that regulates axon growth by enhancing NGF-TrkA signaling in a translation-independent manner.Graphical Graphical abstract for this article
  • Intrinsic Variable Learning for Brain-Machine Interface Control by Human
           Anterior Intraparietal Cortex
    • Abstract: Publication date: Available online 7 March 2019Source: NeuronAuthor(s): Sofia Sakellaridi, Vassilios N. Christopoulos, Tyson Aflalo, Kelsie W. Pejsa, Emily R. Rosario, Debra Ouellette, Nader Pouratian, Richard A. AndersenSummaryAlthough animal studies provided significant insights in understanding the neural basis of learning and adaptation, they often cannot dissociate between different learning mechanisms due to the lack of verbal communication. To overcome this limitation, we examined the mechanisms of learning and its limits in a human intracortical brain-machine interface (BMI) paradigm. A tetraplegic participant controlled a 2D computer cursor by modulating single-neuron activity in the anterior intraparietal area (AIP). By perturbing the neuron-to-movement mapping, the participant learned to modulate the activity of the recorded neurons to solve the perturbations by adopting a target re-aiming strategy. However, when no cognitive strategies were adequate to produce correct responses, AIP failed to adapt to perturbations. These findings suggest that learning is constrained by the pre-existing neuronal structure, although it is possible that AIP needs more training time to learn to generate novel activity patterns when cognitive re-adaptation fails to solve the perturbations.
  • Higher-Order Thalamic Circuits Channel Parallel Streams of Visual
           Information in Mice
    • Abstract: Publication date: Available online 5 March 2019Source: NeuronAuthor(s): Corbett Bennett, Samuel D. Gale, Marina E. Garrett, Melissa L. Newton, Edward M. Callaway, Gabe J. Murphy, Shawn R. OlsenSummaryHigher-order thalamic nuclei, such as the visual pulvinar, play essential roles in cortical function by connecting functionally related cortical and subcortical brain regions. A coherent framework describing pulvinar function remains elusive because of its anatomical complexity and involvement in diverse cognitive processes. We combined large-scale anatomical circuit mapping with high-density electrophysiological recordings to dissect a homolog of the pulvinar in mice, the lateral posterior thalamic nucleus (LP). We define three broad LP subregions based on correspondence between connectivity and functional properties. These subregions form corticothalamic loops biased toward ventral or dorsal stream cortical areas and contain separate representations of visual space. Silencing the visual cortex or superior colliculus revealed that they drive visual tuning properties in separate LP subregions. Thus, by specifying the driving input sources, functional properties, and downstream targets of LP circuits, our data provide a roadmap for understanding the mechanisms of higher-order thalamic function in vision.
  • ARNT2 Tunes Activity-Dependent Gene Expression through NCoR2-Mediated
           Repression and NPAS4-Mediated Activation
    • Abstract: Publication date: Available online 4 March 2019Source: NeuronAuthor(s): Nikhil Sharma, Elizabeth A. Pollina, M. Aurel Nagy, Ee-Lynn Yap, Florence A. DiBiase, Sinisa Hrvatin, Linda Hu, Cindy Lin, Michael E. GreenbergSummaryNeuronal activity-dependent transcription is tuned to ensure precise gene induction during periods of heightened synaptic activity, allowing for appropriate responses of activated neurons within neural circuits. The consequences of aberrant induction of activity-dependent genes on neuronal physiology are not yet clear. Here, we demonstrate that, in the absence of synaptic excitation, the basic-helix-loop-helix (bHLH)-PAS family transcription factor ARNT2 recruits the NCoR2 co-repressor complex to suppress neuronal activity-dependent regulatory elements and maintain low basal levels of inducible genes. This restricts inhibition of excitatory neurons, maintaining them in a state that is receptive to future sensory stimuli. By contrast, in response to heightened neuronal activity, ARNT2 recruits the neuronal-specific bHLH-PAS factor NPAS4 to activity-dependent regulatory elements to induce transcription and thereby increase somatic inhibitory input. Thus, the interplay of bHLH-PAS complexes at activity-dependent regulatory elements maintains temporal control of activity-dependent gene expression and scales somatic inhibition with circuit activity.Graphical Graphical abstract for this article
  • Axo-axonic Innervation of Neocortical Pyramidal Neurons by GABAergic
           Chandelier Cells Requires AnkyrinG-Associated L1CAM
    • Abstract: Publication date: Available online 4 March 2019Source: NeuronAuthor(s): Yilin Tai, Nicholas B. Gallo, Minghui Wang, Jia-Ray Yu, Linda Van AelstSummaryAmong the diverse interneuron subtypes in the neocortex, chandelier cells (ChCs) are the only population that selectively innervate pyramidal neurons (PyNs) at their axon initial segment (AIS), the site of action potential initiation, allowing them to exert powerful control over PyN output. Yet, mechanisms underlying their subcellular innervation of PyN AISs are unknown. To identify molecular determinants of ChC/PyN AIS innervation, we performed an in vivo RNAi screen of PyN-expressed axonal cell adhesion molecules (CAMs) and select Ephs/ephrins. Strikingly, we found the L1 family member L1CAM to be the only molecule required for ChC/PyN AIS innervation. Further, we show that L1CAM is required during both the establishment and maintenance of innervation, and that selective innervation of PyN AISs by ChCs requires AIS anchoring of L1CAM by the cytoskeletal ankyrin-G/βIV-spectrin complex. Thus, our findings identify PyN-expressed L1CAM as a critical CAM required for innervation of neocortical PyN AISs by ChCs.Graphical Graphical abstract for this article
  • Microglial Phagocytosis of Newborn Cells Is Induced by Endocannabinoids
           and Sculpts Sex Differences in Juvenile Rat Social Play
    • Abstract: Publication date: Available online 28 February 2019Source: NeuronAuthor(s): Jonathan W. VanRyzin, Ashley E. Marquardt, Kathryn J. Argue, Haley A. Vecchiarelli, Sydney E. Ashton, Sheryl E. Arambula, Matthew N. Hill, Margaret M. McCarthySummaryBrain sex differences are established developmentally and generate enduring changes in circuitry and behavior. Steroid-mediated masculinization of the rat amygdala during perinatal development produces higher levels of juvenile rough-and-tumble play by males. This sex difference in social play is highly conserved across mammals, yet the mechanisms by which it is established are unknown. Here, we report that androgen-induced increases in endocannabinoid tone promote microglia phagocytosis during a critical period of amygdala development. Phagocytic microglia engulf more viable newborn cells in males; in females, less phagocytosis allows more astrocytes to survive to the juvenile age. Blocking complement-dependent phagocytosis in males increases astrocyte survival and prevents masculinization of play. Moreover, increased astrocyte density in the juvenile amygdala reduces neuronal excitation during play. These findings highlight novel mechanisms of brain development whereby endocannabinoids induce microglia phagocytosis to regulate newborn astrocyte number and shape the sexual differentiation of social circuitry and behavior.
  • Distinct Modes of Presynaptic Inhibition of Cutaneous Afferents and Their
           Functions in Behavior
    • Abstract: Publication date: Available online 27 February 2019Source: NeuronAuthor(s): Amanda L. Zimmerman, Eleni M. Kovatsis, Riana Y. Pozsgai, Aniqa Tasnim, Qiyu Zhang, David D. GintySummaryPresynaptic inhibition (PSI) of primary sensory neurons is implicated in controlling gain and acuity in sensory systems. Here, we define circuit mechanisms and functions of PSI of cutaneous somatosensory neuron inputs to the spinal cord. We observed that PSI can be evoked by different sensory neuron populations and mediated through at least two distinct dorsal horn circuit mechanisms. Low-threshold cutaneous afferents evoke a GABAA-receptor-dependent form of PSI that inhibits similar afferent subtypes, whereas small-diameter afferents predominantly evoke an NMDA-receptor-dependent form of PSI that inhibits large-diameter fibers. Behaviorally, loss of either GABAA receptors (GABAARs) or NMDA receptors (NMDARs) in primary afferents leads to tactile hypersensitivity across skin types, and loss of GABAARs, but not NMDARs, leads to impaired texture discrimination. Post-weaning age loss of either GABAARs or NMDARs in somatosensory neurons causes systemic behavioral abnormalities, revealing critical roles of two distinct modes of PSI of somatosensory afferents in adolescence and throughout adulthood.
  • RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43
    • Abstract: Publication date: Available online 27 February 2019Source: NeuronAuthor(s): Jacob R. Mann, Amanda M. Gleixner, Jocelyn C. Mauna, Edward Gomes, Michael R. DeChellis-Marks, Patrick G. Needham, Katie E. Copley, Bryan Hurtle, Bede Portz, Noah J. Pyles, Lin Guo, Christopher B. Calder, Zachary P. Wills, Udai B. Pandey, Julia K. Kofler, Jeffrey L. Brodsky, Amantha Thathiah, James Shorter, Christopher J. DonnellySummaryTDP-43 proteinopathy is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia where cytoplasmic TDP-43 inclusions are observed within degenerating regions of patient postmortem tissue. The mechanism by which TDP-43 aggregates has remained elusive due to technological limitations, which prevent the analysis of specific TDP-43 interactions in live cells. We present an optogenetic approach to reliably induce TDP-43 proteinopathy under spatiotemporal control. We show that the formation of pathologically relevant inclusions is driven by aberrant interactions between low-complexity domains of TDP-43 that are antagonized by RNA binding. Although stress granules are hypothesized to be a conduit for seeding TDP-43 proteinopathy, we demonstrate pathological inclusions outside these RNA-rich structures. Furthermore, we show that aberrant phase transitions of cytoplasmic TDP-43 are neurotoxic and that treatment with oligonucleotides composed of TDP-43 target sequences prevent inclusions and rescue neurotoxicity. Collectively, these studies provide insight into the mechanisms that underlie TDP-43 proteinopathy and present a potential avenue for therapeutic intervention.Graphical Graphical abstract for this article
  • Adult Neural Stem Cells and Multiciliated Ependymal Cells Share a Common
           Lineage Regulated by the Geminin Family Members
    • Abstract: Publication date: Available online 26 February 2019Source: NeuronAuthor(s): Gonzalo Ortiz-Álvarez, Marie Daclin, Asm Shihavuddin, Pauline Lansade, Aurélien Fortoul, Marion Faucourt, Solène Clavreul, Maria-Eleni Lalioti, Stavros Taraviras, Simon Hippenmeyer, Jean Livet, Alice Meunier, Auguste Genovesio, Nathalie SpasskySummaryAdult neural stem cells and multiciliated ependymal cells are glial cells essential for neurological functions. Together, they make up the adult neurogenic niche. Using both high-throughput clonal analysis and single-cell resolution of progenitor division patterns and fate, we show that these two components of the neurogenic niche are lineally related: adult neural stem cells are sister cells to ependymal cells, whereas most ependymal cells arise from the terminal symmetric divisions of the lineage. Unexpectedly, we found that the antagonist regulators of DNA replication, GemC1 and Geminin, can tune the proportion of neural stem cells and ependymal cells. Our findings reveal the controlled dynamic of the neurogenic niche ontogeny and identify the Geminin family members as key regulators of the initial pool of adult neural stem cells.
  • Parallel Multimodal Circuits Control an Innate Foraging Behavior
    • Abstract: Publication date: Available online 26 February 2019Source: NeuronAuthor(s): Alejandro López-Cruz, Aylesse Sordillo, Navin Pokala, Qiang Liu, Patrick T. McGrath, Cornelia I. BargmannSummaryForaging strategies emerge from genetically encoded programs that are similar across animal species. Here, we examine circuits that control a conserved foraging state, local search behavior after food removal, in Caenorhabditis elegans. We show that local search is triggered by two parallel groups of chemosensory and mechanosensory glutamatergic neurons that detect food-related cues. Each group of sensory neurons suppresses distinct integrating neurons through a G protein-coupled metabotropic glutamate receptor, MGL-1, to release local search. The chemosensory and mechanosensory modules are separate and redundant; glutamate release from either module can drive the full behavior. A transition from local search to global search over several minutes after food removal is associated with two changes in circuit function. First, the spontaneous activity of sensory neurons falls. Second, the motor pattern generator for local search becomes less responsive to sensory input. This multimodal, distributed short-term food memory provides robust control of an innate behavior.
  • The Mechanosensitive Ion Channel Piezo Inhibits Axon Regeneration
    • Abstract: Publication date: Available online 25 February 2019Source: NeuronAuthor(s): Yuanquan Song, Dan Li, Olivia Farrelly, Leann Miles, Feng Li, Sung Eun Kim, Tsz Y. Lo, Fei Wang, Tun Li, Katherine L. Thompson-Peer, Jiaxin Gong, Swetha E. Murthy, Bertrand Coste, Nikita Yakubovich, Ardem Patapoutian, Yang Xiang, Panteleimon Rompolas, Lily Yeh Jan, Yuh Nung JanSummaryNeurons exhibit a limited ability of repair. Given that mechanical forces affect neuronal outgrowth, it is important to investigate whether mechanosensitive ion channels may regulate axon regeneration. Here, we show that DmPiezo, a Ca2+-permeable non-selective cation channel, functions as an intrinsic inhibitor for axon regeneration in Drosophila. DmPiezo activation during axon regeneration induces local Ca2+ transients at the growth cone, leading to activation of nitric oxide synthase and the downstream cGMP kinase Foraging or PKG to restrict axon regrowth. Loss of DmPiezo enhances axon regeneration of sensory neurons in the peripheral and CNS. Conditional knockout of its mammalian homolog Piezo1 in vivo accelerates regeneration, while its pharmacological activation in vitro modestly reduces regeneration, suggesting the role of Piezo in inhibiting regeneration may be evolutionarily conserved. These findings provide a precedent for the involvement of mechanosensitive channels in axon regeneration and add a potential target for modulating nervous system repair.
  • Hippocampal Reactivation of Random Trajectories Resembling Brownian
    • Abstract: Publication date: Available online 25 February 2019Source: NeuronAuthor(s): Federico Stella, Peter Baracskay, Joseph O’Neill, Jozsef CsicsvariSummaryHippocampal activity patterns representing movement trajectories are reactivated in immobility and sleep periods, a process associated with memory recall, consolidation, and decision making. It is thought that only fixed, behaviorally relevant patterns can be reactivated, which are stored across hippocampal synaptic connections. To test whether some generalized rules govern reactivation, we examined trajectory reactivation following non-stereotypical exploration of familiar open-field environments. We found that random trajectories of varying lengths and timescales were reactivated, resembling that of Brownian motion of particles. The animals’ behavioral trajectory did not follow Brownian diffusion demonstrating that the exact behavioral experience is not reactivated. Therefore, hippocampal circuits are able to generate random trajectories of any recently active map by following diffusion dynamics. This ability of hippocampal circuits to generate representations of all behavioral outcome combinations, experienced or not, may underlie a wide variety of hippocampal-dependent cognitive functions such as learning, generalization, and planning.
  • Mouse dLGN Receives Functional Input from a Diverse Population of Retinal
           Ganglion Cells with Limited Convergence
    • Abstract: Publication date: Available online 21 February 2019Source: NeuronAuthor(s): Miroslav Román Rosón, Yannik Bauer, Ann H. Kotkat, Philipp Berens, Thomas Euler, Laura BusseSummaryMouse vision is based on the parallel output of more than 30 functional types of retinal ganglion cells (RGCs). Little is known about how representations of visual information change between retina and dorsolateral geniculate nucleus (dLGN) of the thalamus, the main relay between retina and cortex. Here, we functionally characterized responses of retrogradely labeled dLGN-projecting RGCs and dLGN neurons to the same set of visual stimuli. We found that many of the previously identified functional RGC types innervate dLGN, which maintained a high degree of functional diversity. Using a linear model to assess functional connectivity between RGC types and dLGN neurons, we found that responses of dLGN neurons could be predicted as linear combination of inputs from on average five RGC types, but only two of those had the strongest functional impact. Thus, mouse dLGN receives functional input from a diverse population of RGC types with limited convergence.
  • A Visual Circuit Related to Habenula Underlies the Antidepressive Effects
           of Light Therapy
    • Abstract: Publication date: Available online 19 February 2019Source: NeuronAuthor(s): Lu Huang, Yue Xi, Yanfang Peng, Yan Yang, Xiaodan Huang, Yunwei Fu, Qian Tao, Jia Xiao, Tifei Yuan, Kai An, Huan Zhao, Mingliang Pu, Fuqiang Xu, Tian Xue, Minmin Luo, Kwok-Fai So, Chaoran RenSummaryLight plays a pivotal role in the regulation of affective behaviors. However, the precise circuits that mediate the impact of light on depressive-like behaviors are not well understood. Here, we show that light influences depressive-like behaviors through a disynaptic circuit linking the retina and the lateral habenula (LHb). Specifically, M4-type melanopsin-expressing retinal ganglion cells (RGCs) innervate GABA neurons in the thalamic ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL), which in turn inhibit CaMKIIα neurons in the LHb. Specific activation of vLGN/IGL-projecting RGCs, activation of LHb-projecting vLGN/IGL neurons, or inhibition of postsynaptic LHb neurons is sufficient to decrease the depressive-like behaviors evoked by long-term exposure to aversive stimuli or chronic social defeat stress. Furthermore, we demonstrate that the antidepressive effects of light therapy require activation of the retina-vLGN/IGL-LHb pathway. These results reveal a dedicated retina-vLGN/IGL-LHb circuit that regulates depressive-like behaviors and provide a potential mechanistic explanation for light treatment of depression.Graphical Graphical abstract for this article
  • Spatial and Temporal Locomotor Learning in Mouse Cerebellum
    • Abstract: Publication date: Available online 19 February 2019Source: NeuronAuthor(s): Dana M. Darmohray, Jovin R. Jacobs, Hugo G. Marques, Megan R. CareySummaryStable and efficient locomotion requires the precise coordination of movement across the limbs and body. Learned changes in interlimb coordination can be induced by exposure to a split-belt treadmill that imposes different speeds under each side of the body. Here, we demonstrate locomotor learning on a split-belt treadmill in mice. Mouse locomotor adaptation is specific to measures of interlimb coordination, has spatial and temporal components that adapt at different rates, and is context specific. The many similarities between human and mouse locomotor adaptation suggest that this form of locomotor learning is highly conserved across vertebrates. Using a variety of approaches, we demonstrate that split-belt adaptation in mice specifically depends on the intermediate cerebellum but is insensitive to large lesions of the cerebral cortex. Finally, cell-type-specific chemogenetics combined with quantitative behavioral analysis reveals that spatial and temporal components of locomotor adaptation are dissociable on the circuit level.
  • Neuron-Specific Genome Modification in the Adult Rat Brain Using
           CRISPR-Cas9 Transgenic Rats
    • Abstract: Publication date: Available online 18 February 2019Source: NeuronAuthor(s): Susanne Bäck, Julie Necarsulmer, Leslie R. Whitaker, Lamarque M. Coke, Pyry Koivula, Emily J. Heathward, Lowella V. Fortuno, Yajun Zhang, C. Grace Yeh, Heather A. Baldwin, Morgan D. Spencer, Carlos A. Mejias-Aponte, James Pickel, Alexander F. Hoffman, Charles E. Spivak, Carl R. Lupica, Suzanne M. Underhill, Susan G. Amara, Andrii Domanskyi, Jenni E. AnttilaSummaryHistorically, the rat has been the preferred animal model for behavioral studies. Limitations in genome modification have, however, caused a lag in their use compared to the bevy of available transgenic mice. Here, we have developed several transgenic tools, including viral vectors and transgenic rats, for targeted genome modification in specific adult rat neurons using CRISPR-Cas9 technology. Starting from wild-type rats, knockout of tyrosine hydroxylase was achieved with adeno-associated viral (AAV) vectors expressing Cas9 or guide RNAs (gRNAs). We subsequently created an AAV vector for Cre-dependent gRNA expression as well as three new transgenic rat lines to specifically target CRISPR-Cas9 components to dopaminergic neurons. One rat represents the first knockin rat model made by germline gene targeting in spermatogonial stem cells. The rats described herein serve as a versatile platform for making cell-specific and sequence-specific genome modifications in the adult brain and potentially other Cre-expressing tissues of the rat.Graphical Graphical abstract for this article
  • Somatostatin-Expressing Interneurons Enable and Maintain
           Learning-Dependent Sequential Activation of Pyramidal Neurons
    • Abstract: Publication date: Available online 18 February 2019Source: NeuronAuthor(s): Avital Adler, Ruohe Zhao, Myung Eun Shin, Ryohei Yasuda, Wen-Biao GanSummaryThe activities of neuronal populations exhibit temporal sequences that are thought to mediate spatial navigation, cognitive processing, and motor actions. The mechanisms underlying the generation and maintenance of sequential neuronal activity remain unclear. We found that layer 2 and/or 3 pyramidal neurons (PNs) showed sequential activation in the mouse primary motor cortex during motor skill learning. Concomitantly, the activity of somatostatin (SST)-expressing interneurons increased and decreased in a task-specific manner. Activating SST interneurons during motor training, either directly or via inhibiting vasoactive-intestinal-peptide-expressing interneurons, prevented learning-induced sequential activities of PNs and behavioral improvement. Conversely, inactivating SST interneurons during the learning of a new motor task reversed sequential activities and behavioral improvement that occurred during a previous task. Furthermore, the control of SST interneurons over sequential activation of PNs required CaMKII-dependent synaptic plasticity. These findings indicate that SST interneurons enable and maintain synaptic plasticity-dependent sequential activation of PNs during motor skill learning.
  • Differential Co-release of Two Neurotransmitters from a Vesicle Fusion
           Pore in Mammalian Adrenal Chromaffin Cells
    • Abstract: Publication date: Available online 14 February 2019Source: NeuronAuthor(s): Quanfeng Zhang, Bin Liu, Qihui Wu, Bing Liu, Yinglin Li, Suhua Sun, Yuan Wang, Xi Wu, Zuying Chai, Xiaohan Jiang, Xiaoyao Liu, Meiqin Hu, Yeshi Wang, Yunting Yang, Li Wang, Xinjiang Kang, Yingfei Xiong, Yang Zhou, Xiaoke Chen, Lianghong ZhengSummaryCo-release of multiple neurotransmitters from secretory vesicles is common in neurons and neuroendocrine cells. However, whether and how the transmitters co-released from a single vesicle are differentially regulated remains unknown. In matrix-containing dense-core vesicles (DCVs) in chromaffin cells, there are two modes of catecholamine (CA) release from a single DCV: quantal and sub-quantal. By combining two microelectrodes to simultaneously record co-release of the native CA and ATP from a DCV, we report that (1) CA and ATP were co-released during a DCV fusion; (2) during kiss-and-run (KAR) fusion, the co-released CA was sub-quantal, whereas the co-released ATP was quantal; and (3) knockdown and knockout of the DCV matrix led to quantal co-release of both CA and ATP even in KAR mode. These findings strongly imply that, in contrast to sub-quantal CA release in chromaffin cells, fast synaptic transmission without transmitter-matrix binding is mediated exclusively via quantal release in neurons.
  • The Spatial Structure of Neural Encoding in Mouse Posterior Cortex during
    • Abstract: Publication date: Available online 13 February 2019Source: NeuronAuthor(s): Matthias Minderer, Kristen D. Brown, Christopher D. HarveySummaryNavigation engages many cortical areas, including visual, parietal, and retrosplenial cortices. These regions have been mapped anatomically and with sensory stimuli and studied individually during behavior. Here, we investigated how behaviorally driven neural activity is distributed and combined across these regions. We performed dense sampling of single-neuron activity across the mouse posterior cortex and developed unbiased methods to relate neural activity to behavior and anatomical space. Most parts of the posterior cortex encoded most behavior-related features. However, the relative strength with which features were encoded varied across space. Therefore, the posterior cortex could be divided into discriminable areas based solely on behaviorally relevant neural activity, revealing functional structure in association regions. Multimodal representations combining sensory and movement signals were strongest in posterior parietal cortex, where gradients of single-feature representations spatially overlapped. We propose that encoding of behavioral features is not constrained by retinotopic borders and instead varies smoothly over space within association regions.
  • Feedback-Driven Mechanisms between Microtubules and the Endoplasmic
           Reticulum Instruct Neuronal Polarity
    • Abstract: Publication date: Available online 13 February 2019Source: NeuronAuthor(s): Ginny G. Farías, Amélie Fréal, Elena Tortosa, Riccardo Stucchi, Xingxiu Pan, Sybren Portegies, Lena Will, Maarten Altelaar, Casper C. HoogenraadSummaryEstablishment of neuronal polarity depends on local microtubule (MT) reorganization. The endoplasmic reticulum (ER) consists of cisternae and tubules and, like MTs, forms an extensive network throughout the entire cell. How the two networks interact and control neuronal development is an outstanding question. Here we show that the interplay between MTs and the ER is essential for neuronal polarity. ER tubules localize within the axon, whereas ER cisternae are retained in the somatodendritic domain. MTs are essential for axonal ER tubule stabilization, and, reciprocally, the ER is required for stabilizing and organizing axonal MTs. Recruitment of ER tubules into one minor neurite initiates axon formation, whereas ER retention in the perinuclear area or disruption of ER tubules prevent neuronal polarization. The ER-shaping protein P180, present in axonal ER tubules, controls axon specification by regulating local MT remodeling. We propose a model in which feedback-driven regulation between the ER and MTs instructs neuronal polarity.
  • Cortical Areas Interact through a Communication Subspace
    • Abstract: Publication date: Available online 12 February 2019Source: NeuronAuthor(s): João D. Semedo, Amin Zandvakili, Christian K. Machens, Byron M. Yu, Adam KohnSummaryMost brain functions involve interactions among multiple, distinct areas or nuclei. For instance, visual processing in primates requires the appropriate relaying of signals across many distinct cortical areas. Yet our understanding of how populations of neurons in interconnected brain areas communicate is in its infancy. Here we investigate how trial-to-trial fluctuations of population responses in primary visual cortex (V1) are related to simultaneously recorded population responses in area V2. Using dimensionality reduction methods, we find that V1-V2 interactions occur through a communication subspace: V2 fluctuations are related to a small subset of V1 population activity patterns, distinct from the largest fluctuations shared among neurons within V1. In contrast, interactions between subpopulations within V1 are less selective. We propose that the communication subspace may be a general, population-level mechanism by which activity can be selectively routed across brain areas.
  • Multimodal Single-Cell Analysis Reveals Physiological Maturation in the
           Developing Human Neocortex
    • Abstract: Publication date: Available online 12 February 2019Source: NeuronAuthor(s): Simone Mayer, Jiadong Chen, Dmitry Velmeshev, Andreas Mayer, Ugomma C. Eze, Aparna Bhaduri, Carlos E. Cunha, Diane Jung, Arpana Arjun, Emmy Li, Beatriz Alvarado, Shaohui Wang, Nils Lovegren, Michael L. Gonzales, Lukasz Szpankowski, Anne Leyrat, Jay A.A. West, Georgia Panagiotakos, Arturo Alvarez-Buylla, Mercedes F. ParedesSummaryIn the developing human neocortex, progenitor cells generate diverse cell types prenatally. Progenitor cells and newborn neurons respond to signaling cues, including neurotransmitters. While single-cell RNA sequencing has revealed cellular diversity, physiological heterogeneity has yet to be mapped onto these developing and diverse cell types. By combining measurements of intracellular Ca2+ elevations in response to neurotransmitter receptor agonists and RNA sequencing of the same single cells, we show that Ca2+ responses are cell-type-specific and change dynamically with lineage progression. Physiological response properties predict molecular cell identity and additionally reveal diversity not captured by single-cell transcriptomics. We find that the serotonin receptor HTR2A selectively activates radial glia cells in the developing human, but not mouse, neocortex, and inhibiting HTR2A receptors in human radial glia disrupts the radial glial scaffold. We show highly specific neurotransmitter signaling during neurogenesis in the developing human neocortex and highlight evolutionarily divergent mechanisms of physiological signaling.Graphical Graphical abstract for this article
  • Punishment-Predictive Cues Guide Avoidance through Potentiation of
           Hypothalamus-to-Habenula Synapses
    • Abstract: Publication date: Available online 11 February 2019Source: NeuronAuthor(s): Massimo Trusel, Alvaro Nuno-Perez, Salvatore Lecca, Harumi Harada, Arnaud L. Lalive, Mauro Congiu, Kiwamu Takemoto, Takuya Takahashi, Francesco Ferraguti, Manuel MameliSummaryThroughout life, individuals learn to predict a punishment via its association with sensory stimuli. This process ultimately prompts goal-directed actions to prevent the danger, a behavior defined as avoidance. Neurons in the lateral habenula (LHb) respond to aversive events as well as to environmental cues predicting them, supporting LHb contribution to cue-punishment association. However, whether synaptic adaptations at discrete habenular circuits underlie such associative learning to instruct avoidance remains elusive. Here, we find that, in mice, contingent association of an auditory cue (tone) with a punishment (foot shock) progressively causes cue-driven LHb neuronal excitation during avoidance learning. This process is concomitant with the strengthening of LHb AMPA receptor-mediated neurotransmission. Such a phenomenon occludes long-term potentiation and occurs specifically at hypothalamus-to-habenula synapses. Silencing hypothalamic-to-habenulainputs or optically inactivating postsynaptic AMPA receptors within the LHb disrupts avoidance learning. Altogether, synaptic strengthening at a discrete habenular circuit transforms neutral stimuli into salient punishment-predictive cues to guide avoidance.
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Heriot-Watt University
Edinburgh, EH14 4AS, UK
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