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Publisher: Elsevier   (Total: 3161 journals)

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Showing 1 - 200 of 3161 Journals sorted alphabetically
A Practical Logic of Cognitive Systems     Full-text available via subscription   (Followers: 9)
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 33, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 23, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 94, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 25, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 34, 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: 411, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 27, 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: 249, 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: 6)
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: 16, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 8, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 9, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 22)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 147, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 11, SJR: 1.167, CiteScore: 4)
Advanced Powder Technology     Hybrid Journal   (Followers: 16, 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: 12, 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: 22, 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: 31, SJR: 3.043, CiteScore: 6)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 8, 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: 3)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 27, 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: 29, SJR: 1.562, CiteScore: 3)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 19, 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: 11)
Advances in Digestive Medicine     Open Access   (Followers: 9)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 24)
Advances in Ecological Research     Full-text available via subscription   (Followers: 44, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 28, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 44, 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: 56, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Genetics     Full-text available via subscription   (Followers: 16, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 8, 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: 21, 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: 8, 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: 9)
Advances in Marine Biology     Full-text available via subscription   (Followers: 16, 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: 6, 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: 21)
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: 3)
Advances in Oncobiology     Full-text available via subscription   (Followers: 1)
Advances in Organ Biology     Full-text available via subscription   (Followers: 1)
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: 24, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 10)
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: 9)
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: 18)
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: 62)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (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: 5)
Advances in Space Research     Full-text available via subscription   (Followers: 397, 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: 10, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 31, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 17)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 47, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 341, 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: 446, 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: 32, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 44, SJR: 1.272, CiteScore: 3)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 2)
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: 11, SJR: 1.153, CiteScore: 3)
Alcoholism and Drug Addiction     Open Access   (Followers: 9)
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: 11, 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: 9, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 50, 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: 50, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 54, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 45, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 10)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, 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: 28, SJR: 1.062, CiteScore: 2)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 34, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 46)
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: 205, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 62, 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: 27, SJR: 2.139, CiteScore: 4)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 28, 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: 6)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.144, CiteScore: 3)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 62, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 17, SJR: 0.411, CiteScore: 1)
Anales de Cirugia Vascular     Full-text available via subscription  
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: 177, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 11, SJR: 0.411, CiteScore: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 11)
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: 189, SJR: 1.58, CiteScore: 3)

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Journal Cover
Journal Prestige (SJR): 10.654
Citation Impact (citeScore): 11
Number of Followers: 213  
  Full-text available via subscription Subscription journal
ISSN (Print) 0896-6273 - ISSN (Online) 1097-4199
Published by Elsevier Homepage  [3161 journals]
  • Sequential Nonlinear Filtering of Local Motion Cues by Global Motion
    • Abstract: Publication date: Available online 13 September 2018Source: NeuronAuthor(s): Erin L. Barnhart, Irving E. Wang, Huayi Wei, Claude Desplan, Thomas R. ClandininSummaryMany animals guide their movements using optic flow, the displacement of stationary objects across the retina caused by self-motion. How do animals selectively synthesize a global motion pattern from its local motion components' To what extent does this feature selectivity rely on circuit mechanisms versus dendritic processing' Here we used in vivo calcium imaging to identify pre- and postsynaptic mechanisms for processing local motion signals in global motion detection circuits in Drosophila. Lobula plate tangential cells (LPTCs) detect global motion by pooling input from local motion detectors, T4/T5 neurons. We show that T4/T5 neurons suppress responses to adjacent local motion signals whereas LPTC dendrites selectively amplify spatiotemporal sequences of local motion signals consistent with preferred global patterns. We propose that sequential nonlinear suppression and amplification operations allow optic flow circuitry to simultaneously prevent saturating responses to local signals while creating selectivity for global motion patterns critical to behavior.
  • Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating
           Astrocyte-Mediated Neuroinflammation
    • Abstract: Publication date: Available online 13 September 2018Source: NeuronAuthor(s): Lige Leng, Kai Zhuang, Zeyue Liu, Changquan Huang, Yuehong Gao, Guimiao Chen, Hui Lin, Yu Hu, Di Wu, Meng Shi, Wenting Xie, Hao Sun, Zhicheng Shao, Huifang Li, Kunkun Zhang, Wei Mo, Timothy Y. Huang, Maoqiang Xue, Zengqiang Yuan, Xia ZhangSummaryAstrocyte dysfunction and inflammation are associated with the pathogenesis of major depressive disorder (MDD). However, the mechanisms underlying these effects remain largely unknown. Here, we found that multiple endocrine neoplasia type 1 (Men1; protein: menin) expression is attenuated in the brain of mice exposed to CUMS (chronic unpredictable mild stress) or lipopolysaccharide. Astrocyte-specific reduction of Men1 (GcKO) led to depressive-like behaviors in mice. We observed enhanced NF-κB activation and IL-1β production with menin deficiency in astrocytes, where depressive-like behaviors in GcKO mice were restored by NF-κB inhibitor or IL-1β receptor antagonist. Importantly, we identified a SNP, rs375804228, in human MEN1, where G503D substitution is associated with a higher risk of MDD onset. G503D substitution abolished menin-p65 interactions, thereby enhancing NF-κB activation and IL-1β production. Our results reveal a distinct astroglial role for menin in regulating neuroinflammation in depression, indicating that menin may be an attractive therapeutic target in MDD.
  • Distinct Laminar Processing of Local and Global Context in Primate Primary
           Visual Cortex
    • Abstract: Publication date: Available online 13 September 2018Source: NeuronAuthor(s): Maryam Bijanzadeh, Lauri Nurminen, Sam Merlin, Andrew M. Clark, Alessandra AngelucciSummaryVisual perception is affected by spatial context. In visual cortex, neuronal responses to stimuli inside the receptive field (RF) are suppressed by stimuli in the RF surround. To understand the circuits and cortical layers processing spatial context, we simultaneously recorded across all layers of macaque primary visual cortex while presenting stimuli at increasing distances from the recorded cells’ RF. We find that near versus far-surround stimuli activate distinct layers, thus revealing unique laminar contributions to the processing of local and global spatial context. Stimuli in the near-surround evoke the earliest subthreshold responses in superficial and upper-deep layers, and earliest suppression of spiking responses in superficial layers. Conversely, far-surround stimuli evoke the earliest subthreshold responses in feedback-recipient layer 1 and lower-deep layers, and earliest suppression of spiking responses almost simultaneously in all layers, except 4C, where suppression emerges last. Our results suggest distinct circuits for local and global signal integration.Graphical Abstract
  • Gap Junctions Contribute to Differential Light Adaptation across
           Direction-Selective Retinal Ganglion Cells
    • Abstract: Publication date: Available online 13 September 2018Source: NeuronAuthor(s): Xiaoyang Yao, Jon Cafaro, Amanda J. McLaughlin, Friso R. Postma, David L. Paul, Gautam Awatramani, Greg D. FieldSummaryDirection-selective ganglion cells (DSGCs) deliver signals from the retina to multiple brain areas to indicate the presence and direction of motion. Delivering reliable signals in response to motion is critical across light levels. Here we determine how populations of DSGCs adapt to changes in light level, from moonlight to daylight. Using large-scale measurements of neural activity, we demonstrate that the population of DSGCs switches encoding strategies across light levels. Specifically, the direction tuning of superior (upward)-preferring ON-OFF DSGCs becomes broader at low light levels, whereas other DSGCs exhibit stable tuning. Using a conditional knockout of gap junctions, we show that this differential adaptation among superior-preferring ON-OFF DSGCs is caused by connexin36-mediated electrical coupling and differences in effective GABAergic inhibition. Furthermore, this adaptation strategy is beneficial for balancing motion detection and direction estimation at the lower signal-to-noise ratio encountered at night. These results provide insights into how light adaptation impacts motion encoding in the retina.
  • FoxO Function Is Essential for Maintenance of Autophagic Flux and Neuronal
           Morphogenesis in Adult Neurogenesis
    • Abstract: Publication date: Available online 6 September 2018Source: NeuronAuthor(s): Iris Schäffner, Georgia Minakaki, M. Amir Khan, Elli-Anna Balta, Ursula Schlötzer-Schrehardt, Tobias J. Schwarz, Ruth Beckervordersandforth, Beate Winner, Ashley E. Webb, Ronald A. DePinho, Jihye Paik, Wolfgang Wurst, Jochen Klucken, D. Chichung LieSummaryAutophagy is a conserved catabolic pathway with emerging functions in mammalian neurodevelopment and human neurodevelopmental diseases. The mechanisms controlling autophagy in neuronal development are not fully understood. Here, we found that conditional deletion of the Forkhead Box O transcription factors FoxO1, FoxO3, and FoxO4 strongly impaired autophagic flux in developing neurons of the adult mouse hippocampus. Moreover, FoxO deficiency led to altered dendritic morphology, increased spine density, and aberrant spine positioning in adult-generated neurons. Strikingly, pharmacological induction of autophagy was sufficient to correct abnormal dendrite and spine development of FoxO-deficient neurons. Collectively, these findings reveal a novel link between FoxO transcription factors, autophagic flux, and maturation of developing neurons.Graphical Graphical abstract for this article
  • Cadherin Combinations Recruit Dendrites of Distinct Retinal Neurons to a
           Shared Interneuronal Scaffold
    • Abstract: Publication date: Available online 6 September 2018Source: NeuronAuthor(s): Xin Duan, Arjun Krishnaswamy, Mallory A. Laboulaye, Jinyue Liu, Yi-Rong Peng, Masahito Yamagata, Kenichi Toma, Joshua R. SanesSummaryDistinct neuronal types connect in complex ways to generate functional neural circuits. The molecular diversity required to specify this connectivity could be supplied by multigene families of synaptic recognition molecules, but most studies to date have assessed just one or a few members at a time. Here, we analyze roles of cadherins (Cdhs) in formation of retinal circuits comprising eight neuronal types that inform the brain about motion in four directions. We show that at least 15 classical Cdhs are expressed by neurons in these circuits and at least 6 (Cdh6–10 and 18) act individually or in combinations to promote specific connectivity among the cells. They act in part by directing the processes of output neurons and excitatory interneurons to a cellular scaffold formed by inhibitory interneurons. Because Cdhs are expressed combinatorially by many central neurons, similar interactions could be involved in patterning circuits throughout the brain.
  • Interplay between Oxytocin and Sensory Systems in the Orchestration of
           Socio-Emotional Behaviors
    • Abstract: Publication date: 5 September 2018Source: Neuron, Volume 99, Issue 5Author(s): Valery Grinevich, Ron StoopThe neuropeptide oxytocin (OT) attracts the interest of neuroscientists, psychologists, and psychiatrists due to its capacity to modulate emotional and social behavior. Although much has been published on the effects of OT on brain regions and mechanisms at the core of these processes, its role in sensory processing, so important for detecting social context with sufficient accuracy and sensitivity, has been much less studied. In the present review, we summarize evidence for OT modulation of sensory processing and, conversely, effects of sensory input on endogenous OT signaling. We concentrate on mammals, aiming to provide a systematic analysis of the current knowledge on this reciprocal regulation and the role it may play in social and emotional behaviors.
  • Common Variant Burden Contributes to the Familial Aggregation of Migraine
           in 1,589 Families
    • Abstract: Publication date: 5 September 2018Source: Neuron, Volume 99, Issue 5Author(s): Padhraig Gormley, Mitja I. Kurki, Marjo Eveliina Hiekkala, Kumar Veerapen, Paavo Häppölä, Adele A. Mitchell, Dennis Lal, Priit Palta, Ida Surakka, Mari Anneli Kaunisto, Eija Hämäläinen, Salli Vepsäläinen, Hannele Havanka, Hanna Harno, Matti Ilmavirta, Markku Nissilä, Erkki Säkö, Marja-Liisa Sumelahti, Jarmo Liukkonen, Matti Sillanpää
  • Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer’s
    • Abstract: Publication date: 5 September 2018Source: Neuron, Volume 99, Issue 5Author(s): Bahareh Eftekharzadeh, J. Gavin Daigle, Larisa E. Kapinos, Alyssa Coyne, Julia Schiantarelli, Yari Carlomagno, Casey Cook, Sean J. Miller, Simon Dujardin, Ana S. Amaral, Jonathan C. Grima, Rachel E. Bennett, Katharina Tepper, Michael DeTure, Charles R. Vanderburgh, Bianca T. Corjuc, Sarah L. DeVos, Jose Antonio Gonzalez, Jeannie Chew, Svetlana VidenskySummaryTau is the major constituent of neurofibrillary tangles in Alzheimer’s disease (AD), but the mechanism underlying tau-associated neural damage remains unclear. Here, we show that tau can directly interact with nucleoporins of the nuclear pore complex (NPC) and affect their structural and functional integrity. Pathological tau impairs nuclear import and export in tau-overexpressing transgenic mice and in human AD brain tissue. Furthermore, the nucleoporin Nup98 accumulates in the cell bodies of some tangle-bearing neurons and can facilitate tau aggregation in vitro. These data support the hypothesis that tau can directly interact with NPC components, leading to their mislocalization and consequent disruption of NPC function. This raises the possibility that NPC dysfunction contributes to tau-induced neurotoxicity in AD and tauopathies.Graphical Graphical abstract for this article
  • Prospection, Perseverance, and Insight in Sequential Behavior
    • Abstract: Publication date: 5 September 2018Source: Neuron, Volume 99, Issue 5Author(s): Nils Kolling, Jacqueline Scholl, Adam Chekroud, Hailey A. Trier, Matthew F.S. RushworthSummaryReal-world decisions have benefits occurring only later and dependent on additional decisions taken in the interim. We investigated this in a novel decision-making task in humans (n = 76) while measuring brain activity with fMRI (n = 24). Modeling revealed that participants computed the prospective value of decisions: they planned their future behavior taking into account how their decisions might affect which states they would encounter and how they themselves might respond in these states. They considered their own likely future behavioral biases (e.g., failure to adapt to changes in prospective value) and avoided situations in which they might be prone to such biases. Three neural networks in adjacent medial frontal regions were linked to distinct components of prospective decision making: activity in dorsal anterior cingulate cortex, area 8 m/9, and perigenual anterior cingulate cortex reflected prospective value, anticipated changes in prospective value, and the degree to which prospective value influenced decisions.
  • Mu-ming Poo
    • Abstract: Publication date: 5 September 2018Source: Neuron, Volume 99, Issue 5Author(s): Mu-ming Poo is currently working on higher cognitive functions and models of brain disorders in China, where he’s spearheaded the China Brain Project. In an interview with Neuron, he discusses the ethics of using non-human primates for research and enthuses about the potential for collaboration between AI and neuroscience researchers.
  • Carla Shatz
    • Abstract: Publication date: 5 September 2018Source: Neuron, Volume 99, Issue 5Author(s): Carla J. Shatz is interested in how precise connectivity is established during brain development. In an interview with Neuron, she shares her excitement that we might someday restore plasticity to the aging or damaged brain, and the thrill of going scientifically where few have ventured before.
  • Wilfrid Rall (1922–2018)
    • Abstract: Publication date: 5 September 2018Source: Neuron, Volume 99, Issue 5Author(s): Idan Segev, Michael Häusser, John Rinzel, Gordon M. Shepherd
  • Planning Your Way: How Humans Strategically Evaluate Prospective Decisions
    • Abstract: Publication date: 5 September 2018Source: Neuron, Volume 99, Issue 5Author(s): Adrian G. FischerWe are capable of planning ahead by incorporating dynamic factors influencing future choices. In this issue of Neuron, Kolling et al. (2018) present fMRI results of a novel task that demonstrates how humans evaluate alternative environments by prospectively incorporating their characteristics over time and account for their own decision tendencies.
  • Circuits for Raiders
    • Abstract: Publication date: 5 September 2018Source: Neuron, Volume 99, Issue 5Author(s): Gregorio Luis Galiñanes, Daniel HuberHeindorf et al. (2018) report that motor cortex plays a key role in behavioral tasks that rely on continuous sensory feedback. They propose a layer-based circuit that might be of particular importance when coping with unexpected perturbations in dynamic environments.
  • The Tau of Nuclear-Cytoplasmic Transport
    • Abstract: Publication date: 5 September 2018Source: Neuron, Volume 99, Issue 5Author(s): Evan Lester, Roy ParkerAggregation of microtubule-associated protein tau is the hallmark of tauopathies, including Alzheimer’s disease. Eftekharzadeh et al. (2018) demonstrate that pathogenic tau alters nucleocytoplasmic transport by interacting with components of the nuclear pore complex, revealing a perturbation shared by multiple neurodegenerative diseases.
  • Gyrification Needs Correct Sodium Flux!
    • Abstract: Publication date: 5 September 2018Source: Neuron, Volume 99, Issue 5Author(s): Silvia CappelloChannelopathies are disorders that affect the function of ion channels, typically resulting in epilepsy. Smith et al. (2018) discover an unusual association between SCN3A, neuronal migration, and cortical folding, outlining sodium channels as important regulators of brain development.
  • Muskelin Coordinates PrPC Lysosome versus Exosome Targeting and Impacts
           Prion Disease Progression
    • Abstract: Publication date: Available online 30 August 2018Source: NeuronAuthor(s): Frank F. Heisler, Yvonne Pechmann, Ines Wieser, Hermann C. Altmeppen, Leonhard Veenendaal, Mary Muhia, Michaela Schweizer, Markus Glatzel, Susanne Krasemann, Matthias KneusselSummaryCellular prion protein (PrPC) modulates cell adhesion and signaling in the brain. Conversion to its infectious isoform causes neurodegeneration, including Creutzfeldt-Jakob disease in humans. PrPC undergoes rapid plasma membrane turnover and extracellular release via exosomes. However, the intracellular transport of PrPC and its potential impact on prion disease progression is barely understood. Here we identify critical components of PrPC trafficking that also link intracellular and extracellular PrPC turnover. PrPC associates with muskelin, dynein, and KIF5C at transport vesicles. Notably, muskelin coordinates bidirectional PrPC transport and facilitates lysosomal degradation over exosomal PrPC release. Muskelin gene knockout consequently causes PrPC accumulation at the neuronal surface and on secreted exosomes. Moreover, prion disease onset is accelerated following injection of pathogenic prions into muskelin knockout mice. Our data identify an essential checkpoint in PrPC turnover. They propose a novel connection between neuronal intracellular lysosome targeting and extracellular exosome trafficking, relevant to the pathogenesis of neurodegenerative conditions.Graphical Graphical abstract for this article
  • Reducing Astrocyte Calcium Signaling In Vivo Alters Striatal
           Microcircuits and Causes Repetitive Behavior
    • Abstract: Publication date: Available online 30 August 2018Source: NeuronAuthor(s): Xinzhu Yu, Anna M.W. Taylor, Jun Nagai, Peyman Golshani, Christopher J. Evans, Giovanni Coppola, Baljit S. KhakhSummaryAstrocytes tile the central nervous system, but their functions in neural microcircuits in vivo and their roles in mammalian behavior remain incompletely defined. We used two-photon laser scanning microscopy, electrophysiology, MINIscopes, RNA-seq, and a genetic approach to explore the effects of reduced striatal astrocyte Ca2+ signaling in vivo. In wild-type mice, reducing striatal astrocyte Ca2+-dependent signaling increased repetitive self-grooming behaviors by altering medium spiny neuron (MSN) activity. The mechanism involved astrocyte-mediated neuromodulation facilitated by ambient GABA and was corrected by blocking astrocyte GABA transporter 3 (GAT-3). Furthermore, in a mouse model of Huntington’s disease, dysregulation of GABA and astrocyte Ca2+ signaling accompanied excessive self-grooming, which was relieved by blocking GAT-3. Assessments with RNA-seq revealed astrocyte genes and pathways regulated by Ca2+ signaling in a cell-autonomous and non-cell-autonomous manner, including Rab11a, a regulator of GAT-3 functional expression. Thus, striatal astrocytes contribute to neuromodulation controlling mouse obsessive-compulsive-like behavior.
  • Thalamocortical Axonal Activity in Motor Cortex Exhibits Layer-Specific
           Dynamics during Motor Learning
    • Abstract: Publication date: Available online 30 August 2018Source: NeuronAuthor(s): Yasuyo H. Tanaka, Yasuhiro R. Tanaka, Masashi Kondo, Shin-Ichiro Terada, Yasuo Kawaguchi, Masanori MatsuzakiSummaryThe thalamus is the hub through which neural signals are transmitted from the basal ganglia and cerebellum to the neocortex. However, thalamocortical axonal activity during motor learning remains largely undescribed. We conducted two-photon calcium imaging of thalamocortical axonal activity in the motor cortex of mice learning a self-initiated lever-pull task. Layer 1 (L1) axons came to exhibit activity at lever-pull initiation and termination, while layer 3 (L3) axons did so at lever-pull initiation. L1 population activity had a sequence structure related to both lever-pull duration and reproducibility. Stimulation of the substantia nigra pars reticulata activated more L1 than L3 axons, whereas deep cerebellar nuclei (DCN) stimulation did the opposite. Lesions to either the dorsal striatum or the DCN impaired motor learning and disrupted temporal dynamics in both layers. Thus, layer-specific thalamocortical signals evolve with the progression of learning, which requires both the basal ganglia and cerebellar activities.
  • Correlation of Synaptic Inputs in the Visual Cortex of Awake, Behaving
    • Abstract: Publication date: Available online 30 August 2018Source: NeuronAuthor(s): Sergio Arroyo, Corbett Bennett, Shaul HestrinSummaryThe subthreshold mechanisms that underlie neuronal correlations in awake animals are poorly understood. Here, we perform dual whole-cell recordings in the visual cortex (V1) of awake mice to investigate membrane potential (Vm) correlations between upper-layer sensory neurons. We find that the membrane potentials of neighboring neurons display large, correlated fluctuations during quiet wakefulness, including pairs of cells with disparate tuning properties. These fluctuations are driven by correlated barrages of excitation followed closely by inhibition (∼5-ms lag). During visual stimulation, low-frequency activity is diminished, and coherent high-frequency oscillations appear, even for non-preferred stimuli. These oscillations are generated by alternating excitatory and inhibitory inputs at a similar lag. The temporal sequence of depolarization for pairs of neurons is conserved during both spontaneous- and visually-evoked activity, suggesting a stereotyped flow of activation that may function to produce temporally precise “windows of opportunity” for additional synaptic inputs.
  • Hippocampal CB1 Receptors Control Incidental Associations
    • Abstract: Publication date: Available online 30 August 2018Source: NeuronAuthor(s): Arnau Busquets-Garcia, José F. Oliveira da Cruz, Geoffrey Terral, Antonio C. Pagano Zottola, Edgar Soria-Gómez, Andrea Contini, Hugo Martin, Bastien Redon, Marjorie Varilh, Christina Ioannidou, Filippo Drago, Federico Massa, Xavier Fioramonti, Pierre Trifilieff, Guillaume Ferreira, Giovanni MarsicanoSummaryBy priming brain circuits, associations between low-salience stimuli often guide future behavioral choices through a process known as mediated or inferred learning. However, the precise neurobiological mechanisms of these incidental associations are largely unknown. Using sensory preconditioning procedures, we show that type 1 cannabinoid receptors (CB1R) in hippocampal GABAergic neurons are necessary and sufficient for mediated but not direct learning. Deletion and re-expression of CB1R in hippocampal GABAergic neurons abolishes and rescues mediated learning, respectively. Interestingly, paired presentations of low-salience sensory cues induce a specific protein synthesis-dependent enhancement of hippocampal CB1R expression and facilitate long-term synaptic plasticity at inhibitory synapses. CB1R blockade or chemogenetic manipulations of hippocampal GABAergic neurons upon preconditioning affect incidental associations, as revealed by impaired mediated learning. Thus, CB1R-dependent control of inhibitory hippocampal neurotransmission mediates incidental associations, allowing future associative inference, a fundamental process for everyday life, which is altered in major neuropsychiatric diseases.
  • Presynaptic Biogenesis Requires Axonal Transport of Lysosome-Related
    • Abstract: Publication date: Available online 30 August 2018Source: NeuronAuthor(s): Anela Vukoja, Ulises Rey, Astrid G. Petzoldt, Christoph Ott, Dennis Vollweiter, Christine Quentin, Dymtro Puchkov, Eric Reynolds, Martin Lehmann, Svea Hohensee, Stefanie Rosa, Reinhard Lipowsky, Stephan J. Sigrist, Volker HauckeSummaryNervous system function relies on the polarized architecture of neurons, established by directional transport of pre- and postsynaptic cargoes. While delivery of postsynaptic components depends on the secretory pathway, the identity of the membrane compartment(s) supplying presynaptic active zone (AZ) and synaptic vesicle (SV) proteins is unclear. Live imaging in Drosophila larvae and mouse hippocampal neurons provides evidence that presynaptic biogenesis depends on axonal co-transport of SV and AZ proteins in presynaptic lysosome-related vesicles (PLVs). Loss of the lysosomal kinesin adaptor Arl8 results in the accumulation of SV- and AZ-protein-containing vesicles in neuronal cell bodies and a corresponding depletion of SV and AZ components from presynaptic sites, leading to impaired neurotransmission. Conversely, presynaptic function is facilitated upon overexpression of Arl8. Our data reveal an unexpected function for a lysosome-related organelle as an important building block for presynaptic biogenesis.Graphical Graphical abstract for this article
  • Generative Predictive Codes by Multiplexed Hippocampal Neuronal Tuplets
    • Abstract: Publication date: Available online 23 August 2018Source: NeuronAuthor(s): Kefei Liu, Jeremie Sibille, George DragoiSummaryRapid internal representations are continuously formed based on single experiential episodes in space and time, but the neuronal ensemble mechanisms enabling rapid encoding without constraining the capacity for multiple distinct representations are unknown. We developed a probabilistic statistical model of hippocampal spontaneous sequential activity and revealed existence of an internal model of generative predictive codes for the regularities of multiple future novel spatial sequences. During navigation, the inferred difference between external stimuli and the internal model was encoded by emergence of intrinsic-unlikely, novel functional connections, which updated the model by preferentially potentiating post-experience. This internal model and these predictive codes depended on neuronal organization into inferred modules of short, high-repeat sequential neuronal “tuplets” operating as “neuro-codons.” We propose that flexible multiplexing of neuronal tuplets into repertoires of extended sequences vastly expands the capacity of hippocampal predictive codes, which could initiate top-down hierarchical cortical loops for spatial and mental navigation and rapid learning.
  • Monitoring and Updating of Action Selection for Goal-Directed Behavior
           through the Striatal Direct and Indirect Pathways
    • Abstract: Publication date: Available online 23 August 2018Source: NeuronAuthor(s): Satoshi Nonomura, Kayo Nishizawa, Yutaka Sakai, Yasuo Kawaguchi, Shigeki Kato, Motokazu Uchigashima, Masahiko Watanabe, Ko Yamanaka, Kazuki Enomoto, Satomi Chiken, Hiromi Sano, Shogo Soma, Junichi Yoshida, Kazuyuki Samejima, Masaaki Ogawa, Kazuto Kobayashi, Atsushi Nambu, Yoshikazu Isomura, Minoru KimuraSummaryThe basal ganglia play key roles in adaptive behaviors guided by reward and punishment. However, despite accumulating knowledge, few studies have tested how heterogeneous signals in the basal ganglia are organized and coordinated for goal-directed behavior. In this study, we investigated neuronal signals of the direct and indirect pathways of the basal ganglia as rats performed a lever push/pull task for a probabilistic reward. In the dorsomedial striatum, we found that optogenetically and electrophysiologically identified direct pathway neurons encoded reward outcomes, whereas indirect pathway neurons encoded no-reward outcome and next-action selection. Outcome coding occurred in association with the chosen action. In support of pathway-specific neuronal coding, light activation induced a bias on repeat selection of the same action in the direct pathway, but on switch selection in the indirect pathway. Our data reveal the mechanisms underlying monitoring and updating of action selection for goal-directed behavior through basal ganglia circuits.
  • Defective Inflammatory Pathways in Never-Treated Depressed Patients Are
           Associated with Poor Treatment Response
    • Abstract: Publication date: Available online 23 August 2018Source: NeuronAuthor(s): Shariful A. Syed, Eléonore Beurel, David A. Loewenstein, Jeffrey A. Lowell, W. Edward Craighead, Boadie W. Dunlop, Helen S. Mayberg, Firdaus Dhabhar, W. Dalton Dietrich, Robert W. Keane, Juan Pablo de Rivero Vaccari, Charles B. NemeroffSummaryInflammation has been involved in the pathophysiology and treatment response of major depressive disorder (MDD). Plasma cytokine profiles of 171 treatment-naive MDD patients (none of the MDD patients received an adequate trial of antidepressants or evidence-based psychotherapy) and 64 healthy controls (HCs) were obtained. MDD patients exhibited elevated concentrations of 18 anti- and proinflammatory markers and decreased concentrations of 6 cytokines. Increased inflammasome protein expression was observed in MDD patients, indicative of an activated inflammatory response. The plasma of MDD patients was immunosuppressive on healthy donor peripheral blood mononuclear cells, inducing reduced activation of monocytes/dendritic cells and B cells and reduced T cell memory. Comparison between 33 non-responders and 71 responders at baseline and 12 weeks revealed that after treatment, anti-inflammatory cytokine levels increase in both groups, whereas 5 proinflammatory cytokine levels were stabilized in responders, but continued to increase in non-responders. MDD patients exhibit remodeling of their inflammatory landscape.
  • Multi-dimensional Coding by Basolateral Amygdala Neurons
    • Abstract: Publication date: Available online 23 August 2018Source: NeuronAuthor(s): Pinelopi Kyriazi, Drew B. Headley, Denis PareSummaryConditioned appetitive and aversive responses (CRs) are thought to result from the activation of specific subsets of valence-coding basolateral amygdala (BLA) neurons. Under this model, the responses of BLA cells to conditioned stimuli (CSs) and the activity that drives CRs are closely related. We tested the strength of this correlation using a task where rats could emit different CRs in response to the same CSs. At odds with this model, the CS responses and CR-related activity of individual BLA cells were separable. Moreover, while the incidence of valence-coding cells did not exceed chance, at the population level there was similarity between valence coding for CSs and CRs. In fact, both lateral and basolateral neurons concurrently encoded multiple task features and behaviors. Thus, conditioned emotional behaviors may not depend on the recruitment of single cells that explicitly encode individual task variables but from multiplexed representations distributed across the BLA.Graphical Graphical abstract for this article
  • Developmental Coordination during Olfactory Circuit Remodeling in
    • Abstract: Publication date: Available online 23 August 2018Source: NeuronAuthor(s): Oded Mayseless, Dominic S. Berns, Xiaomeng M. Yu, Thomas Riemensperger, André Fiala, Oren SchuldinerSummaryDevelopmental neuronal remodeling is crucial for proper wiring of the adult nervous system. While remodeling of individual neuronal populations has been studied, how neuronal circuits remodel—and whether remodeling of synaptic partners is coordinated—is unknown. We found that the Drosophila anterior paired lateral (APL) neuron undergoes stereotypic remodeling during metamorphosis in a similar time frame as the mushroom body (MB) ɣ-neurons, with whom it forms a functional circuit. By simultaneously manipulating both neuronal populations, we found that cell-autonomous inhibition of ɣ-neuron pruning resulted in the inhibition of APL pruning in a process that is mediated, at least in part, by Ca2+-Calmodulin and neuronal activity dependent interaction. Finally, ectopic unpruned MB ɣ axons display ectopic connections with the APL, as well as with other neurons, at the adult, suggesting that inhibiting remodeling of one neuronal type can affect the functional wiring of the entire micro-circuit.Graphical Graphical abstract for this article
  • Sodium Channel SCN3A (NaV1.3) Regulation of Human Cerebral Cortical
           Folding and Oral Motor Development
    • Abstract: Publication date: Available online 23 August 2018Source: NeuronAuthor(s): Richard S. Smith, Connor J. Kenny, Vijay Ganesh, Ahram Jang, Rebeca Borges-Monroy, Jennifer N. Partlow, R. Sean Hill, Taehwan Shin, Allen Y. Chen, Ryan N. Doan, Anna-Kaisa Anttonen, Jaakko Ignatius, Livija Medne, Carsten G. Bönnemann, Jonathan L. Hecht, Oili Salonen, A. James Barkovich, Annapurna Poduri, Martina Wilke, Marie Claire Y. de WitSummaryChannelopathies are disorders caused by abnormal ion channel function in differentiated excitable tissues. We discovered a unique neurodevelopmental channelopathy resulting from pathogenic variants in SCN3A, a gene encoding the voltage-gated sodium channel NaV1.3. Pathogenic NaV1.3 channels showed altered biophysical properties including increased persistent current. Remarkably, affected individuals showed disrupted folding (polymicrogyria) of the perisylvian cortex of the brain but did not typically exhibit epilepsy; they presented with prominent speech and oral motor dysfunction, implicating SCN3A in prenatal development of human cortical language areas. The development of this disorder parallels SCN3A expression, which we observed to be highest early in fetal cortical development in progenitor cells of the outer subventricular zone and cortical plate neurons and decreased postnatally, when SCN1A (NaV1.1) expression increased. Disrupted cerebral cortical folding and neuronal migration were recapitulated in ferrets expressing the mutant channel, underscoring the unexpected role of SCN3A in progenitor cells and migrating neurons.Graphical Graphical abstract for this article
  • Mouse Motor Cortex Coordinates the Behavioral Response to Unpredicted
           Sensory Feedback
    • Abstract: Publication date: Available online 23 August 2018Source: NeuronAuthor(s): Matthias Heindorf, Silvia Arber, Georg B. KellerSummaryMotor cortex (M1) lesions result in motor impairments, yet how M1 contributes to the control of movement remains controversial. To investigate the role of M1 in sensory guided motor coordination, we trained mice to navigate a virtual corridor using a spherical treadmill. This task required directional adjustments through spontaneous turning, while unexpected visual offset perturbations prompted induced turning. We found that M1 is essential for execution and learning of this visually guided task. Turn-selective layer 2/3 and layer 5 pyramidal tract (PT) neuron activation was shaped differentially with learning but scaled linearly with turn acceleration during spontaneous turns. During induced turns, however, layer 2/3 neurons were activated independent of behavioral response, while PT neurons still encoded behavioral response magnitude. Our results are consistent with a role of M1 in the detection of sensory perturbations that result in deviations from intended motor state and the initiation of an appropriate corrective response.
  • An Afferent Neuropeptide System Transmits Mechanosensory Signals
           Triggering Sensitization and Arousal in C. elegans
    • Abstract: Publication date: Available online 23 August 2018Source: NeuronAuthor(s): Yee Lian Chew, Yoshinori Tanizawa, Yongmin Cho, Buyun Zhao, Alex J. Yu, Evan L. Ardiel, Ithai Rabinowitch, Jihong Bai, Catharine H. Rankin, Hang Lu, Isabel Beets, William R. SchaferSummarySensitization is a simple form of behavioral plasticity by which an initial stimulus, often signaling danger, leads to increased responsiveness to subsequent stimuli. Cross-modal sensitization is an important feature of arousal in many organisms, yet its molecular and neural mechanisms are incompletely understood. Here we show that in C. elegans, aversive mechanical stimuli lead to both enhanced locomotor activity and sensitization of aversive chemosensory pathways. Both locomotor arousal and cross-modal sensitization depend on the release of FLP-20 neuropeptides from primary mechanosensory neurons and on their receptor FRPR-3. Surprisingly, the critical site of action of FRPR-3 for both sensory and locomotor arousal is RID, a single neuroendocrine cell specialized for the release of neuropeptides that responds to mechanical stimuli in a FLP-20-dependent manner. Thus, FLP-20 peptides function as an afferent arousal signal that conveys mechanosensory information to central neurons that modulate arousal and other behavioral states.
  • Coordinated Reductions in Excitatory Input to the Nucleus Accumbens
           Underlie Food Consumption
    • Abstract: Publication date: Available online 23 August 2018Source: NeuronAuthor(s): Sean J. Reed, Christopher K. Lafferty, Jesse A. Mendoza, Angela K. Yang, Thomas J. Davidson, Logan Grosenick, Karl Deisseroth, Jonathan P. BrittSummaryReward-seeking behavior is regulated by a diverse collection of inputs to the nucleus accumbens (NAc). The information encoded in each excitatory afferent to the NAc is unknown, in part because it is unclear when these pathways are active in relation to behavior. Here we compare the activity profiles of amygdala, hippocampal, and thalamic inputs to the NAc shell in mice performing a cued reward-seeking task using GCaMP-based fiber photometry. We find that the rostral and caudal ends of the NAc shell are innervated by distinct but intermingled populations of forebrain neurons that exhibit divergent feeding-related activity. In the rostral NAc shell, a coordinated network-wide reduction in excitatory drive correlates with feeding, and reduced input from individual pathways is sufficient to promote it. Overall, the data suggest that pathway-specific input activity at a population level may vary more across the NAc than between pathways.
  • Human Autoantibodies against the AMPA Receptor Subunit GluA2 Induce
           Receptor Reorganization and Memory Dysfunction
    • Abstract: Publication date: Available online 23 August 2018Source: NeuronAuthor(s): Holger Haselmann, Francesco Mannara, Christian Werner, Jesús Planagumà, Federico Miguez-Cabello, Lars Schmidl, Benedikt Grünewald, Mar Petit-Pedrol, Knut Kirmse, Joseph Classen, Fatih Demir, Nikolaj Klöcker, David Soto, Sören Doose, Josep Dalmau, Stefan Hallermann, Christian GeisSummaryAMPA receptors are essential for fast excitatory transmission in the CNS. Autoantibodies to AMPA receptors have been identified in humans with autoimmune encephalitis and severe defects of hippocampal function. Here, combining electrophysiology and high-resolution imaging with neuronal culture preparations and passive-transfer models in wild-type and GluA1-knockout mice, we analyze how specific human autoantibodies against the AMPA receptor subunit GluA2 affect receptor function and composition, synaptic transmission, and plasticity. Anti-GluA2 antibodies induce receptor internalization and a reduction of synaptic GluA2-containing AMPARs followed by compensatory ryanodine receptor-dependent incorporation of synaptic non-GluA2 AMPARs. Furthermore, application of human pathogenic anti-GluA2 antibodies to mice impairs long-term synaptic plasticity in vitro and affects learning and memory in vivo. Our results identify a specific immune-neuronal rearrangement of AMPA receptor subunits, providing a framework to explain disease symptoms.
  • Parcellating Cerebral Cortex: How Invasive Animal Studies Inform
           Noninvasive Mapmaking in Humans
    • Abstract: Publication date: 22 August 2018Source: Neuron, Volume 99, Issue 4Author(s): David C. Van Essen, Matthew F. GlasserSummaryThe cerebral cortex in mammals contains a mosaic of cortical areas that differ in function, architecture, connectivity, and/or topographic organization. A combination of local connectivity (within-area microcircuitry) and long-distance (between-area) connectivity enables each area to perform a unique set of computations. Some areas also have characteristic within-area mesoscale organization, reflecting specialized representations of distinct types of information. Cortical areas interact with one another to form functional networks that mediate behavior, and each area may be a part of multiple, partially overlapping networks. Given their importance to the understanding of brain organization, mapping cortical areas across species is a major objective of systems neuroscience and has been a century-long challenge. Here, we review recent progress in multi-modal mapping of mouse and nonhuman primate cortex, mainly using invasive experimental methods. These studies also provide a neuroanatomical foundation for mapping human cerebral cortex using noninvasive neuroimaging, including a new map of human cortical areas that we generated using a semiautomated analysis of high-quality, multimodal neuroimaging data. We contrast our semiautomated approach to human multimodal cortical mapping with various extant fully automated human brain parcellations that are based on only a single imaging modality and offer suggestions on how to best advance the noninvasive brain parcellation field. We discuss the limitations as well as the strengths of current noninvasive methods of mapping brain function, architecture, connectivity, and topography and of current approaches to mapping the brain’s functional networks.
  • A Dynamic Interplay within the Frontoparietal Network Underlies Rhythmic
           Spatial Attention
    • Abstract: Publication date: 22 August 2018Source: Neuron, Volume 99, Issue 4Author(s): Ian C. Fiebelkorn, Mark A. Pinsk, Sabine KastnerSummaryClassic studies of spatial attention assumed that its neural and behavioral effects were continuous over time. Recent behavioral studies have instead revealed that spatial attention leads to alternating periods of heightened or diminished perceptual sensitivity. Yet, the neural basis of these rhythmic fluctuations has remained largely unknown. We show that a dynamic interplay within the macaque frontoparietal network accounts for the rhythmic properties of spatial attention. Neural oscillations characterize functional interactions between the frontal eye fields (FEF) and the lateral intraparietal area (LIP), with theta phase (3–8 Hz) coordinating two rhythmically alternating states. The first is defined by FEF-dominated beta-band activity, associated with suppressed attentional shifts, and LIP-dominated gamma-band activity, associated with enhanced visual processing and better behavioral performance. The second is defined by LIP-specific alpha-band activity, associated with attenuated visual processing and worse behavioral performance. Our findings reveal how network-level interactions organize environmental sampling into rhythmic cycles.
  • Attention Cycles
    • Abstract: Publication date: 22 August 2018Source: Neuron, Volume 99, Issue 4Author(s): Rufin VanRullenCurrent evidence challenges the traditional view of attention as a continuously active spotlight, suggesting instead a rhythmic operation at around 4–8 Hz. New intracranial recordings in monkeys and humans, including two papers in this issue of Neuron, by Helfrich et al. (2018) and Fiebelkorn et al. (2018), now validate this alternative notion and characterize its oscillatory neural bases.
  • Melanopsin Shows Its (Contrast-)Sensitive Side
    • Abstract: Publication date: 22 August 2018Source: Neuron, Volume 99, Issue 4Author(s): Joseph Pottackal, Jonathan B. DembMelanopsin is a photopigment expressed by certain types of retinal ganglion cells that mediate non-image-forming visual functions, such as circadian photoentrainment. In this issue of Neuron, Sonoda et al. (2018) reveal how melanopsin also regulates the sensitivity of conventional image-forming vision.
  • Honing In on TMC as the Hair Cell’s Transduction Channel
    • Abstract: Publication date: 22 August 2018Source: Neuron, Volume 99, Issue 4Author(s): Peter G. Barr-GillespieThe identity of the inner ear’s transduction channel has bedeviled auditory neuroscientists for decades. In this issue of Neuron, Pan et al. (2018) report the most convincing evidence to date implicating the transmembrane channel-like (TMC) proteins as forming the pore of the transduction channel.
  • Bridging the Gap between Mechanics and Genetics in Cortical Folding: ECM
           as a Major Driving Force
    • Abstract: Publication date: 22 August 2018Source: Neuron, Volume 99, Issue 4Author(s): Florence Wianny, Henry Kennedy, Colette DehayFolding of the cerebral cortex results from interrelated biological and mechanical processes that are incompletely understood. In this issue, Long et al. identify the key roles of HAPLN1, lumican, collagen I, and HA in relationship with changes in tissue stiffness.
  • Neural Mechanisms of Sustained Attention Are Rhythmic
    • Abstract: Publication date: 22 August 2018Source: Neuron, Volume 99, Issue 4Author(s): Randolph F. Helfrich, Ian C. Fiebelkorn, Sara M. Szczepanski, Jack J. Lin, Josef Parvizi, Robert T. Knight, Sabine KastnerSummaryClassic models of attention suggest that sustained neural firing constitutes a neural correlate of sustained attention. However, recent evidence indicates that behavioral performance fluctuates over time, exhibiting temporal dynamics that closely resemble the spectral features of ongoing, oscillatory brain activity. Therefore, it has been proposed that periodic neuronal excitability fluctuations might shape attentional allocation and overt behavior. However, empirical evidence to support this notion is sparse. Here, we address this issue by examining data from large-scale subdural recordings, using two different attention tasks that track perceptual ability at high temporal resolution. Our results reveal that perceptual outcome varies as a function of the theta phase even in states of sustained spatial attention. These effects were robust at the single-subject level, suggesting that rhythmic perceptual sampling is an inherent property of the frontoparietal attention network. Collectively, these findings support the notion that the functional architecture of top-down attention is intrinsically rhythmic.
  • Ultrasound Produces Extensive Brain Activation via a Cochlear Pathway
    • Abstract: Publication date: 22 August 2018Source: Neuron, Volume 99, Issue 4Author(s): Hongsun Guo, Mark Hamilton II, Sarah J. Offutt, Cory D. Gloeckner, Tianqi Li, Yohan Kim, Wynn Legon, Jamu K. Alford, Hubert H. Lim
  • TMC1 Forms the Pore of Mechanosensory Transduction Channels in Vertebrate
           Inner Ear Hair Cells
    • Abstract: Publication date: 22 August 2018Source: Neuron, Volume 99, Issue 4Author(s): Bifeng Pan, Nurunisa Akyuz, Xiao-Ping Liu, Yukako Asai, Carl Nist-Lund, Kiyoto Kurima, Bruce H. Derfler, Bence György, Walrati Limapichat, Sanket Walujkar, Lahiru N. Wimalasena, Marcos Sotomayor, David P. Corey, Jeffrey R. HoltSummaryThe proteins that form the permeation pathway of mechanosensory transduction channels in inner-ear hair cells have not been definitively identified. Genetic, anatomical, and physiological evidence support a role for transmembrane channel-like protein (TMC) 1 in hair cell sensory transduction, yet the molecular function of TMC proteins remains unclear. Here, we provide biochemical evidence suggesting TMC1 assembles as a dimer, along with structural and sequence analyses suggesting similarity to dimeric TMEM16 channels. To identify the pore region of TMC1, we used cysteine mutagenesis and expressed mutant TMC1 in hair cells of Tmc1/2-null mice. Cysteine-modification reagents rapidly and irreversibly altered permeation properties of mechanosensory transduction. We propose that TMC1 is structurally similar to TMEM16 channels and includes ten transmembrane domains with four domains, S4–S7, that line the channel pore. The data provide compelling evidence that TMC1 is a pore-forming component of sensory transduction channels in auditory and vestibular hair cells.
  • Advancing Science: How Bias Holds Us Back
    • Abstract: Publication date: 22 August 2018Source: Neuron, Volume 99, Issue 4Author(s): Maria Asplund, Cristin G. WelleAs scientists and engineers, we must recognize the overwhelming evidence that we each harbor bias that influences our professional decisions. Yet, solving today’s increasingly complex public health challenges requires diverse perspectives from multidisciplinary teams. We all have the opportunity to actively promote a more representative scientific community; let’s harness the power of collective action to build diverse teams that deliver the most innovative science.
  • Inhibitory Control of Prefrontal Cortex by the Claustrum
    • Abstract: Publication date: Available online 16 August 2018Source: NeuronAuthor(s): Jesse Jackson, Mahesh M. Karnani, Boris V. Zemelman, Denis Burdakov, Albert K. LeeSummaryThe claustrum is a small subcortical nucleus that has extensive excitatory connections with many cortical areas. While the anatomical connectivity from the claustrum to the cortex has been studied intensively, the physiological effect and underlying circuit mechanisms of claustrocortical communication remain elusive. Here we show that the claustrum provides strong, widespread, and long-lasting feedforward inhibition of the prefrontal cortex (PFC) sufficient to silence ongoing neural activity. This claustrocortical feedforward inhibition was predominantly mediated by interneurons containing neuropeptide Y, and to a lesser extent those containing parvalbumin. Therefore, in contrast to other long-range excitatory inputs to the PFC, the claustrocortical pathway is designed to provide overall inhibition of cortical activity. This unique circuit organization allows the claustrum to rapidly and powerfully suppress cortical networks and suggests a distinct role for the claustrum in regulating cognitive processes in prefrontal circuits.Graphical Graphical abstract for this article
  • Timing Mechanisms Underlying Gate Control by Feedforward Inhibition
    • Abstract: Publication date: Available online 16 August 2018Source: NeuronAuthor(s): Yan Zhang, Shenbin Liu, Yu-Qiu Zhang, Martyn Goulding, Yan-Qing Wang, Qiufu MaSummaryThe gate control theory proposes that Aβ mechanoreceptor inputs to spinal pain transmission T neurons are gated via feedforward inhibition, but it remains unclear how monosynaptic excitation is gated by disynaptic inhibitory inputs that arrive later. Here we report that Aβ-evoked, non-NMDAR-dependent EPSPs in T neurons are subthreshold, allowing time for inhibitory inputs to prevent action potential firing that requires slow-onset NMDAR activation. Potassium channel activities—including IA, whose sizes are established constitutively by PreprodynorphinCre-derived inhibitory neurons—either completely filter away Aβ inputs or make them subthreshold, thereby creating a permissive condition to achieve gate control. Capsaicin-activated nociceptor inputs reduce IA and sensitize the T neurons, allowing Aβ inputs to cause firing before inhibitory inputs arrive. Thus, distinct kinetics of glutamate receptors and electric filtering by potassium channels solve the timing problem underlying the gating by feedforward inhibition, and their modulation offers a way to bypass the gate control.
  • Optogenetic Control of Synaptic AMPA Receptor Endocytosis Reveals Roles of
           LTD in Motor Learning
    • Abstract: Publication date: Available online 16 August 2018Source: NeuronAuthor(s): Wataru Kakegawa, Akira Katoh, Sakae Narumi, Eriko Miura, Junko Motohashi, Akiyo Takahashi, Kazuhisa Kohda, Yugo Fukazawa, Michisuke Yuzaki, Shinji MatsudaSummaryLong-term depression (LTD) of AMPA-type glutamate receptor (AMPA receptor)-mediated synaptic transmission has been proposed as a cellular substrate for learning and memory. Although activity-induced AMPA receptor endocytosis is believed to underlie LTD, it remains largely unclear whether LTD and AMPA receptor endocytosis at specific synapses are causally linked to learning and memory in vivo. Here we developed a new optogenetic tool, termed PhotonSABER, which enabled the temporal, spatial, and cell-type-specific control of AMPA receptor endocytosis at active synapses, while the basal synaptic properties and other forms of synaptic plasticity were unaffected. We found that fiberoptic illumination to Purkinje cells expressing PhotonSABER in vivo inhibited cerebellar motor learning during adaptation of the horizontal optokinetic response and vestibulo-ocular reflex, as well as synaptic AMPA receptor decrease in the flocculus. Our results demonstrate that LTD and AMPA receptor endocytosis at specific neuronal circuits were directly responsible for motor learning in vivo.Graphical Graphical abstract for this article
  • Mechanisms of Channel Block in Calcium-Permeable AMPA Receptors
    • Abstract: Publication date: Available online 16 August 2018Source: NeuronAuthor(s): Edward C. Twomey, Maria V. Yelshanskaya, Alexander A. Vassilevski, Alexander I. SobolevskySummaryAMPA receptors mediate fast excitatory neurotransmission and are critical for CNS development and function. Calcium-permeable subsets of AMPA receptors are strongly implicated in acute and chronic neurological disorders. However, despite the clinical importance, the therapeutic landscape for specifically targeting them, and not the calcium-impermeable AMPA receptors, remains largely undeveloped. To address this problem, we used cryo-electron microscopy and electrophysiology to investigate the mechanisms by which small-molecule blockers selectively inhibit ion channel conductance in calcium-permeable AMPA receptors. We determined the structures of calcium-permeable GluA2 AMPA receptor complexes with the auxiliary subunit stargazin bound to channel blockers, including the orb weaver spider toxin AgTx-636, the spider toxin analog NASPM, and the adamantane derivative IEM-1460. Our structures provide insights into the architecture of the blocker binding site and the mechanism of trapping, which are critical for development of small molecules that specifically target calcium-permeable AMPA receptors.Graphical Graphical abstract for this article
  • Transforming Sensory Cues into Aversive Emotion via Septal-Habenular
    • Abstract: Publication date: Available online 16 August 2018Source: NeuronAuthor(s): Guang-Wei Zhang, Li Shen, Wen Zhong, Ying Xiong, Li I. Zhang, Huizhong W. TaoSummaryEmotions evoked by environmental cues are important for animal survival and life quality. However, neural circuits responsible for transforming sensory signals to aversive emotion and behavioral avoidance remain unclear. Here, we found that medial septum (MS) mediates aversion induced by both auditory and somatosensory stimuli. Ablation of glutamatergic or GABAergic MS neurons results in impaired or strengthened aversion, respectively. Optogenetic activation of the two cell types results in place avoidance and preference, respectively. Cell-type-specific screening reveals that glutamatergic MS projections to the lateral habenula (LHb) are responsible for the induction of aversion, which can be antagonized by GABAergic MS projections to LHb. Additionally, the sensory-induced place avoidance is facilitated by enhanced locomotion mediated by glutamatergic MS projections to the preoptic area. Thus, MS can transmit innately aversive signals via a bottom-up multimodal sensory pathway and produce concurrent emotional and motional effects, allowing animals to efficiently avoid unfavorable environments.
  • Counterfactual Reasoning Underlies the Learning of Priors in Decision
    • Abstract: Publication date: Available online 16 August 2018Source: NeuronAuthor(s): Ariel Zylberberg, Daniel M. Wolpert, Michael N. ShadlenSummaryAccurate decisions require knowledge of prior probabilities (e.g., prevalence or base rate), but it is unclear how prior probabilities are learned in the absence of a teacher. We hypothesized that humans could learn base rates from experience making decisions, even without feedback. Participants made difficult decisions about the direction of dynamic random dot motion. Across blocks of 15–42 trials, the base rate favoring left or right varied. Participants were not informed of the base rate or choice accuracy, yet they gradually biased their choices and thereby increased accuracy and confidence in their decisions. They achieved this by updating knowledge of base rate after each decision, using a counterfactual representation of confidence that simulates a neutral prior. The strategy is consistent with Bayesian updating of belief and suggests that humans represent both true confidence, which incorporates the evolving belief of the prior, and counterfactual confidence, which discounts the prior.
  • The Locus Coeruleus Is a Complex and Differentiated Neuromodulatory System
    • Abstract: Publication date: Available online 16 August 2018Source: NeuronAuthor(s): Nelson K. Totah, Ricardo M. Neves, Stefano Panzeri, Nikos K. Logothetis, Oxana EschenkoSummaryDiffuse projections of locus coeruleus (LC) neurons and evidence of synchronous spiking have long been perceived as features of global neuromodulation. Recent studies demonstrated the possibility of targeted modulation by subsets of LC neurons. Non-global neuromodulation depends on target specificity and the differentiated spatiotemporal dynamics within LC. Here, we characterized interactions between 3,164 LC cell pairs in the rat LC under urethane anesthesia. Spike count correlations were near zero and only a small proportion of unit pairs had synchronized spontaneous (15%) or evoked (16%) discharge. We identified infra-slow (0.01–1 Hz) fluctuations of LC unit spike rate, which were also asynchronous across the population. Despite overall sparse population synchrony, we report the existence of LC ensembles and relate them to forebrain projection targets. We also show that spike waveform width was related to ensemble membership, propensity for synchronization, and interactions with cortex. Our findings suggest a partly differentiated and target-specific noradrenergic signal.
  • Two Forms of Synaptic Depression Produced by Differential Neuromodulation
           of Presynaptic Calcium Channels
    • Abstract: Publication date: Available online 16 August 2018Source: NeuronAuthor(s): Kenneth J. Burke, Caroline M. Keeshen, Kevin J. BenderSummaryNeuromodulators are important regulators of synaptic transmission throughout the brain. At the presynaptic terminal, neuromodulation of calcium channels (CaVs) can affect transmission not only by changing neurotransmitter release probability, but also by shaping short-term plasticity (STP). Indeed, changes in STP are often considered a requirement for defining a presynaptic site of action. Nevertheless, some synapses exhibit non-canonical forms of neuromodulation, where release probability is altered without a corresponding change in STP. Here, we identify biophysical mechanisms whereby both canonical and non-canonical presynaptic neuromodulation can occur at the same synapse. At a subset of glutamatergic terminals in prefrontal cortex, GABAB and D1/D5 dopamine receptors suppress release probability with and without canonical increases in short-term facilitation by modulating different aspects of presynaptic CaV function. These findings establish a framework whereby signaling from multiple neuromodulators can converge on presynaptic CaVs to differentially tune release dynamics at the same synapse.Graphical Graphical abstract for this article
  • Graded Control of Climbing-Fiber-Mediated Plasticity and Learning by
           Inhibition in the Cerebellum
    • Abstract: Publication date: Available online 16 August 2018Source: NeuronAuthor(s): Matthew J.M. Rowan, Audrey Bonnan, Ke Zhang, Samantha B. Amat, Chikako Kikuchi, Hiroki Taniguchi, George J. Augustine, Jason M. ChristieSummaryPurkinje cell dendrites convert excitatory climbing fiber input into signals that instruct plasticity and motor learning. Modulation of instructive signaling may increase the range in which learning is encoded, yet the mechanisms that allow for this are poorly understood. We found that optogenetic activation of molecular layer interneurons (MLIs) that inhibit Purkinje cells suppressed climbing-fiber-evoked dendritic Ca2+ spiking. Inhibitory suppression of Ca2+ spiking depended on the level of MLI activation and influenced the induction of associative synaptic plasticity, converting climbing-fiber-mediated potentiation of parallel fiber-evoked responses into depression. In awake mice, optogenetic activation of floccular climbing fibers in association with head rotation produced an adaptive increase in the vestibulo-ocular reflex (VOR). However, when climbing fibers were co-activated with MLIs, adaptation occurred in the opposite direction, decreasing the VOR. Thus, MLIs can direct a continuous spectrum of plasticity and learning through their influence on Purkinje cell dendritic Ca2+ signaling.
  • A Highly Sensitive A-Kinase Activity Reporter for Imaging Neuromodulatory
           Events in Awake Mice
    • Abstract: Publication date: Available online 9 August 2018Source: NeuronAuthor(s): Lei Ma, Bart C. Jongbloets, Wei-Hong Xiong, Joshua B. Melander, Maozhen Qin, Tess J. Lameyer, Madeleine F. Harrison, Boris V. Zemelman, Tianyi Mao, Haining ZhongSummaryNeuromodulation imposes powerful control over brain function, and cAMP-dependent protein kinase (PKA) is a central downstream mediator of multiple neuromodulators. Although genetically encoded PKA sensors have been developed, single-cell imaging of PKA activity in living mice has not been established. Here, we used two-photon fluorescence lifetime imaging microscopy (2pFLIM) to visualize genetically encoded PKA sensors in response to the neuromodulators norepinephrine and dopamine. We screened available PKA sensors for 2pFLIM and further developed a variant (named tAKARα) with increased sensitivity and a broadened dynamic range. This sensor allowed detection of PKA activation by norepinephrine at physiologically relevant concentrations and kinetics, and by optogenetically released dopamine. In vivo longitudinal 2pFLIM imaging of tAKARα tracked bidirectional PKA activities in individual neurons in awake mice and revealed neuromodulatory PKA events that were associated with wakefulness, pharmacological manipulation, and locomotion. This new sensor combined with 2pFLIM will enable interrogation of neuromodulation-induced PKA signaling in awake animals.
  • Striatal Microstimulation Induces Persistent and Repetitive Negative
           Decision-Making Predicted by Striatal Beta-Band Oscillation
    • Abstract: Publication date: Available online 9 August 2018Source: NeuronAuthor(s): Ken-ichi Amemori, Satoko Amemori, Daniel J. Gibson, Ann M. GraybielSummaryPersistent thoughts inducing irrationally pessimistic and repetitive decisions are often symptoms of mood and anxiety disorders. Regional neural hyperactivities have been associated with these disorders, but it remains unclear whether there is a specific brain region causally involved in these persistent valuations. Here, we identified potential sources of such persistent states by microstimulating the striatum of macaques performing a task by which we could quantitatively estimate their subjective pessimistic states using their choices to accept or reject conflicting offers. We found that this microstimulation induced irrationally repetitive choices with negative evaluations. Local field potentials recorded in the same microstimulation sessions exhibited modulations of beta-band oscillatory activity that paralleled the persistent negative states influencing repetitive decisions. These findings demonstrate that local striatal zones can causally affect subjective states influencing persistent negative valuation and that abnormal beta-band oscillations can be associated with persistency in valuation accompanied by an anxiety-like state.
  • Behavioral Strategy Determines Frontal or Posterior Location of Short-Term
           Memory in Neocortex
    • Abstract: Publication date: Available online 9 August 2018Source: NeuronAuthor(s): Ariel Gilad, Yasir Gallero-Salas, Dominik Groos, Fritjof HelmchenSummaryThe location of short-term memory in mammalian neocortex remains elusive. Here we show that distinct neocortical areas maintain short-term memory depending on behavioral strategy. Using wide-field and single-cell calcium imaging, we measured layer 2/3 neuronal activity in mice performing a whisker-based texture discrimination task with delayed response. Mice either deployed an active strategy—engaging their body toward the approaching texture—or passively awaited the touch. Independent of strategy, whisker-related posterior areas encoded choice early after touch. During the delay, in contrast, persistent cortical activity was located medio-frontally in active trials but in a lateral posterior area in passive trials. Perturbing these areas impaired performance for the associated strategy and also provoked strategy switches. Frontally maintained information related to future action, whereas activity in the posterior cortex reflected past stimulus identity. Thus, depending on behavioral strategy, cortical activity is routed differentially to hold information either frontally or posteriorly before converging to similar action.Graphical Graphical abstract for this article
  • Architecture of the Mouse Brain Synaptome
    • Abstract: Publication date: Available online 2 August 2018Source: NeuronAuthor(s): Fei Zhu, Mélissa Cizeron, Zhen Qiu, Ruth Benavides-Piccione, Maksym V. Kopanitsa, Nathan G. Skene, Babis Koniaris, Javier DeFelipe, Erik Fransén, Noboru H. Komiyama, Seth G.N. GrantSummarySynapses are found in vast numbers in the brain and contain complex proteomes. We developed genetic labeling and imaging methods to examine synaptic proteins in individual excitatory synapses across all regions of the mouse brain. Synapse catalogs were generated from the molecular and morphological features of a billion synapses. Each synapse subtype showed a unique anatomical distribution, and each brain region showed a distinct signature of synapse subtypes. Whole-brain synaptome cartography revealed spatial architecture from dendritic to global systems levels and previously unknown anatomical features. Synaptome mapping of circuits showed correspondence between synapse diversity and structural and functional connectomes. Behaviorally relevant patterns of neuronal activity trigger spatiotemporal postsynaptic responses sensitive to the structure of synaptome maps. Areas controlling higher cognitive function contain the greatest synapse diversity, and mutations causing cognitive disorders reorganized synaptome maps. Synaptome technology and resources have wide-ranging application in studies of the normal and diseased brain.Graphical Graphical abstract for this article
  • Parvalbumin-Interneuron Output Synapses Show Spike-Timing-Dependent
           Plasticity that Contributes to Auditory Map Remodeling
    • Abstract: Publication date: Available online 2 August 2018Source: NeuronAuthor(s): Evan D. Vickers, Christopher Clark, Denys Osypenko, Alex Fratzl, Olexiy Kochubey, Bernhard Bettler, Ralf SchneggenburgerSummaryParvalbumin (PV)-expressing interneurons mediate fast inhibition of principal neurons in many brain areas; however, long-term plasticity at PV-interneuron output synapses has been less well studied. In the auditory cortex, thalamic inputs drive reliably timed action potentials (APs) in principal neurons and PV-interneurons. Using paired recordings in the input layer of the mouse auditory cortex, we found a marked spike-timing-dependent plasticity (STDP) at PV-interneuron output synapses. Long-term potentiation of inhibition (iLTP) is observed upon postsynaptic (principal neuron) then presynaptic (PV-interneuron) AP firing. The opposite AP order causes GABAB-mediated long-term depression of inhibition (iLTD), which is developmentally converted to iLTP in an experience-dependent manner. Genetic deletion of GABAB receptors in principal neurons suppressed iLTD and produced deficits in auditory map remodeling. Output synapses of PV-interneurons thus show marked STDP, and one limb of this plasticity, GABAB-dependent iLTD, is a candidate mechanism for disinhibition during auditory critical period plasticity.
  • Extracellular Matrix Components HAPLN1, Lumican, and Collagen I Cause
           Hyaluronic Acid-Dependent Folding of the Developing Human Neocortex
    • Abstract: Publication date: Available online 2 August 2018Source: NeuronAuthor(s): Katherine R. Long, Ben Newland, Marta Florio, Nereo Kalebic, Barbara Langen, Anna Kolterer, Pauline Wimberger, Wieland B. HuttnerSummaryNeocortical expansion, thought to underlie the cognitive traits unique to humans, is accompanied by cortical folding. This folding starts around gestational week (GW) 20, but what causes it remains largely unknown. Extracellular matrix (ECM) has been previously implicated in neocortical expansion and here we investigate the potential role of ECM in the formation of neocortical folds. We focus on three specific ECM components localized in the human fetal cortical plate (CP): hyaluronan and proteoglycan link protein 1 (HAPLN1), lumican and collagen I (collectively, HLC). Addition of HLC to cultures of human fetal neocortex (11–22 GW) caused local changes in tissue stiffness, induced CP folding, increased CP hyaluronic acid (HA), and required the HA-receptor CD168 and downstream ERK signaling. Importantly, loss of HA reduced HLC-induced and 22 GW physiological nascent folds. This was altered in samples with neurodevelopmental disorders, indicating it may be a useful system to study such disorders.Graphical Graphical abstract for this article
  • Enhancing Oligodendrocyte Myelination Rescues Synaptic Loss and Improves
           Functional Recovery after Chronic Hypoxia
    • Abstract: Publication date: Available online 2 August 2018Source: NeuronAuthor(s): Fei Wang, Yu-Jian Yang, Nian Yang, Xian-Jun Chen, Nan-Xin Huang, Jun Zhang, Yi Wu, Zhi Liu, Xing Gao, Tao Li, Guang-Qiang Pan, Shu-Bao Liu, Hong-Li Li, Stephen P.J. Fancy, Lan Xiao, Jonah R. Chan, Feng MeiSummaryTo address the significance of enhancing myelination for functional recovery after white matter injury (WMI) in preterm infants, we characterized hypomyelination associated with chronic hypoxia and identified structural and functional deficits of excitatory cortical synapses with a prolonged motor deficit. We demonstrate that genetically delaying myelination phenocopies the synaptic and functional deficits observed in mice after hypoxia, suggesting that myelination may possibly facilitate excitatory presynaptic innervation. As a gain-of-function experiment, we specifically ablated the muscarinic receptor 1 (M1R), a negative regulator of oligodendrocyte differentiation in oligodendrocyte precursor cells. Genetically enhancing oligodendrocyte differentiation and myelination rescued the synaptic loss after chronic hypoxia and promoted functional recovery. As a proof of concept, drug-based myelination therapies also resulted in accelerated differentiation and myelination with functional recovery after chronic hypoxia. Together, our data indicate that myelination-enhancing strategies in preterm infants may represent a promising therapeutic approach for structural/functional recovery after hypoxic WMI.Graphical Graphical abstract for this article
  • A Mirror-Symmetric Excitatory Link Coordinates Odor Maps across Olfactory
           Bulbs and Enables Odor Perceptual Unity
    • Abstract: Publication date: Available online 2 August 2018Source: NeuronAuthor(s): Mark Grobman, Tal Dalal, Hagar Lavian, Ronit Shmuel, Katya Belelovsky, Fuqiang Xu, Alon Korngreen, Rafi HaddadSummarySensory input reaching the brain from bilateral and offset channels is nonetheless perceived as unified. This unity could be explained by simultaneous projections to both hemispheres, or inter-hemispheric information transfer between sensory cortical maps. Odor input, however, is not topographically organized, nor does it project bilaterally, making olfactory perceptual unity enigmatic. Here we report a circuit that interconnects mirror-symmetric isofunctional mitral/tufted cells between the mouse olfactory bulbs. Connected neurons respond to similar odors from ipsi- and contra-nostrils, whereas unconnected neurons do not respond to odors from the contralateral nostril. This connectivity is likely mediated through a one-to-one mapping from mitral/tufted neurons to the ipsilateral anterior olfactory nucleus pars externa, which activates the mirror-symmetric isofunctional mitral/tufted neurons glutamatergically. This circuit enables sharing of odor information across hemispheres in the absence of a cortical topographical organization, suggesting that olfactory glomerular maps are the equivalent of cortical sensory maps found in other senses.
  • NonA and CPX Link the Circadian Clockwork to Locomotor Activity in
    • Abstract: Publication date: Available online 26 July 2018Source: NeuronAuthor(s): Weifei Luo, Fang Guo, Aoife McMahon, Shalise Couvertier, Hua Jin, Madelen Diaz, Allegra Fieldsend, Eranthie Weerapana, Michael RosbashSummaryDrosophila NonA and its mammalian ortholog NONO are members of the Drosophila behavior and human splicing (DBHS) family. NONO also has a strong circadian connection: it associates with the circadian repressor protein PERIOD (PER) and contributes to circadian timekeeping. Here, we investigate NonA, which is required for proper levels of evening locomotor activity as well as a normal free-running period in Drosophila. NonA is associated with the positive transcription factor CLOCK/CYCLE (CLK/CYC), interacts directly with complexin (cpx) pre-mRNA, and upregulates gene expression, including the gene cpx. Downregulation of cpx expression in circadian neurons phenocopies NonA downregulation, whereas cpx overexpression rescues the nonA RNAi phenotypes, indicating that cpx is an important NonA target gene. As the cpx protein contributes to proper neurotransmitter and neuropeptide release in response to calcium, these results and others indicate that this control is important for the normal circadian regulation of locomotor activity.
  • Linear Summation Underlies Direction Selectivity in Drosophila
    • Abstract: Publication date: Available online 26 July 2018Source: NeuronAuthor(s): Carl F.R. Wienecke, Jonathan C.S. Leong, Thomas R. ClandininSummaryWhile linear mechanisms lay the foundations of feature selectivity in many brain areas, direction selectivity in the elementary motion detector (EMD) of the fly has become a paradigm of nonlinear neuronal computation. We have bridged this divide by demonstrating that linear spatial summation can generate direction selectivity in the fruit fly Drosophila. Using linear systems analysis and two-photon imaging of a genetically encoded voltage indicator, we measure the emergence of direction-selective (DS) voltage signals in the Drosophila OFF pathway. Our study is a direct, quantitative investigation of the algorithm underlying directional signals, with the striking finding that linear spatial summation is sufficient for the emergence of direction selectivity. A linear stage of the fly EMD strongly resembles similar computations in vertebrate visual cortex, demands a reappraisal of the role of upstream nonlinearities, and implicates the voltage-to-calcium transformation in the refinement of feature selectivity in this system.
  • Melanopsin Phototransduction Is Repurposed by ipRGC Subtypes to Shape the
           Function of Distinct Visual Circuits
    • Abstract: Publication date: Available online 12 July 2018Source: NeuronAuthor(s): Takuma Sonoda, Seul Ki Lee, Lutz Birnbaumer, Tiffany M. SchmidtSummaryMelanopsin is expressed in distinct types of intrinsically photosensitive retinal ganglion cells (ipRGCs), which drive behaviors from circadian photoentrainment to contrast detection. A major unanswered question is how the same photopigment, melanopsin, influences such vastly different functions. Here we show that melanopsin’s role in contrast detection begins in the retina, via direct effects on M4 ipRGC (ON alpha RGC) signaling. This influence persists across an unexpectedly wide range of environmental light levels ranging from starlight to sunlight, which considerably expands the functional reach of melanopsin on visual processing. Moreover, melanopsin increases the excitability of M4 ipRGCs via closure of potassium leak channels, a previously unidentified target of the melanopsin phototransduction cascade. Strikingly, this mechanism is selective for image-forming circuits, as M1 ipRGCs (involved in non-image forming behaviors), exhibit a melanopsin-mediated decrease in excitability. Thus, melanopsin signaling is repurposed by ipRGC subtypes to shape distinct visual behaviors.Graphical Graphical abstract for this article
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