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      Cell type–differential modulation of prefrontal cortical GABAergic interneurons on low gamma rhythm and social interaction

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          Abstract

          Prefrontal cortical PV INs and SST INs differentially regulate low gamma rhythms and social interaction behavior.

          Abstract

          Prefrontal GABAergic interneurons (INs) are crucial for social behavior by maintaining excitation/inhibition balance. However, the underlying neuronal correlates and network computations are poorly understood. We identified distinct firing patterns of prefrontal parvalbumin (PV) INs and somatostatin (SST) INs upon social interaction. Moreover, social interaction closely correlated with elevated gamma rhythms particularly at low gamma band (20 to 50 Hz). Pharmacogenetic inhibition of PV INs, instead of SST INs, reduced low gamma power and impaired sociability. Optogenetic synchronization of either PV INs or SST INs at low gamma frequency improved sociability, whereas high gamma frequency or random frequency stimulation had no effect. These results reveal a functional differentiation among IN subtypes and suggest the importance of low gamma rhythms in social interaction behavior. Furthermore, our findings underscore previously unrecognized potential of SST INs as therapeutic targets for social impairments commonly observed in major neuropsychiatric disorders.

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          Most cited references35

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          Neocortical excitation/inhibition balance in information processing and social dysfunction.

          Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30-80 Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms.
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            A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex.

            A key obstacle to understanding neural circuits in the cerebral cortex is that of unraveling the diversity of GABAergic interneurons. This diversity poses general questions for neural circuit analysis: how are these interneuron cell types generated and assembled into stereotyped local circuits and how do they differentially contribute to circuit operations that underlie cortical functions ranging from perception to cognition? Using genetic engineering in mice, we have generated and characterized approximately 20 Cre and inducible CreER knockin driver lines that reliably target major classes and lineages of GABAergic neurons. More select populations are captured by intersection of Cre and Flp drivers. Genetic targeting allows reliable identification, monitoring, and manipulation of cortical GABAergic neurons, thereby enabling a systematic and comprehensive analysis from cell fate specification, migration, and connectivity, to their functions in network dynamics and behavior. As such, this approach will accelerate the study of GABAergic circuits throughout the mammalian brain. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Abnormal neural oscillations and synchrony in schizophrenia.

              Converging evidence from electrophysiological, physiological and anatomical studies suggests that abnormalities in the synchronized oscillatory activity of neurons may have a central role in the pathophysiology of schizophrenia. Neural oscillations are a fundamental mechanism for the establishment of precise temporal relationships between neuronal responses that are in turn relevant for memory, perception and consciousness. In patients with schizophrenia, the synchronization of beta- and gamma-band activity is abnormal, suggesting a crucial role for dysfunctional oscillations in the generation of the cognitive deficits and other symptoms of the disorder. Dysfunctional oscillations may arise owing to anomalies in the brain's rhythm-generating networks of GABA (gamma-aminobutyric acid) interneurons and in cortico-cortical connections.
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                Author and article information

                Journal
                Sci Adv
                Sci Adv
                SciAdv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                July 2020
                22 July 2020
                : 6
                : 30
                : eaay4073
                Affiliations
                [1 ]Center for Neuroscience and Department of Neurology of the Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
                [2 ]Institute of Brain Science, State Key Laboratory of Medical Neurobiology, and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
                [3 ]Center for Brain Science and Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
                Author notes
                [*]

                These authors contributed equally to this work.

                []Corresponding author. Email: xuhan2014@ 123456zju.edu.cn
                Author information
                http://orcid.org/0000-0002-7016-2713
                http://orcid.org/0000-0003-1153-5329
                http://orcid.org/0000-0002-8210-8634
                http://orcid.org/0000-0002-2636-9012
                http://orcid.org/0000-0002-1119-1231
                http://orcid.org/0000-0003-2837-6264
                http://orcid.org/0000-0003-0731-6801
                http://orcid.org/0000-0002-3442-7518
                http://orcid.org/0000-0003-2106-572X
                http://orcid.org/0000-0002-0466-1821
                http://orcid.org/0000-0001-6967-9101
                Article
                aay4073
                10.1126/sciadv.aay4073
                7439507
                32832654
                a79b7368-30dd-4c9b-bb14-a69b80d461c9
                Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                : 21 July 2019
                : 05 June 2020
                Funding
                Funded by: doi http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31471025, 91432110
                Funded by: the Fundamental Research Funds for the Central Universities;
                Funded by: the National Key R&D Program of China;
                Award ID: 2016YFA0501000
                Funded by: Zhejiang Provincial Natural Science Foundation of China;
                Award ID: LR17H090002
                Funded by: The Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences;
                Award ID: 2017PT31038 and 2018PT31041
                Funded by: Chinese Ministry of Education Project 111 Program;
                Award ID: B13026
                Categories
                Research Article
                Research Articles
                SciAdv r-articles
                Neurophysiology
                Neuroscience
                Neuroscience
                Custom metadata
                Kyle Solis

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