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      A limbic circuitry involved in emotional stress-induced grooming

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          Abstract

          Prolonged exposure to negative stressors could be harmful if a subject cannot respond appropriately. Strategies evolved to respond to stress, including repetitive displacement behaviours, are important in maintaining behavioural homoeostasis. In rodents, self-grooming is a frequently observed repetitive behaviour believed to contribute to post-stress de-arousal with adaptive value. Here we identified a rat limbic di-synaptic circuit that regulates stress-induced self-grooming with positive affective valence. This circuit links hippocampal ventral subiculum to ventral lateral septum (LSv) and then lateral hypothalamus tuberal nucleus. Optogenetic activation of this circuit triggers delayed but robust excessive grooming with patterns closely resembling those evoked by emotional stress. Consistently, the neural activity of LSv reaches a peak before emotional stress-induced grooming while inhibition of this circuit significantly suppresses grooming triggered by emotional stress. Our results uncover a previously unknown limbic circuitry involved in regulating stress-induced self-grooming and pinpoint a critical role of LSv in this ethologically important behaviour.

          Abstract

          Self-grooming is a frequently observed repetitive behaviour in rodents that is believed to contribute to post-stress de-arousal. The authors identified a previously unknown limbic circuit that includes the ventral lateral septum in rats and is involved in regulating stress-induced self-grooming.

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          Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

          Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. Shank3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for development of 22q13 deletion syndrome (Phelan-McDermid Syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for Shank3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic like-behaviours in mice.
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            Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response.

            The hypothalamo-pituitary-adrenocortical (HPA) axis is required for stress adaptation. Activation of the HPA axis causes secretion of glucocorticoids, which act on multiple organ systems to redirect energy resources to meet real or anticipated demand. The HPA stress response is driven primarily by neural mechanisms, invoking corticotrophin releasing hormone (CRH) release from hypothalamic paraventricular nucleus (PVN) neurons. Pathways activating CRH release are stressor dependent: reactive responses to homeostatic disruption frequently involve direct noradrenergic or peptidergic drive of PVN neurons by sensory relays, whereas anticipatory responses use oligosynaptic pathways originating in upstream limbic structures. Anticipatory responses are driven largely by disinhibition, mediated by trans-synaptic silencing of tonic PVN inhibition via GABAergic neurons in the amygdala. Stress responses are inhibited by negative feedback mechanisms, whereby glucocorticoids act to diminish drive (brainstem) and promote transsynaptic inhibition by limbic structures (e.g., hippocampus). Glucocorticoids also act at the PVN to rapidly inhibit CRH neuronal activity via membrane glucocorticoid receptors. Chronic stress-induced activation of the HPA axis takes many forms (chronic basal hypersecretion, sensitized stress responses, and even adrenal exhaustion), with manifestation dependent upon factors such as stressor chronicity, intensity, frequency, and modality. Neural mechanisms driving chronic stress responses can be distinct from those controlling acute reactions, including recruitment of novel limbic, hypothalamic, and brainstem circuits. Importantly, an individual's response to acute or chronic stress is determined by numerous factors, including genetics, early life experience, environmental conditions, sex, and age. The context in which stressors occur will determine whether an individual's acute or chronic stress responses are adaptive or maladaptive (pathological).
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              Endocrinology of the stress response.

              The stress response is subserved by the stress system, which is located both in the central nervous system and the periphery. The principal effectors of the stress system include corticotropin-releasing hormone (CRH); arginine vasopressin; the proopiomelanocortin-derived peptides alpha-melanocyte-stimulating hormone and beta-endorphin, the glucocorticoids; and the catecholamines norepinephrine and epinephrine. Appropriate responsiveness of the stress system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of tasks, and positive social interactions. By contrast, inappropriate responsiveness of the stress system may impair growth and development and may account for a number of endocrine, metabolic, autoimmune, and psychiatric disorders. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors, and the timing of the stressful events, given that prenatal life, infancy, childhood, and adolescence are critical periods characterized by increased vulnerability to stressors.
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                Author and article information

                Contributors
                Qianzhongming@fudan.edu.cn
                whyung@cuhk.edu.hk
                yake@cuhk.edu.hk
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                8 May 2020
                8 May 2020
                2020
                : 11
                : 2261
                Affiliations
                [1 ]ISNI 0000 0004 1937 0482, GRID grid.10784.3a, School of Biomedical Sciences, Faculty of Medicine, , The Chinese University of Hong Kong, Shatin, NT, ; Hong Kong SAR, China
                [2 ]ISNI 0000 0001 0125 2443, GRID grid.8547.e, Laboratory of Neuropharmacology, School of Pharmacy, , Fudan University, ; Shanghai, China
                [3 ]ISNI 0000 0004 1937 0482, GRID grid.10784.3a, Gerald Choa Neuroscience Centre, , The Chinese University of Hong Kong, Shatin, NT, ; Hong Kong SAR, China
                Author information
                http://orcid.org/0000-0003-0815-6555
                http://orcid.org/0000-0001-6266-9429
                http://orcid.org/0000-0002-9812-5690
                http://orcid.org/0000-0001-7615-3546
                http://orcid.org/0000-0002-6399-938X
                http://orcid.org/0000-0002-5542-8173
                http://orcid.org/0000-0001-8166-6653
                Article
                16203
                10.1038/s41467-020-16203-x
                7210270
                32385304
                a50fc8a1-63bc-4876-bdfa-bc50cf7ba07a
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 17 July 2019
                : 16 April 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100004853, Chinese University of Hong Kong (CUHK);
                Award ID: 7105306
                Award Recipient :
                Funded by: Hong Kong Research Grants Council
                Categories
                Article
                Custom metadata
                © The Author(s) 2020

                Uncategorized
                neural circuits,stress and resilience
                Uncategorized
                neural circuits, stress and resilience

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