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Neural circuit and brain system alterations underlying social recognition memory deficits

社会认知记忆缺陷背后的神经回路和大脑系统改变

基本信息

批准号：
10410400
负责人：
Hala Harony-Nicolas
金额：
$ 42.31万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-09 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10410400
关键词：
Address Affect Axon Behavior Behavior Therapy Behavioral Brain Brain region Corpus striatum structure Data Dendrites Dense Core Vesicle Docking Electron Microscopy Etiology Exocytosis Fiber Functional disorder Genes Genetic Glutamates Hippocampus (Brain)Hormones Hypothalamic structure Impairment Individual Intervention Knowledge Lead Lentivirus Link Memory impairment Mental disorders Microdialysis Mission Modeling Molecular Mutation Neurodevelopmental Disorder Neurons Neuropeptides Outcome Oxytocin Peptides Peripheral Pharmacological Treatment Pharmacology Pharmacology Study Photometry Physiological Play Population Process Public Health Rattus Regulation Research Rodent Role Social Behavior Social Interaction Symptoms System Testing Therapeutic United States National Institutes of Health Vesicle Viral autism spectrum disorder base behavior test behavioral study cohort designer receptors exclusively activated by designer drugs experimental study glutamatergic signaling high risk immunoreactivity in vivo imaging individuals with autism spectrum disorder memory recognition molecular dynamics nerve supply neural circuit neuronal cell body paraventricular nucleus relating to nervous system risk variant social social deficits supraoptic nucleus tool trafficking

项目摘要

Abstract Social deficits are a hallmark feature of several psychiatric and neurodevelopmental disorders and are a core symptom of autism spectrum disorder. To date, behavioral therapies are the first line of intervention for treating impaired social behaviors, whereas pharmacological treatments have been ineffective at addressing this symptom domain. To inform treatment targets, there is an urgent need to understand the pathophysiology underlying social deficits. Several neural circuits and hormones involved in social behaviors have been identified and are conserved across species, e.g., the hypothalamic paraventricular nucleus and the release of the oxytocin peptide. Despite the wealth of behavioral and pharmacological studies implicating the paraventricular nucleus and oxytocin in social behavior, little is known about the effect of autism-associated mutations on the oxytocin system and whether malfunction in this system underlies social deficits in autism. Oxytocin is primarily synthesized by neurons in the paraventricular and supraoptic nuclei of the hypothalamus and is released peripherally to regulate physiological functions and centrally to modulate social behavior. Glutamatergic signaling is involved in the process of oxytocin release. Notably, mutations in the Shank3 gene, a high-risk gene for autism, perturb glutamatergic signaling in the hippocampus and striatum. However, the effect of Shank3 mutations on glutamatergic signaling and oxytocin release in the paraventricular nucleus has never been studied before. In this proposal, we study the effect of Shank3 mutations on the oxytocin system to ask how a Shank3 mutation in rats affect the activity of oxytocin neurons, glutamatergic signaling in the paraventricular nucleus, and the release of oxytocin at brain regions of social behavior. We also investigate whether the effect of Shank3 mutations on the oxytocin system underlies social behavior deficits. Our central hypothesis is that Shank3 mutations impair oxytocin release within the paraventricular nucleus and at brain regions of the social recognition circuit (Aim 1) by interfering with glutamatergic signaling and neural activity of oxytocin neurons in the paraventricular nucleus (Aim 2), leading to social recognition deficits (Aim 3). To this end, we will utilize a rat model with a Shank3 mutation and employ molecular, behavioral, and in vivo imaging experiments to capture alterations in neural activity of oxytocin neurons and identify impairments in oxytocin release during behavior. We will also employ viral-based approaches and chemo-genetic tools for neural-specific manipulations to determine causality between alteration in the oxytocin system and deficits in social behavior, caused by a Shank3 mutation. This study will lead to a clearer understanding of Shank3 function in the hypothalamic oxytocin system, which is part of a larger social brain circuit that could be targeted pharmacologically, genetically, or via circuit-specific non-invasive interventions to treat social behavior deficits in individuals with SHANK3 mutations and in individuals with autism that present similar brain alterations.

摘要