Impact of BDNF on the Development of Social Behavior Circuits

BDNF 对社会行为回路发展的影响

基本信息

批准号：
10556426
负责人：
Francis Sang Yong Lee
金额：
$ 58.8万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10556426
关键词：
Acute Adolescence Adolescent Adolescent Development Adult Amygdaloid structure Anxiety Anxiety Disorders Behavior Behavior Therapy Behavioral Biological Assay Brain Brain region Brain-Derived Neurotrophic Factor Calcium Costs and Benefits Data Decision Making Development Disease Electrophysiology (science)Exhibits Fiber Future Genetic Growth Factor Hippocampus Human Imaging Techniques Knock-in Mouse Knockout Mice Longevity LoxP-flanked allele Medial Mediating Mental Depression Mental disorders Molecular Mood Disorders Motivation Mus Neuromodulator Neurons Neuropeptides Outcome Oxytocin Pharmacologic Substance Photometry Play Point Mutation Prefrontal Cortex Prevalence Primates Reagent Rodent Role Schizophrenia Shapes Signal Transduction Social Behavior Social Development Social Functioning Social Interaction Synaptic plasticity Techniques Testing Time Update Ventral Tegmental Area Viral Visualization Wild Type Mouse Withdrawal approach behavior autism spectrum disorder behavioral impairment behavioral outcome cell cortex common symptom critical developmental period design disabling symptom in vivo calcium imaging loss of function mutant neural correlate neuroimaging neuropsychiatric disorder nonhuman primate novel optogenetics overexpression periadolescent social social anxiety social deficits tool young adult

项目摘要

Project Summary Social behavioral impairments are common and highly disabling symptoms in many psychiatric disorders, including depression and anxiety disorders that emerge in adolescence and young adulthood. The intrinsic complexity of social behavioral outcomes have made understanding their underlying neural correlates difficult. In particular, the molecular mechanisms regulating the development and function of social behavioral circuits remain largely unknown. In this context, one potential candidate molecule is brain-derived neurotrophic factor (BDNF), a key regulator of neuronal synaptic plasticity that has been implicated in depression and anxiety disorders, and is also highly expressed in brain regions implicated in social behaviors. Our central hypothesis is that BDNF is required for the proper development during a peri-adolescent timeframe of a key orbitofrontal cortex (OFC)-to-amygdala circuit that supports social approach behavior. Multiple studies in rodents, non-human primates, and humans indicate that the OFC supports cost-benefit decision making, and encodes and updates representations of the expected value of future outcomes, suggesting that the OFC may play a role in motivating social approach behavior. Our extensive preliminary data in loss-of-function BDNF mouse lines support the premise of the requirement of BDNF in the peri-adolescent development of OFC-amygdala circuits related to social function. We propose to assess the impact of BDNF on the structural and functional development of this OFC-to-amygdala circuit during the peri-adolescent period. We will use a live calcium imaging technique (fiber photometry) to record the activity of this circuit during a repertoire of social behaviors. In addition, we will use chemogenetic tools to bi-directionally modulate the activity of these neurons and to delineate more precisely what aspects of social behavior are mediated by these OFC projections. Finally, we will utilize newly developed viral reagents for circuit-specific and developmentally-timed manipulations of BDNF signaling. Our studies are designed identify a new role for BDNF during peri-adolescence to establish optimal function of cortico-amygdala circuits related to social behaviors.

项目概要社会行为障碍是许多精神疾病中常见且高度致残的症状，包括青春期和成年早期出现的抑郁症和焦虑症。内在的社会行为结果的复杂性使得理解其潜在的神经关联变得困难。特别是调节社会行为回路的发展和功能的分子机制仍然很大程度上不为人所知。在这种情况下，一种潜在的候选分子是脑源性神经营养因子（BDNF），神经元突触可塑性的关键调节因子，与抑郁和焦虑有关疾病，并且在与社会行为有关的大脑区域也高度表达。我们的中心假设是 BDNF 是关键眶额皮质在青春期期间正常发育所必需的（OFC）到杏仁核的回路，支持社交接近行为。针对啮齿动物、非人类的多项研究灵长类动物和人类表明 OFC 支持成本效益决策，并进行编码和更新未来结果的预期值的表示，表明 OFC 可能在激励方面发挥作用社交接近行为。我们关于 BDNF 功能丧失小鼠品系的大量初步数据支持 BDNF 在与 OFC-杏仁核回路相关的青春期发育过程中需要的前提社会功能。我们建议评估 BDNF 对其结构和功能发展的影响青春期期间的 OFC 至杏仁核回路。我们将使用实时钙成像技术（纤维光度测定）来记录该电路在一系列社会行为期间的活动。此外，我们将使用化学遗传学工具可以双向调节这些神经元的活动并更精确地描绘这些 OFC 预测调节了社会行为的哪些方面。最后，我们将利用新开发的用于 BDNF 信号传导的电路特异性和发育定时操作的病毒试剂。我们的研究是旨在确定 BDNF 在青春期期间的新作用，以建立皮质杏仁核的最佳功能与社会行为相关的回路。