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.

项目摘要社会行为障碍是许多精神疾病中常见且高度残疾的症状，包括在青春期和成年后出现的抑郁症和焦虑症。固有的社会行为结果的复杂性使他们了解其潜在的神经相关性很难。特别是，调节社会行为回路的发展和功能的分子机制在很大程度上未知。在这种情况下，一个潜在的候选分子是脑衍生的神经营养因子（BDNF），神经元突触可塑性的关键调节剂，与抑郁症和焦虑有关疾病，并且在与社会行为有关的大脑区域中也高度表达。我们的中心假设是在钥匙眶额皮质的围周期间，该BDNF是正确开发所必需的（OFC） - 支持社会方法行为的至杏仁核电路。对啮齿动物的多次研究，非人类灵长类动物，人类表示OFC支持成本效益决策，并编码和更新未来结果的预期价值的表示，表明OFC可能在激励中发挥作用社会方法行为。我们在功能丧失bdnf小鼠线中的广泛初步数据支持 BDNF要求在与A-Amygdala电路的围场发展中的需求前提社会功能。我们建议评估BDNF对此的结构和功能发展的影响在围场期间OFC到杏仁核电路。我们将使用实时钙成像技术（纤维光度法）记录在社会行为曲目中该电路的活动。此外，我们将使用化学发生工具以调节这些神经元的活性并更精确地描绘这些OFC预测介导了社会行为的哪些方面。最后，我们将利用新开发 BDNF信号传导的电路特异性和开发时期操作的病毒试剂。我们的研究是设计的确定在青春期期间BDNF的新作用，以建立Cortico-Amygdala的最佳功能与社会行为有关的电路。