Synaptic and Genetic Mechanisms of Sex-Specific Effects of Stress

压力的性别特异性影响的突触和遗传机制

基本信息

批准号：
10551274
负责人：
Zhen Yan
金额：
$ 50.21万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-05 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10551274
关键词：
Address Adolescent Aggressive behavior Amygdaloid structure Animal Model Animals Anxiety Disorders Behavioral Behavioral Assay Behavioral Symptoms Brain Calcium Signaling Child Chronic Chronic stress Complex Depressive disorder Development Electrophysiology (science)Emotional Exposure to Female Functional disorder Gene Expression Gene Mutation Gene Transfer Genetic Goals Homeostasis Hormonal Hormones Human Hyperactivity Impulsivity Longevity Mediating Mental Depression Mental disorders Messenger RNA Modeling Molecular Mood Disorders Mus Neurons Pathway interactions Performance Phenotype Physiological Play Precision therapeutics Prefrontal Cortex Prevalence Puberty Role Slice Social isolation Stress Symptoms Synapses Synaptic Transmission Techniques Testing Ventral Tegmental Area Violence Viral Weaning Withdrawal Woman antisocial behavior behavioral impairment behavioral phenotyping early life adversity early life stress emotional neglect genetic technology in vivo insight male men neglect neural neuronal circuitry neuronal excitability novel optogenetics patch clamp sex sexual dimorphism social social contact social exclusion stressor transcriptome sequencing

项目摘要

Summary Stress hormones elicit profound and complex effects throughout the lifespan, and adolescent brain is particularly sensitive to stressors. One important but understudied question is the sexually dimorphic effects of early life stress. Using mice exposed to prolonged post-weaning social isolation stress, we have found distinct behavioral phenotypes that are reminiscent to human symptoms - elevated aggression in males, and diminished sociability in females. The goal of this project is to understand the physiological and molecular mechanisms underlying the sex-specific divergent effects of chronic adolescent isolation stress. We hypothesize that circuit-specific alterations of neuronal functions in stressed males and females, which are driven by circuit-specific changes in gene expression, mediate the sexually dimorphic consequences of early life stress. To test this, we will use the combination of cutting-edge techniques to address three Specific Aims: (1) To identify differential behavioral and physiological changes induced by stress in male and female mice. A battery of behavioral assays will be made to identify stress-induced phenotypes in both sexes. Slice recordings of synaptic currents and in vivo multichannel recordings of neuronal activity in behaving animals will be performed to examine the involvement of prefrontal cortex (PFC), basolateral amygdala (BLA) and ventral tegmental area (VTA) in the heightened aggression in stressed males and diminished sociability in stressed females. (2) To determine neuronal circuits mediating differential effects of stress in male and female mice. By combining chemogenetic technology to manipulate neuronal activity in specific brain circuits with in vivo recordings of calcium signal and neuronal spikes in behaving animals, we will examine whether the disturbed PFCBLA and PFCVTA pathway after chronic isolation stress plays a causal role in controlling the sexually dimorphic behavioral effects of stress. (3) To investigate molecular mechanisms underlying the circuit-specific effects of stress in male and female mice. We will perform RNAseq to analyze the alteration of mRNA profile in PFC, BLA, and VTA from males and females exposed to adolescent isolation stress to determine molecular basis for the sexually dimorphic effects of stress. We will also use viral-based gene transfer to manipulate key molecules to determine their roles in different aspects of stress effects in both males and females. This proposal will address important issues on neuronal underpinnings of the sex-specific diverse consequences of adolescent stress. The identified mechanisms will offer insights into the development of novel precision therapy to mitigate the distinct deficits in males and females after stress exposure.

概括压力激素在整个生命周期中都会引起深刻而复杂的影响，而青春期的大脑是对压力源特别敏感。一个重要但理解的问题是性二态效应早期生活压力。使用暴露于长时间断奶后的社会隔离压力的小鼠，我们发现了独特的让人联想到人类症状的行为表型 - 男性侵略性升高，并且女性的社交能力降低。该项目的目的是了解物理和分子慢性青少年隔离应激的性别特异性分歧作用的基础机制。我们假设在压力男性和女性中，神经元功能的电路特异性改变是在基因表达的电路特异性变化的驱动下，介导了早期的性二态后果生活压力。为了测试这一点，我们将使用尖端技术的组合来解决三个具体目标：（1）确定男性和雌性小鼠压力引起的差异行为和身体变化。一个将进行一系列行为测定，以识别两性的压力引起的表型。切片记录行为动物中神经元活动的突触电流和体内多通道记录进行检查前额叶皮层（PFC），脂质杏仁核（BLA）和腹侧的参与压力男性的侵略性增强中的换段区域（VTA），压力下的社交性降低女性。（2）确定介导雄性和雌性小鼠压力差异作用的神经元电路。经过结合化学发育技术以操纵特定脑回路中的神经元活性与体内钙信号和神经元尖峰的记录，我们将检查是否灾难 PFCBLA和PFCVTA途径慢性隔离应力在控制性别方面起因果作用压力的双态行为效应。（3）研究电路特异性的分子机制男性和雌性小鼠压力的影响。我们将执行RNASEQ来分析mRNA曲线的变化暴露于青少年分离应力的男性和女性的PFC，BLA和VTA以确定分子压力的性二态效应的基础。我们还将使用基于病毒的基因转移来操纵密钥分子在男性和女性中都确定其在压力效应的不同方面的作用。这提案将解决有关性别特异性不同后果的神经元基础的重要问题青少年应力。确定的机制将为新的精确疗法的发展提供见解在压力暴露后减轻男性和女性的明显缺陷。