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.

概括压力荷尔蒙在整个生命周期中都会产生深远而复杂的影响，而青少年的大脑对压力源特别敏感的一个重要但尚未得到充分研究的问题是性别二态效应。早期生活压力。通过使用长期暴露于断奶后社会隔离压力的小鼠，我们发现了明显的差异。让人想起人类症状的行为表型——男性的攻击性增强，以及该项目的目标是了解女性社交能力下降的生理和分子机制。慢性青少年孤立压力的性别特异性不同影响的潜在机制。研究发现，在压力下的男性和女性中，神经功能发生了特定回路的改变，由基因表达的电路特异性变化驱动，介导早期的性别二态性后果为了测试这一点，我们将结合使用尖端技术来实现三个具体目标： (1) 鉴定雄性和雌性小鼠 A 中应激引起的不同行为和生理变化。将进行一系列行为分析，以确定两性的压力诱发表型。突触电流和行为动物神经活动的体内多通道记录将进行检查前额皮质（PFC）、基底外侧杏仁核（BLA）和腹侧的参与情况压力男性哮喘患者的被盖区（VTA）和压力男性社交能力下降 (2) 确定介导雄性和雌性小鼠压力差异效应的神经回路。结合化学遗传学技术来操纵特定脑回路中的神经活动与体内记录行为动物的钙信号和神经尖峰，我们将检查是否受到干扰慢性隔离应激后的PFCBLA和PFCVTA通路在性控制中起着因果作用 (3) 研究电路特异性的分子机制我们将进行 RNAseq 来分析雄性和雌性小鼠中 mRNA 谱的变化。暴露于青少年隔离压力的男性和女性的 PFC、BLA 和 VTA 以确定分子水平我们还将使用基于病毒的基因转移来操纵关键。分子来确定它们在男性和女性压力影响的不同方面的作用。该提案将解决有关特定性别的不同后果的神经基础的重要问题已确定的青少年压力机制将为新型精准疗法的发展提供见解。减轻男性和女性在压力暴露后的明显缺陷。