Synaptic and Genetic Mechanisms of Sex-Specific Effects of Stress

总结 压力荷尔蒙在整个生命周期中都会产生深刻而复杂的影响，青少年的大脑 对压力特别敏感。一个重要但未充分研究的问题是， 早期生活压力使用长时间暴露于断奶后社会隔离压力的小鼠，我们发现了不同的 行为表型，让人联想到人类的症状-男性的侵略性升高， 女性社交能力下降。这个项目的目标是了解生理和分子 慢性青少年隔离压力的性别特异性差异效应的潜在机制。我们 假设在应激的男性和女性中神经元功能的回路特异性改变， 由基因表达中的电路特异性变化驱动，介导早期的性二态性后果。 生活压力为了验证这一点，我们将使用尖端技术的组合来解决三个具体目标： (1)确定应激诱导的雄性和雌性小鼠不同的行为和生理变化。一 将进行一系列行为测定以鉴定两种性别中应激诱导的表型。切片记录 突触电流和体内多通道记录神经元活动的行为动物将是 检查前额叶皮层（PFC），基底外侧杏仁核（BLA）和腹侧杏仁核（BLA）的参与。 被盖区（VTA）在应激男性的攻击性增强和应激男性的社交性减弱中的作用。 女性(2)确定雄性和雌性小鼠介导应激差异效应的神经元回路。通过 结合化学遗传学技术来操纵特定脑回路中的神经元活动， 记录的钙信号和神经元的尖峰行为的动物，我们将检查是否被扰乱 慢性隔离应激后的PFC-BLA和PFC-VTA通路在控制性应激中起着因果作用 压力的二态行为效应。(3)为了研究电路特异性的分子机制， 压力对雄性和雌性小鼠的影响。我们将进行RNAseq来分析mRNA谱的改变， 暴露于青少年隔离应激的男性和女性的PFC、BLA和VTA，以确定分子水平 压力对两性异形影响的基础我们还将使用基于病毒的基因转移来操纵关键基因。 分子，以确定他们的作用，在不同方面的压力影响，在男性和女性。这 这项提案将解决神经元基础的重要问题，这些神经元基础是性别特异性的不同后果， 青春期压力所确定的机制将为新型精确治疗的发展提供见解 以减轻压力暴露后雄性和雌性的明显缺陷。

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.