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远而复杂的影响，而青少年的大脑 对压力源特别敏感。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。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 让人想起人类症状的行为表型——男性的攻击性增强，以及 女性社交能力下降。该项目的目标是了解生理和分子 慢性青少年孤立压力的性别特异性不同影响的潜在机制。我们 假设在压力下的男性和女性中，神经元功能发生了回路特异性改变，这些改变是 由基因表达的电路特异性变化驱动，介导早期性别二态性后果 生活压力。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因压力引起的不同行为和生理变化。一个 将进行一系列行为分析来识别两性中压力诱发的表型。切片录音 突触电流和行为动物神经元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 被盖区（VTA）在压力下男性的攻击性增强和压力下的社交能力下降中的作用 女性。 (2) 确定调节雄性和雌性小鼠应激差异效应的神经元回路。由 结合化学遗传学技术来操纵特定脑回路中的神经元活动与体内 记录行为动物的钙信号和神经元尖峰，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 压力的二态性行为效应。 (3) 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。我们将执行 RNAseq 来分析 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 压力的性别二态效应的基础。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。这个 该提案将解决性别特异性不同后果的神经元基础的重要问题 青春期的压力。已确定的机制将为新型精准治疗的发展提供见解 减轻男性和女性在压力暴露后的明显缺陷。

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.