Synaptic and Genetic Mechanisms of Sex-Specific Effects of Stress

摘要 压力荷尔蒙在一生中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。一个重要但尚未被研究的问题是性二型性的影响。 早年的生活压力。使用暴露在断奶后长期社会隔离压力下的小鼠，我们发现了明显的 让人联想到人类症状的行为表型--男性攻击性增强，以及 女性的社交能力下降。本项目的目标是了解生理学和分子生物学。 青少年慢性隔离应激的性别差异效应的潜在机制。我们 假设男性和女性应激时神经元功能的电路特异性改变，这是 在基因表达的电路特异性变化的驱动下，介导性二型性早熟的后果 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)研究应激对雄性和雌性小鼠行为和生理的影响。一个 将进行一系列行为分析，以确定两性在压力诱导下的表型。切片录制 对行为动物的突触电流和体内神经元活动的多通道记录将是 检查受累的前额叶皮质(PFC)、基底外侧杏仁核(BLA)和腹侧 应激男性攻击性增强和社交能力减弱的被盖区(VTA) 女性。(2)确定介导应激差异效应的神经回路。通过 结合化学遗传学技术在体内操纵特定脑回路中的神经元活动 记录动物的钙信号和神经元棘波的行为，我们将检查是否受到干扰 慢性隔离应激后Pfc--Bla和Pfc--Vta通路在性控制中的因果作用 压力的二态行为效应。(3)研究电路特异性的分子机制。 应激对雄性和雌性小鼠的影响。我们将使用RNAseq来分析基因表达谱的变化。 青春期隔离应激男性和女性PFC、BLA和VTA的分子检测 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 分子来确定它们在男性和女性压力效应不同方面的作用。这 该提案将解决与性别相关的不同后果的神经元基础的重要问题 青春期压力。已确定的机制将为新的精确治疗的发展提供见解 以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.