Mechanisms driving the development of threat sensitivity following early life adversity

暴露于早期生活逆境（ELA）赋予精神疾病的重大风险，这些疾病通常是 对传统治疗反应迟钝。重要的是，大多数ELA归因的精神病理学涉及 对潜在威胁的反应增强，但我们对这种易感性的机械理解 由于对经验、性别和年龄如何相互作用影响的知识不足， 开发威胁响应电路。因此，本项目旨在确定启动的因果机制， 通过ELA驱动皮质边缘连接和增强威胁响应。我们的长期 我们的目标是将这些发现转化为个性化的干预策略。我们的团队 显示ELA导致高度解剖（神经支配）和功能（BOLD; 基底外侧杏仁核（BLA）和前额叶皮层（PFC）之间的局部场电位）连接 在青春期早期，以及更高的焦虑行为。其中一些影响出现在早些时候， 我们的初步研究结果表明，青春期性激素可能会影响 ELA后BLA-PFC连接性的性别特异性发展。因此，我们将测试中央 ELA对青春期前后BLA活性和激素信号传导破坏加速假说 以性别特异性方式发展BLA-PFC连接，改变PFC调节的威胁 在整个生命周期中的反应能力。我们的研究将首先使用电生理学和化学遗传学 揭示BLA活动的性别特异性关键期的方法，这些关键期驱动与 PFC（目标1），增强对潜在威胁的反应性（目标1），以及PFC中的谷氨酸受体 (Aim 2）。目的3将利用RNA沉默来研究青春期周围的神经内分泌机制， 确定BLA中的雌激素受体信号是否驱动与PFC的超连接， 前额叶皮层的谷氨酸传输，以及对威胁的高度反应。这些研究将填补 关于ELA对BLA-PFC影响的发育和性别特异性性质的知识存在重大差距 预计将对制定具体的预防目标产生重大影响 在接触ELA的人群中。

Exposure to early life adversity (ELA) confers significant risk for psychiatric disorders that are often unresponsive to traditional treatments. Importantly, most ELA-attributable psychopathologies involve heightened responsivity to potential threats, yet our mechanistic understanding of this susceptibility remains incipient due to insufficient knowledge about how experience, sex, and age interact to affect the development of threat-responsive circuits. Thus, this project aims to identify causal mechanisms initiated by ELA that drive heightened corticolimbic connectivity and enhanced threat responsivity. Our long-term goal is to enable translation of these findings into individualized intervention strategies. Our groups have shown that ELA leads to development of heightened anatomical (innervation) and functional (BOLD; local field potential) connectivity between the basolateral amygdala (BLA) and the prefrontal cortex (PFC) in early adolescence, as well as higher anxiety-like behaviors. Several of these effects emerged earlier in females than in males, and our preliminary findings suggest that pubertal sex hormones may impact the sex-specific development of BLA-PFC connectivity following ELA. We will therefore test the central hypothesis that ELA disruption of peri-pubertal BLA activity and hormonal signaling accelerate development of BLA-PFC connectivity in a sex-specific manner, altering PFC-regulated threat responsivity across the lifespan. Our studies will first use electrophysiological and chemogenetic approaches to reveal sex-specific critical periods of BLA activity that drive hyper-connectivity with the PFC (Aim 1), enhanced responsivity to potential threat (Aim 1), and glutamate receptivity in the PFC (Aim 2). Aim 3 will investigate a peri-pubertal neuroendocrine mechanism using RNA silencing to determine whether estrogen receptor signaling in the BLA drives hyper-connectivity to the PFC, glutamate transmission in the PFC, and heightened threat responsivity. Together, these studies will fill critical gaps in knowledge about the developmental and sex-specific nature of ELA effects on BLA-PFC circuitry and are expected to have significant impact on the development of specific targets for prevention in ELA-exposed populations.