Mechanisms driving the development of threat sensitivity following early life adversity

暴露在早期生活逆境(ELA)中会增加精神障碍的风险，这种疾病通常 对传统疗法无反应。重要的是，大多数可归因于ELA的精神病理学涉及 对潜在威胁的高度响应，但我们对这种敏感性的机械性理解 由于对经验、性别和年龄的相互作用如何影响 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实现更高的皮质边缘连接和增强的威胁响应能力。我们的长期合作 目标是能够将这些发现转化为个性化的干预策略。我们的团队已经 结果表明，ELA导致高度的解剖(神经支配)和功能的发展(大胆； 杏仁基底外侧核(BLA)和前额叶皮质(PFC)之间的局部场电位)连接 在青春期早期，以及较高的焦虑样行为。其中几种影响早些时候出现在 女性多于男性，我们的初步发现表明青春期性激素可能影响 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加速破坏青春期周围BLA活性和激素信号的假说 以性别特异性的方式发展BLA-PFC连接，改变PFC调节的威胁 整个生命周期的责任感。我们的研究将首先使用电生理学和化学遗传学 揭示特定性别的血乳酸活动关键期的方法，这些关键期推动与 PFC(目标1)，增强对潜在威胁的反应性(目标1)，以及PFC中的谷氨酸接受性 (目标2)。目标3将使用RNA沉默来研究青春期周围神经内分泌机制 确定BLA中的雌激素受体信号是否驱动了与PFC的超连接， PFC中的谷氨酸传输，以及更高的威胁响应能力。总而言之，这些研究将填补 关于ELA对BLA-PFC影响的发育和性别特异性的知识存在严重差距 并预计将对制定具体的预防目标产生重大影响 在暴露于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.