Mechanisms driving the development of threat sensitivity following early life adversity

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Project Summary 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.