Mechanisms driving the development of threat sensitivity following early life adversity

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.

Grant Number: 5R01MH127850-04
NIH Institute/Center: NIH
Principal Investigator: Heather Brenhouse