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Mechanisms driving the development of threat sensitivity following early life adversity

早年逆境后推动威胁敏感性发展的机制

基本信息

批准号：
10656507
负责人：
Heather C Brenhouse
金额：
$ 60.4万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656507
关键词：
Acceleration Adolescence Adolescent Affect Affective Age Amygdaloid structure Anatomy Anxiety Attention Automobile Driving Behavior Behavioral Brain Cells Communication Data Detection Development Early-life trauma Electrophysiology (science)Estrogen Receptor alpha Estrogen Receptors Estrogens Exhibits Exposure to Female Glutamates Goals Gonadal Steroid Hormones Hormonal Hyperactivity Individual Intervention Knowledge Learning Life Experience Link Longevity Mediating Mediator Mental Depression Mental disorders Modeling N-Methyl-D-Aspartate Receptors N-Methylaspartate Nature Neurosecretory Systems Population Predisposition Prefrontal Cortex Prevention Psychopathology Puberty RNA Interference Rattus Receptor Signaling Recording of previous events Regulation Research Risk Role Signal Transduction Specificity Testing Time Translations anxiety-like behavior behavioral response brain circuitry cognitive process critical period designer receptors exclusively activated by designer drugs disorder risk early adolescence early experience early life adversity early life stress effective intervention experience genetic approach high risk hormonal signals in vivo interest male maternal separation nerve supply neuronal circuitry neurophysiology novel periadolescent prevent preventive intervention resilience response sex small hairpin RNA translational study transmission process

项目摘要

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.

早期生活逆境（ELA）会给精神疾病带来很大的风险