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

• 批准号: 10316441
• 负责人: Heather C Brenhouse
• 金额: $ 62.11万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 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/10316441
• 关键词: 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; Lead; Learning; Life Experience; Link; Longevity; Mediating; Mediator of activation protein; 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; base; 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; 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

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.

暴露于早期生命逆境（ELA）对经常是精神疾病的重大风险 对传统疗法无反应。重要的是，大多数ELA-ATRIBUTIBUTIBUT COPHITOPOPOPOPOPIES都涉及 对潜在威胁的反应提高了，但是我们对这种敏感性的机械理解 由于对经验，性别和年龄相互作用的了解不足，因此仍然起步 发展威胁响应电路。因此，该项目旨在确定启动的因果机制 通过ELA，可以提高皮质林的连接性并增强威胁响应能力。我们的长期 目标是将这些发现转换为个性化的干预策略。我们的团体有 表明ELA会导致增强的解剖学（神经）和功能（粗体； 基底外侧杏仁核（BLA）和前额叶皮层（PFC）之间的局部野外电势） 在青春期早期，以及更高的焦虑样行为。这些效果中的几种较早出现 女性比男性，我们的初步发现表明，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 假设ELA围裙周围BLA活性和激素信号的破坏加速 以性别特定的方式发展BLA-PFC连接性，改变了PFC调节的威胁 整个生命周期的反应性。我们的研究将首先使用电生理学和化学发生 揭示BLA活动的性别特定关键时期的方法 PFC（AIM 1），对潜在威胁的响应增强（AIM 1）和PFC中的谷氨酸接受能力 （目标2）。 AIM 3将使用RNA沉默调查Puberbertal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的超连接性 PFC中的谷氨酸传播，并提高了威胁响应能力。这些研究在一起将填补 关于ELA对BLA-PFC的ELA影响的发展和性别特定性质的知识的关键差距 电路，预计将对预防特定目标的发展产生重大影响 在暴露于ELA的人群中。