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.

经历早年逆境（ELA）会带来患精神疾病的重大风险，这些疾病通常是对传统治疗无反应。重要的是，大多数 ELA 归因的精神病理学涉及对潜在威胁的反应增强，但我们对这种敏感性的机械理解由于对经验、性别和年龄如何相互作用影响威胁响应电路的开发。因此，该项目旨在确定引发的因果机制由 ELA 推动增强皮质边缘连接和增强威胁响应能力。我们的长期目标是将这些发现转化为个性化的干预策略。我们的小组有表明 ELA 会导致解剖学（神经支配）和功能性（BOLD；局部场电位）基底外侧杏仁核（BLA）和前额皮质（PFC）之间的连接在青春期早期，以及更高程度的焦虑样行为。其中一些影响早在女性多于男性，我们的初步研究结果表明，青春期性激素可能会影响 ELA 之后 BLA-PFC 连接的性别特异性发展。因此我们将测试中央假设 ELA 破坏青春期前后 BLA 活性和激素信号传导加速以特定性别的方式发展 BLA-PFC 连接，改变 PFC 调节的威胁整个生命周期的响应能力。我们的研究将首先使用电生理学和化学遗传学揭示 BLA 活动的性别特异性关键时期的方法，这些时期驱动与 PFC（目标 1）、增强对潜在威胁的响应能力（目标 1）以及 PFC 中的谷氨酸感受性（目标 2）。目标 3 将利用 RNA 沉默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传导是否驱动与 PFC 的超连接， PFC 中的谷氨酸传输，以及增强的威胁响应能力。这些研究将共同填补关于 ELA 对 BLA-PFC 的发育和性别特异性影响的知识存在重大差距电路，预计将对制定具体预防目标产生重大影响在 ELA 暴露人群中。