Early life stress, neuron-type function and a raphe-amygdala circuit for threat estimation

早期生活压力、神经元类型功能和用于威胁估计的中缝杏仁核回路

• 批准号: 10405496
• 负责人: MICHAEL A MCDANNALD
• 金额: $ 39.13万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405496
• 关键词: Adult; Affect; Amygdaloid structure; Anxiety Disorders; Caspase; Categories; Child; Cues; Depressive disorder; Discrimination; Dorsal; Fire - disasters; Fright; Functional disorder; Goals; Health; Incidence; Individual; Knowledge; Laboratories; Link; Maps; Mental Health; Mental disorders; Neurons; Outcome; Output; Personal Satisfaction; Population; Probability; Procedures; Rattus; Research; Role; Safety; Serotonin; Shock; Signal Transduction; TPH2; Testing; Time; Transgenic Organisms; Uncertainty; Work; design; early experience; early life stress; effective therapy; experience; foot; gamma-Aminobutyric Acid; improved; negative affect; neural circuit; new therapeutic target; optogenetics; prepuberty; relating to nervous system; repaired; stressor

Project Summary. Early life stress (ELS) profoundly and negatively affects mental health into adulthood, disrupting neural circuits for threat estimation. This proposal is designed to test the overarching hypothesis that ELS reprograms signaling of DR gamma-aminobutyric acid (GABA), serotonin (5HT), and non-GABA-non-5HT neurons to inflate BLA threat estimates and exaggerate fear. Specifically, DR 5HT neurons and GABA neurons are responsive to threatening cues, while non-GABA-non-5HT neurons are responsive to surprising omission of aversive outcomes, termed a negative prediction error (–PE). ELS reprograms DR by diminishing GABA inhibition of 5HT, while concurrently diminishing non-GABA-non-5HT output. The net result of ELS on DR function is to increase 5HT output to inflate BLA threat estimation and exaggerate fear. We have designed an ELS procedure in which pre-pubertal rats experience multiple categories of physical stressors. In adulthood, accurate threat estimation is assessed with a fear discrimination paradigm in which three cues signal different probabilities of foot shock: danger (p=1.00), uncertainty (p=0.25), and safety (p=0.00). In Aim 1, we will record single-unit activity from the DR and BLA during fear discrimination in normal or ELS rats with DR intact, DR- 5HT neuron deletion or DR-GABA neuron deletion. Neuron-type deletion will be achieved by using specific transgenic rat lines (GAD-cre or TPH2-cre) in combination with cre-dependent caspases. Primary analyses will focus on neural activity during the cue period, when threat estimates are generated, and post-cue period, when –PEs are generated and will directly determine the impact of ELS, and neuron-type deletion, on single-unit activity. In Aim 2, we will use optogenetic inhibition during the cue period, when threat estimates are generated, and the post-cue period, when –PEs are generated, to demonstrate causal roles for, DR GABA, DR 5HT, DR Non-5HT populations, and DR-to-BLA projections in fear to uncertainty. This will uncover causal roles for DR neuron-types, and direct DR to BLA projections, in accurate threat estimation in normal and ELS individuals. In Aim 3, we will combine neuron-type-specific optogenetic excitation of the DR with single-unit recording in the BLA of ELS rats. DR GABA neurons will be stimulated during cue periods, and DR Non-5HT neurons will be stimulated during –PE periods, in order to restore appropriate fear, and BLA neural activity, to uncertainty. This proposal will demonstrate that ELS reprograms neuron-type-specific signaling in the DR-to- BLA circuit to inflate threat estimation. The results will uncover novel targets for pharmacotherapies to restore accurate estimation in ELS individuals. The long term goal of this research is to map a complete neural for accurate threat estimation, reveal how ELS disrupts circuit function, and use this knowledge to design fully effective therapies to restore accurate threat estimation in ELS-affected individuals.

项目摘要。早期生活压力（ELS）对成年后的心理健康产生深远的负面影响， 破坏神经回路来进行威胁评估这一提议旨在检验一个总体假设， ELS重编程DR γ-氨基丁酸（GABA）、5-羟色胺（5HT）和非GABA-非5-HT的信号传导 神经元夸大BLA威胁估计和夸大恐惧。具体而言，DR 5HT神经元和GABA神经元 非GABA-非5HT神经元对威胁性线索有反应，而非GABA-非5HT神经元对令人惊讶的遗漏有反应。 负预测误差（negative prediction error，-PE）。ELS通过减少GABA重新编程DR 抑制5HT，同时减少非GABA-非5HT输出。灾难恢复上ELS的最终结果 功能是增加5 HT输出，以夸大BLA威胁估计和夸大恐惧。我们设计了一个 ELS程序，其中青春期前大鼠经历多种类型的身体应激源。成年后， 准确的威胁估计是用恐惧辨别范例来评估的，在该范例中，三种线索信号不同 足部电击概率：危险（p = 1.00）、不确定性（p = 0.25）和安全性（p = 0.00）。在目标1中，我们将记录 在正常或DR完整的ELS大鼠中，在恐惧辨别过程中来自DR和BLA的单单位活动， 5 HT神经元缺失或DR-GABA神经元缺失。神经元型缺失将通过使用特定的 转基因大鼠系（GAD-cre或TPH2-cre）与依赖cre的半胱天冬酶组合。主要分析将 在产生威胁估计的提示期间和提示后期间， - 产生PE，并将直接决定ELS和神经元类型缺失对单个单位的影响。 活动在目标2中，我们将在提示期间使用光遗传学抑制，此时威胁估计是 产生的，和后提示期，当-PE产生，以证明因果作用，DR GABA，DR 5 HT、DR非5 HT人群以及恐惧到不确定性的DR到BLA预测。这将揭示因果作用 用于DR神经元类型，并将DR直接用于BLA投影，用于正常和ELS中的准确威胁估计 个体在目标3中，我们将DR的联合收割机神经元类型特异性光遗传学激发与单单位光遗传学激发相结合。 记录在ELS大鼠的BLA中。DR GABA神经元将在提示期间被刺激，并且DR Non-5HT 在-PE期间，神经元将被刺激，以恢复适当的恐惧和BLA神经活动， 不确定性这项提案将证明，ELS重新编程神经元类型特异性信号在DR到 BLA电路夸大威胁估计。研究结果将揭示药物治疗的新靶点， 对ELS个体的准确估计。这项研究的长期目标是绘制一个完整的神经系统， 准确的威胁评估，揭示ELS如何破坏电路功能，并利用这些知识进行全面设计 有效的治疗方法，以恢复对受ELS影响的个人的准确威胁估计。