Neural circuits for stress-impaired extinction learning

压力受损消退学习的神经回路

• 批准号: 10115211
• 负责人: Stephen Maren
• 金额: $ 4.26万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115211
• 关键词: Amygdaloid structure; Anxiety; Area; Attenuated; Behavior Therapy; Brain; Clinical; Cognitive Therapy; Data; Development; Disease; Electric Stimulation; Electrophysiology (science); Extinction (Psychology); Fright; Hour; Impairment; Interneurons; Laboratories; Medial; Mediating; Memory; Mental Depression; Methods; Neurons; Norepinephrine; Outcome; Parvalbumins; Pathologic; Patients; Pharmacogenetics; Prefrontal Cortex; Propranolol; Public Health; Rattus; Relapse; Role; Shock; Stress; Testing; Training; Transgenic Organisms; Trauma; Viral Vector; Work; acute stress; base; combinatorial; conditioned fear; designer receptors exclusively activated by designer drugs; in vivo; learning extinction; locus ceruleus structure; neural circuit; neuromechanism; noradrenergic; novel; prevent; receptor; recruit; selective expression; stressor; transmission process

Project Summary Clinical disorders of fear and anxiety, including trauma- and stressor-related disorders, represent an enormous public health burden. Cognitive-behavioral therapies, such as prolonged exposure therapy, have proven to be remarkably effective in reducing pathological fear in patients with these disorders. Nonetheless, there are a number of factors that limit the efficacy of exposure therapy. In particular, stress undermines exposure-based therapies by impairing extinction learning and promoting fear relapse. Despite years of work elucidating the neural circuitry for extinction, the neural mechanisms responsible for stress-induced extinction impairments remain poorly understood. One possibility is that stress dysregulates neuronal activity in the medial prefrontal cortex (mPFC), a brain area that is critical for extinction learning. In support of this possibility, we have recently shown that footshock stress causes lasting decreases in the spontaneous firing of neurons in the infralimbic (IL) division of the mPFC in rats. Decreases in IL firing were associated with an “immediate extinction deficit” (IED), an extinction impairment that occurs when extinction is performed soon after fear conditioning (a stressor). Importantly, systemic administration of propranolol, a ß-noradrenergic receptor antagonist, prevented both the stress-induced depression of IL firing and the IED, suggesting a role for locus coeruleus norepinephrine (LC-NE) in this phenomenon. Although these data reveal that noradrenergic transmission is involved in the stress-induced depression of mPFC firing, the neural circuit by which stress perturbs mPFC firing is unknown. Interestingly, we have found that propranolol rescues the IED when delivered to the basolateral amygdala (BLA), but not the IL. Based on this work, we propose a novel hypothesis that stress-induced NE release from the LC recruits an inhibitory BLA->IL circuit that dampens activity in IL principal neurons to impair the acquisition and retention of long-term extinction memories. We propose three specific aims to test this hypothesis using a combination of in vivo electrophysiology, functional circuit tracing, and pharmacogenetic manipulations (e.g., `designer receptors exclusively activated by designer drugs' or DREADDs). The first specific aim of the project examines whether LC-NE projections to the IL or BLA are necessary and sufficient for stress-induced changes in mPFC firing and extinction learning deficits. The second specific aim examines explores whether BLA neurons projecting to the IL or PL mediate these effects. The third specific aim determines whether parvalbumin interneurons (PV-INs) in the mPFC are recruited by LC- NE activation and mediate the immediate extinction deficit through feed forward inhibition by BLA afferents. The outcomes of these aims will advance a novel circuit mechanism for stress-induced extinction impairments. Understanding this mechanism will facilitate the development of novel pharmacotherapeutic approaches that optimally engage mPFC circuits to facilitate extinction learning under stress.

项目摘要 恐惧和动画的临床疾病，包括创伤和压力源相关的疾病，代表了巨大 公共卫生伯恩。认知行为疗法（例如长期暴露疗法）已被证明是 在减少这些疾病患者的病理恐惧方面非常有效。但是，有一个 限制暴露疗法效率的因素数量。特别是，压力基于暴露 通过损害扩展学习和促进恐惧缓解的疗法。尽管有多年的工作阐明 延伸的神经回路，导致压力引起的延伸障碍的神经机制 保持不当理解。一种可能性是，应力失调会在培养基前额叶中的神经元活性 Cortex（MPFC），这对于扩展学习至关重要。为了支持这种可能性，我们有 最近表明，脚垫压力导致持续的神经元的发电量下降 MPFC在大鼠中的输液（IL）分裂。 IL发射的减少与“立即 扩展赤字”（IED），一种扩展损伤，当恐惧后不久执行延伸 调理（压力源）。重要的是，全身给药普萘洛尔，β-甲状腺肾上腺素的接收器 拮抗剂，防止了压力引起的IL发射和IED的压力，这表明了座位的作用 在这种现象中，去甲肾上腺素（LC-NE）。尽管这些数据表明甲肾上腺素 传播参与了压力引起的MPFC解散的抑郁症，这是神经回路的压力 Perturbs MPFC射击尚不清楚。有趣的是，我们发现普萘洛尔在 传递到基底外侧杏仁核（BLA），但不是IL。基于这项工作，我们提出了一个新的假设 压力诱导的NE从LC释放募集了舞者在IL中活性的抑制性bla-> IL电路 主要神经元会损害长期扩展记忆的获取和保留。我们提出了三个 具体目的是使用体内电生理学，功能电路跟踪的组合来检验这一假设。 和药物遗传操作（例如，“设计器的设计师专门由设计师药物激活”或 恐怖）。项目考试的第一个具体目的是IL或BLA的LC-NE项目是 必要且足够用于压力引起的MPFC解击和扩展学习的变化。第二个 特定的目标检查探讨了BLA神经元投射到IL或PL是否介导这些效果。这 第三个特定目的决定了MPFC中的白蛋白中间神经元（PV-INS）是否由LC-募集 NE激活并通过BLA传入的饲料向前抑制即时延伸不足。 这些目标的结果将推进应力诱导的延伸障碍的新型电路机制。 了解这种机制将促进新型药物治疗方法的发展 最佳地吸引MPFC电路，以促进压力下的扩展学习。