Neural Circuit Activity Dynamics Supporting Temporal Association Fear Memory

支持时间关联恐惧记忆的神经回路活动动态

• 批准号: 9910449
• 负责人: Mohsin Saeed Ahmed
• 金额: $ 19.98万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-05 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910449
• 关键词: Address; Anxiety; Area; Auditory; Award; Axon; Basic Science; Behavioral; Brain; Brain region; Cells; Characteristics; Clinical; Computer Analysis; Cues; Development; Dissection; Distant; Electrophysiology (science); Elements; Episodic memory; Exposure to; Fright; Goals; Head; Hippocampus (Brain); Human; Image; Impairment; Individual; Learning; Link; Measures; Mediating; Memory; Mental Processes; Mental disorders; Monitor; Mus; Neurons; Neurosciences; Output; Patients; Pattern; Pharmacogenetics; Physicians; Physiology; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Prevention; Process; Psychopathology; Regulation; Research Personnel; Resolution; Reuniens Thalamic Nucleus; Role; Scientist; Signal Transduction; Site; Specificity; Stimulus; Structure; Symptoms; Synapses; System; Techniques; Testing; Thalamic structure; Time; Training; Translational Research; Work; awake; cellular imaging; classical conditioning; conditioned fear; experience; experimental study; fear memory; hippocampal pyramidal neuron; in vivo; insight; memory acquisition; memory process; nervous system disorder; neural circuit; neuromechanism; neuropsychiatric disorder; optogenetics; postsynaptic; presynaptic; programs; relating to nervous system; response; traumatic event; two-photon

Dysregulation of learning and memory processes is often a core and disabling clinical component of a broad variety of neuropsychiatric disorders. For example, the healthy brain continuously links discontiguous, sequential experiences across time. However, in patients who have developed PTSD, a neutral cue may trigger severe symptoms if previous exposure to a similar cue had been temporally followed by, and became mnemonically associated with, a traumatic event. Such temporal association memories can be studied with ‘trace’ fear conditioning paradigms that require selective hippocampal (HPC) circuitry and may also engage distributed prefrontal-thalamo-hippocampal circuits. However, the neural circuit activity mechanisms underlying the key processes of mnemonic temporal association and fear regulation remain largely unclear. This project studies circuit activity mechanisms for these systems level mental processes using current state-of-the-art techniques for combined neural circuit activity monitoring and perturbation. Thus, 2-photon activity imaging of circuit dynamics, opto- and pharmacogenetic manipulations, multi-site electrophysiological recordings of neural activity, and computational analyses, will all be applied to study learning and memory processes in awake, behaving mice. First, the dynamic HPC output activity mechanisms associated with ‘trace’ fear memory will be identified using 2-photon imaging of cellular network activity during learning (Aim 1). Next, the role of long-range thalamo-hippocampal inputs in potentially regulating ‘trace’ fear memories through this HPC circuit output (Aim 2) will be tested using a combination of presynaptic activity imaging, circuit perturbation, and imaging of postsynaptic output activity. Finally, the hypothesis that coordination between prefrontal-thalamo-hippocampal systems is important for ‘trace’ fear memories will be tested (Aim 3) using simultaneous recordings of neural activity from distant brain regions and optogenetic inhibition of circuit elements. The project builds directly from the PI’s prior studies in synaptic physiology, plasticity, and microcircuit dynamics underlying learning and memory in the HPC and leverages previous experience with some of the techniques applied here. The award proposes a program for expanded training with established basic and translational science experts in circuit, systems, computational, and behavioral neurosciences, to facilitate the PI’s development into an independent physician-scientist investigator focusing on memory dysregulation in neuropsychiatric disorders.

学习和记忆过程的失调通常是多种神经精神疾病的核心和致残性临床组成部分。例如，健康的大脑会随着时间的推移不断地将不连续的、连续的经历联系起来。然而，对于患有创伤后应激障碍（PTSD）的患者来说，如果之前接触过类似的线索，随后又发生了创伤事件，并且在记忆上与创伤事件相关，那么中性线索可能会引发严重的症状。这种时间关联记忆可以通过“痕迹”恐惧调节范式进行研究，该范式需要选择性海马（HPC）回路，也可能涉及分布式前额叶-丘脑-海马回路。然而，记忆时间关联和恐惧调节关键过程背后的神经回路活动机制仍不清楚。该项目使用当前最先进的技术来组合神经回路活动监测和扰动，研究这些系统级心理过程的回路活动机制。因此，电路动力学的 2 光子活动成像、光和药物遗传学操作、神经活动的多位点电生理记录以及计算分析都将应用于研究清醒、行为小鼠的学习和记忆过程。首先，将使用学习期间细胞网络活动的 2 光子成像来识别与“痕迹”恐惧记忆相关的动态 HPC 输出活动机制（目标 1）。接下来，将结合突触前活动成像、电路扰动和突触后输出活动成像来测试远程丘脑-海马输入通过该 HPC 电路输出（目标 2）潜在调节“痕迹”恐惧记忆的作用。最后，前额叶-丘脑-海马系统之间的协调对于“追踪”恐惧记忆很重要的假设将通过同时记录远处大脑区域的神经活动和电路元件的光遗传学抑制来测试（目标 3）。该项目直接基于 PI 之前在 HPC 学习和记忆的突触生理学、可塑性和微电路动力学方面的研究，并利用了此处应用的一些技术的先前经验。该奖项提出了一项扩大培训计划，对电路、系统、计算和行为神经科学领域的基础科学和转化科学专家进行扩大培训，以促进 PI 发展成为一名独立的医师科学家，专注于神经精神疾病的记忆失调。