Neural Circuit Activity Dynamics Supporting Temporal Association Fear Memory

学习和记忆过程的失调通常是各种神经精神障碍的核心和致残的临床组成部分。例如，健康的大脑不断地将不连续的、连续的经历与时间联系在一起。然而，在患有创伤后应激障碍的患者中，如果之前接触过类似的线索，并在记忆上与创伤事件有关，那么中性线索可能会引发严重症状。这种时间联想记忆可以用需要选择性海马体(HPC)回路的“痕迹”恐惧条件反射范式来研究，也可能涉及前额叶-丘脑-海马体的分布式回路。然而，记忆时间联想和恐惧调节的关键过程背后的神经回路活动机制仍然很不清楚。这个项目使用当前最先进的技术，结合神经回路活动监测和扰动，研究这些系统层面的心理过程的回路活动机制。因此，电路动力学的双光子活动成像、光和药物遗传学操作、神经活动的多点电生理记录和计算分析都将被应用于研究清醒的、行为正常的小鼠的学习和记忆过程。首先，将使用学习过程中细胞网络活动的双光子成像(目标1)来识别与“痕迹”恐惧记忆相关的动态HPC输出活动机制。接下来，将使用突触前活动成像、电路扰动和突触后输出活动成像的组合来测试长程丘脑-海马体输入在通过该HPC电路输出潜在地调节‘痕迹’恐惧记忆中的作用(目标2)。最后，前额-丘脑-海马体系统之间的协调对“痕迹”恐惧记忆很重要的假设将通过同时记录来自遥远大脑区域的神经活动和电路元件的光遗传抑制来检验(目标3)。该项目直接建立在PI以前在HPC学习和记忆基础上的突触生理学、可塑性和微电路动力学方面的研究基础上，并利用了这里应用的一些技术的先前经验。该奖项建议与电路、系统、计算和行为神经科学方面的知名基础和翻译科学专家一起扩大培训计划，以促进PI发展成为专注于神经精神障碍的记忆失调的独立医生-科学家研究员。

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.