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疾病的核心和致残临床成分。例如，健康的大脑不断地将不连续的、连续的经历联系起来。然而，在患有创伤后应激障碍的患者中，如果之前短暂地接触过类似的线索，并在记忆中与创伤事件联系在一起，中性线索可能会引发严重的症状。这种时间关联记忆可以用“痕量”恐惧条件反射范式来研究，这种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的关键过程背后的神经回路活动机制仍不清楚。本项目利用当前最先进的神经回路活动监测和扰动技术，研究这些系统级心理过程的回路活动机制。因此，电路动力学的双光子活动成像、光学和药理学操作、神经活动的多位点电生理记录和计算分析，都将被应用于研究清醒行为小鼠的学习和记忆过程。首先，将使用学习过程中细胞网络活动的双光子成像来识别与“痕量”恐惧记忆相关的动态HPC输出活动机制（目的1）。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相结合的方法来测试远程丘脑-海马输入在通过HPC回路输出潜在地调节“痕量”恐惧记忆中的作用（目的2）。最后，前额叶-丘脑-海马体系统之间的协调对“痕量”恐惧记忆很重要的假设将被测试（目的3），使用来自远端大脑区域的神经活动同时记录和电路元件的光遗传抑制。该项目直接建立在PI之前在突触生理学、可塑性和HPC学习和记忆基础的微电路动力学方面的研究基础上，并利用了之前在这里应用的一些技术的经验。该奖项提出了一项扩大培训计划，由电路、系统、计算和行为神经科学方面的基础和转化科学专家进行培训，以促进PI发展成为专注于神经精神疾病中记忆失调的独立医师科学家调查员。

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.