Neural Circuit Activity Dynamics Supporting Temporal Association Fear Memory

学习和记忆过程的失调通常是广泛的 各种神经精神障碍。例如，健康的大脑不断地连接不连续的， 跨越时间的顺序体验。然而，在患有创伤后应激障碍的患者中，中性提示可能会触发 如果之前接触到类似的线索后曾短暂地出现严重症状，并成为 与创伤性事件联系在一起。这种时间联想记忆可以用来研究 需要选择性海马区(HPC)回路的“痕迹”恐惧条件反射范式 前额-丘脑-海马区的分布。然而，神经回路的活动机制 在记忆、时间联想和恐惧的关键过程中，调控在很大程度上仍然不清楚。 该项目使用当前状态来研究这些系统级别的心理过程的回路活动机制。 结合神经回路活动监测和微扰的最先进技术。因此，双光子活动 电路动力学成像、光和药物遗传学操作、多部位电生理学 神经活动的记录和计算分析都将用于研究学习和记忆 清醒的、行为正常的小鼠的过程。首先，与`trace‘关联的动态HPC输出活动机制 恐惧记忆将通过学习过程中细胞网络活动的双光子成像来识别(目标1)。 接下来，长程和局部微电路输入在潜在调节“痕迹”恐惧记忆中的作用 通过该HPC电路，将使用突触前活动成像的组合来测试输出(AIM 2)， 电路扰动和突触后输出活动的成像。最后，关于协调的假设 前额-丘脑-海马体系统之间对于“痕迹”恐惧记忆的重要作用将被测试(目标3) 同时记录远程脑区的神经活动和光遗传抑制 电路元件。该项目直接建立在PI先前在突触生理学、可塑性和 微电路动力学是HPC学习和记忆的基础，并利用了以前的经验 这里应用的一些技术。该奖项提出了一项扩大培训的计划，该计划将与 电路、系统、计算和行为神经科学方面的基础科学和翻译科学专家 促进PI发展成为专注于记忆的独立医生-科学家调查员 神经精神障碍中的调节失调。

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 and local microcircuit 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.