Using hippocampal-prefrontal theta synchrony to enhance spatial working memory

利用海马-前额叶θ同步增强空间工作记忆

• 批准号: 9752196
• 负责人: Amy L. Griffin
• 金额: $ 18.76万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752196
• 关键词: Anatomy; Animal Model; Animals; Automobile Driving; Behavior; Behavioral; Brain; Brain region; Cognition; Cognitive deficits; Decision Making; Detection; Development; Distant; Dorsal; Ensure; Equipment; Frequencies; Future; Goals; Grant; Hippocampus (Brain); Human; Implant; Laboratories; Light; Link; Medial; Memory; Memory impairment; Midline Thalamic Nuclei; Monitor; Neurons; Opsin; Optics; Performance; Phase; Play; Prefrontal Cortex; Publishing; Rattus; Reporting; Reuniens Thalamic Nucleus; Rodent; Role; Short-Term Memory; System; Task Performances; Techniques; Time; Training; Work; Workplace; arm; base; cognitive enhancement; cognitive function; control trial; density; experimental study; falls; improved; in vivo; innovation; millisecond; neural circuit; neural network; neurophysiology; neuropsychiatric disorder; optogenetics; patient population; real time monitoring; relating to nervous system; response; success; tool; trial comparing

PROJECT SUMMARY Efforts to improve cognitive function by harnessing endogenous brain rhythms have yielded promising results in both humans and experimental animals. However, this approach has not yet been extended to use interregional oscillatory synchrony for cognitive enhancement. Rodent neurophysiology studies have shown that oscillations within the theta band coordinate interactions between the hippocampus (HC) and the medial prefrontal cortex (mPFC) during the performance of spatial working memory (SWM) tasks. These tasks require the rat to use the memory of a previous traversal to guide an upcoming behavioral choice. Although recent work shows that disruptions of HC-mPFC theta synchrony result in SWM deficits, it is not yet known if HC- mPFC theta synchrony can be used to enhance SWM. Recently, new tools have been developed that not only allow real-time monitoring of neural synchrony, but also are capable of driving interregional synchrony with millisecond precision. Therefore, the goal of the current project is to facilitate SWM by first harnessing (Aim 1), then manipulating (Aim 2) HC-mPFC theta synchrony using a combination of in vivo recording and optogenetic techniques in freely moving rats during SWM task performance. The scientific premise of the proposed project is based on published work that shows a strong link between HC-mPFC synchrony and SWM. The overarching hypothesis is that SWM can be enhanced by ensuring that memory-guided decisions are accompanied by high HC-mPFC theta synchrony. For Aim 1, HC-mPFC theta coherence will be monitored in real time while rats perform a SWM-dependent delayed alternation (DA) task. A trial will be initiated when coherence exceeds or falls below values that have been shown previously to be associated with good or poor SWM performance. It is predicted that choice accuracy on the DA task will be highest for sessions in which trials were initiated based on high HC-mPFC theta coherence. This finding would be the first to demonstrate a working memory improvement simply by timing trials to coincide with strong HC-mPFC theta synchrony. For Aim 2, theta frequency optical stimulation using the excitatory opsin, channelrhodopsin (ChR2) will be delivered to mPFC triggered by real-time detection of HC theta. It is predicted that choice accuracy will be higher on stimulation trials compared to light-off trials. These results would demonstrate for the first time that SWM can be improved through direct induction of HC-mPFC theta synchrony. The success of this exploratory grant will direct future work by setting the stage for experiments that will (1) use HC-mPFC theta synchrony to rescue cognitive deficits in animal models of developmental insults and neuropsychiatric disorders, and (2) explore the specific mechanisms that drive synchrony within the extended HC-mPFC circuit.

项目摘要 通过利用内源性脑节律来改善认知功能的努力已经取得了可喜的成果 在人类和实验动物身上。然而，这种方法还没有被推广使用 区域间振荡同步以增强认知能力。啮齿类动物的神经生理学研究表明 θ波带内的振荡协调海马（HC）和内侧皮层之间的相互作用， 前额叶皮层（mPFC）在空间工作记忆（SWM）任务的性能。这些任务需要 RAT使用先前遍历的记忆来指导即将到来的行为选择。虽然最近 工作表明，HC-mPFC θ同步性的破坏导致SWM缺陷，尚不清楚HC- mPFC θ同步可用于增强SWM。最近，新的工具已经开发出来，不仅 允许实时监测神经同步，但也能够驱动区域间同步， 毫秒精度因此，当前项目的目标是通过首先利用（目标1）， 然后使用体内记录和光遗传学的组合来操纵（目标2）HC-mPFC θ同步 技术在自由移动大鼠在SWM任务的性能。建议项目的科学前提 基于已发表的工作，该工作显示HC-mPFC同步性和SWM之间的密切联系。总体 假设是，SWM可以通过确保记忆引导的决策伴随着高的 HC-mPFC θ同步。对于目标1，将真实的时间监测HC-mPFC θ相干性，而大鼠 执行SWM依赖的延迟交替（DA）任务。当一致性超过或超过 福尔斯低于先前已显示的与良好或不良SWM性能相关的值。是 预测DA任务的选择准确性将是最高的会议中，试验开始的基础上， 关于高HC-mPFC theta相干性。这一发现将首次证明工作记忆 只需通过定时试验即可实现改善，以与强HC-mPFC theta同步一致。对于目标2，θ 使用兴奋性视蛋白，通道视紫红质（ChR 2）的频率光刺激将被递送到mPFC 由HC θ的实时检测触发。据预测，选择的准确性将更高的刺激 与点火试验相比。这些结果将首次证明SWM可以得到改善 通过直接诱导HC-mPFC θ同步。这一探索性赠款的成功将指导未来 通过为实验搭建舞台来工作，这些实验将（1）使用HC-mPFC θ同步来拯救认知 发育性损伤和神经精神障碍动物模型的缺陷，和（2）探索特定的 驱动扩展HC-mPFC电路内同步的机制。