Using hippocampal-prefrontal theta synchrony to enhance spatial working memory

项目总结 通过利用内源性大脑节律改善认知功能的努力取得了令人振奋的结果 对人类和实验动物都是如此。然而，这种方法还没有扩展到使用 认知增强的区域间振荡同步性。啮齿动物神经生理学研究表明 Theta带内的振荡协调了海马区(HC)和内侧脑区之间的相互作用 空间工作记忆(SWM)任务执行过程中的前额叶皮质(MPFC)。这些任务需要 大鼠利用对先前遍历的记忆来指导即将到来的行为选择。虽然是最近的 工作表明，HC-mPFC theta同步的中断会导致SWM缺陷，目前尚不清楚HC-mPFC- MPFC的theta同步性可用于增强SWM。最近，新的工具被开发出来，不仅是 允许实时监控神经同步，但也能够推动区域间同步 毫秒精度。因此，当前项目的目标是通过首先利用(目标1)来促进水资源管理， 然后使用活体记录和光遗传相结合的方式操纵(目标2)HC-mPFCθ同步 SWM任务执行过程中大鼠自由活动的技巧。拟议项目的科学前提 是基于已发表的工作，表明HC-mPFC同步和SWM之间有很强的联系。最重要的是 假设SWM可以通过确保记忆引导的决定伴随着高水平的 HC-mPFC theta同步。对于目标1，将实时监测HC-mPFC的theta一致性，而大鼠 执行依赖于SWM的延迟交替(DA)任务。当一致性超过或 低于先前显示的与SWM性能好或差相关的值。它是 预测，DA任务的选择准确率将在启动试验的会话中最高 关于高HC-mPFC的theta一致性。这一发现将是第一次证明工作记忆 只需通过计时试验来与强大的HC-mPFC theta同步性相一致即可改进。对于目标2，theta 使用兴奋性视紫红质(ChR2)的频率光刺激将被传递到mPFC 由HC theta的实时检测触发。据预测，在刺激的情况下，选择的准确率会更高 试验与点火试验相比。这些结果将首次证明SWM是可以改进的 通过直接诱导HC-mPFC theta同步化。这笔探索性赠款的成功将指导未来 通过为实验做准备，这些实验将(1)使用HC-mPFC theta同步来拯救认知 发展性侮辱和神经精神障碍动物模型的缺陷，以及(2)探索特定的 在扩展的HC-mPFC电路内驱动同步的机构。

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.