HIPPOCAMPAL-PREFRONTAL SYNCHRONY IN WORKING MEMORY

描述（由申请人提供）：尽管经过数十年的研究，工作记忆的神经机制，即在时间延迟内保持信息以指导目标导向行为的能力，仍然知之甚少。虽然海马（HC）和前额叶皮层（PFC）之间的振荡同步性在高工作记忆需求的情况下增加，但在工作记忆期间支持HC-PFC相互作用的机制和电路尚不清楚。丘脑中线核团（RE）与前额叶皮层（PFC）和前额叶皮层（HC）相连，并已被证明对工作记忆任务至关重要。因此，当前提案的指导假设是HC-PFC振荡同步由RE调节。如果这一假设是正确的，当工作记忆的需求是高的，RE应该驱动HC-PFC振荡同步，从而产生相对较高的HC-PFC θ相干性和更强的PFC锁相海马θ节律。同样地，抑制RE活动会降低HC-PFC振荡同步性，并导致工作记忆障碍。我们已经表明，海马神经元表现出不同的空间编码模式，以应对操纵工作记忆的需求。我们实验室新发表的数据表明，RE失活选择性地损害工作记忆任务，留下一个非常相似的，但非工作记忆，任务不变。额外的初步数据表明，HC-PFC振荡同步也调制工作记忆的需求。拟议的研究将使用电生理学方法、神经元兴奋的双向光遗传学操纵和行为的组合来解决以下问题：（1）RE失活是否会降低海马-PFC同步性并伴随损害工作记忆？(2)RE激活是否增加了HC-PFC的同步性并同时改善了工作记忆？(3)RE在工作记忆任务执行中是否表现出与HC和PFC的振荡同步性增加？如果获得资助，拟议的工作将产生重大影响的记忆研究和神经科学领域的HC，RE和PFC之间的电路水平的相互作用的基本理解。更广泛地说，该提案将通过揭示HC-PFC振荡同步的机制，推进工作记忆的神经机制的理解。此外，通过在记忆引导行为过程中开创RE记录，我们不仅将首次表征RE行为相关性，而且还将确定RE在调节HC和PFC之间的功能相互作用中的作用。最后，我们将首次使用光遗传学方法来操纵RE的活性并测量对记忆引导行为以及HC-PFC同步的影响。虽然光遗传学方法正得到越来越广泛的应用，但本文提出的研究将促进这种最先进技术的使用，作为理解高级认知功能的电路和机制的工具。

DESCRIPTION (provided by applicant): Despite decades of research, the neural mechanisms of working memory, the ability to hold information over a temporal delay to guide goal-directed behavior, remain poorly understood. Although oscillatory synchrony between the hippocampus (HC) and the prefrontal cortex (PFC) is known to increase in situations of high working memory demand, the mechanisms and circuitry supporting HC-PFC interactions during working memory is unknown. The midline thalamic nucleus reuniens (RE) is reciprocally connected to both the HC and the PFC and has been shown to be critical for working memory tasks. Therefore, the guiding hypothesis of the current proposal is that HC-PFC oscillatory synchrony is regulated by the RE. If this hypothesis is true, when working memory demand is high, RE should drive HC-PFC oscillatory synchrony, giving rise to relatively higher HC-PFC theta coherence and stronger PFC phase-locking to the hippocampal theta rhythm. Similarly, suppression of RE activity should yield reduced HC-PFC oscillatory synchrony and lead to working memory impairments. We have shown that hippocampal neurons exhibit different patterns of spatial coding in response to manipulation of working memory demand. New published data from our lab demonstrate that RE inactivation selectively impairs a working memory task, leaving a very similar, but non-working memory, task unchanged. Additional preliminary data show that HC-PFC oscillatory synchrony is also modulated by working memory demand. The proposed studies will use a combination of electrophysiological methods, bidirectional optogenetic manipulation of neuronal excitation, and behavior to address the following questions (1) Does RE inactivation reduce hippocampal-PFC synchrony and concomitantly impair working memory? (2) Does RE activation increase HC-PFC synchrony and concomitantly improve working memory? (3) Does RE show increased oscillatory synchrony with the HC and PFC during working memory task performance? If funded, the proposed work will have a significant impact on memory research and on the field of neuroscience by advancing the basic understanding of the circuit-level interactions between the HC, RE and PFC. More broadly, the proposal will advance the understanding of the neural mechanisms underlying working memory by uncovering the mechanisms underlying HC-PFC oscillatory synchrony. Moreover, by pioneering RE recordings during memory-guided behavior, we will not only characterize RE behavioral correlates for the first time, but also identify the role of the RE in regulating functinal interactions between the HC and the PFC. Finally, we will be the first to use optogenetic methods to manipulate the activity of the RE and measure the effects on memory-guided behavior as well as on HC-PFC synchrony. Although optogenetic methods are becoming more widely used, the studies proposed here will advance the use of this state-of-the-art technique as a tool for understanding circuits and mechanisms underlying higher cognitive functions.