Modifying temporal coordination of hippocampal place cells through theta rhythmic stimulation of hippocampal inputs

项目概要/摘要。Theta节律是发生在各种脑区的~4-12 Hz神经元振荡， gions和已经链接到特定的行为和认知过程。异常的θ节律 在包括精神分裂症、自闭症谱系障碍和阿尔茨海默氏症在内的几种认知障碍中观察到 疾病，并可能导致这些疾病的认知缺陷。因此，电路级干预旨在 促进θ节律可能是治疗相关脑部疾病认知障碍的有效治疗方法 θ波节律异常大量严谨的研究支持这样一个前提，即成功的学习 而记忆需要海马体中的θ节律，海马体是大脑存储记忆的关键区域。θ节律 在大鼠主动探索行为期间显著地发生在海马中。在行为正常的大鼠中，θ-coor- 编码空间轨迹的海马神经元的定向集合随着学习而发展， 是空间记忆存储的关键机制。θ-协调的神经元集合是活动的， 以序列的形式进行，提供学习路径的时间压缩表示，其中单元格 分别表示在θ周期的较早和较晚相位上激发的较早和较晚位置。最近的工作 我们实验室的研究表明，海马子区CA 1中记录的神经元的θ协调序列不同 在执行空间记忆任务的大鼠中的正确和错误试验之间（Zheng等人，2021年）。θ坐标 序列在时间上压缩较小，并且在θ周期的显著延迟阶段开始， 错误试验与正确试验的比较。这些结果提出了关于网络机制的新的令人兴奋的假设， 记忆错误背后的矛盾然而，在很大程度上仍然不清楚CA 1神经元的哪些输入驱动 θ-协调序列的时间压缩，以及哪些输入触发神经元放电开始时， 顺序这项拟议中的工作有望通过行为神经生理学填补这些知识空白 采用最先进的多位点记录、光遗传学操作和神经元内分泌的大鼠实验， 解码技术。具体目标1将测试从CA 1到CA 1的输入的θ节律刺激是否 内侧内嗅皮层（MEC），一个传递动物的感官信息的区域。 在空间中的当前位置，触发序列激活。具体目标1还将测试θ节律是否 MEC输入的刺激减少了空间延迟匹配到样本记忆任务上的记忆错误。具体 目标2将测试是否theta节律刺激的子场CA 3，一个区域的记忆被认为是 存储，增加了序列的时间压缩，并提高了空间延迟匹配的性能， to-sample记忆task任务。这项工作有望揭示成功记忆的新机制， 编码这项工作也有望为增强认知障碍患者的记忆力提出新的治疗策略。 涉及学习障碍和记忆缺陷的疾病。

Project Summary/Abstract. Theta rhythms are ~4-12 Hz neuronal oscillations that occur in various brain re- gions and have been linked to specific behaviors and cognitive processes. Aberrant theta rhythms have been observed in several cognitive disorders including schizophrenia, autism spectrum disorders, and Alzheimer’s disease and may contribute to cognitive deficits in these disorders. Therefore, circuit-level interventions aimed at promoting theta rhythms may be effective treatments for cognitive impairments in brain disorders associated with aberrant theta rhythms. A large body of rigorous research supports the premise that successful learning and memory require theta rhythms in the hippocampus, a key brain region for memory storage. Theta rhythms occur prominently in the hippocampus of rats during active exploratory behaviors. In behaving rats, theta-coor- dinated ensembles of hippocampal neurons that code spatial trajectories develop with learning and are thought to be a key mechanism underlying spatial memory storage. Theta-coordinated neuronal ensembles are acti- vated in sequences that provide temporally compressed representations of learned paths, with cells that represent earlier and later locations firing on earlier and later phases of theta cycles, respectively. Recent work from our lab showed that theta-coordinated sequences of neurons recorded in hippocampal subfield CA1 differed between correct and error trials in rats performing a spatial memory task (Zheng et al., 2021). Theta-coordinated sequences were less temporally compressed and began at a significantly delayed phase of the theta cycle during error trials compared to correct trials. These results suggest new and exciting hypotheses about network mech- anisms underlying errors in memory. However, it remains largely unknown which inputs to CA1 neurons drive temporal compression of theta-coordinated sequences and which inputs trigger neuronal firing at the start of a sequence. The proposed work is expected to fill these gaps in knowledge through behavioral neurophysiology experiments in rats that employ state-of-the-art multisite recording, optogenetic manipulation, and neuronal en- semble decoding techniques. Specific Aim 1 will test whether theta rhythmic stimulation of inputs to CA1 from the medial entorhinal cortex (MEC), a region that transmits processed sensory information about an animal’s current position in space, triggers sequence activation. Specific Aim 1 will also test whether theta rhythmic stimulation of MEC inputs reduces memory errors on a spatial delayed match-to-sample memory task. Specific Aim 2 will test whether theta rhythmic stimulation of subfield CA3, a region where memories are thought to be stored, increases temporal compression of sequences and improves performance on a spatial delayed match- to-sample memory task. The work is expected to reveal new mechanisms underlying successful memory en- coding. The work is also expected to suggest novel treatment strategies for enhancing memory in cognitive disorders involving learning disabilities and memory deficits.