Memory computations across hippocampal, entorhinal, and prefrontal circuits

项目总结 内嗅觉、海马体和前额叶病理的结合在大多数神经病学中起着关键作用。 和神经退行性疾病，以及与这些相关的记忆障碍的出现 疾病。尽管我们知道这些大脑区域特别脆弱，但神经元的多样性 这些大脑区域内部和之间的计算才刚刚开始揭开面纱。例如，密钥 海马和内侧内嗅皮层(MEC)的功能是在大脑中连接不连续的事件 时间，以及顺序活跃的内嗅觉和海马细胞(“时间细胞”)被认为是 Pivotal用于在多秒的延迟间隔内保持记忆。在我们之前的工作中，我们因此 研究了空间工作记忆(WM)任务在延迟间隔内的放电模式。我们 意外地发现，海马区时间细胞不是WM滞留的一般机制 依赖海马体的任务。相反，初步数据表明关于过去和未来的信息 在海马区短暂的种群爆发期间，延迟间隔期间的选择是显而易见的，而MEC细胞 可能表现出与记忆相关的活动，这种活动与大脑状态无关。因此，我们假设 记忆保持不需要在延迟间隔内进行时变活动，但在 在整个延迟期，海马区和内侧前额叶皮质(MPFC)都有零星的种群爆发 以及内嗅觉细胞的放电模式，这种模式提供了与大脑状态无关的连续性。记录活动 在大脑状态不同的延迟期内，我们将在每只动物体内使用空间的两种变体 WM任务，一个在整个延迟过程中强制运行，另一个不在整个延迟期间强制运行，使得theta或非theta 各州占主导地位。目标1将专注于海马体中的种群爆发，并确定它们是否 仅在非theta状态下提供信息，如我们的初步数据所示，或整个大脑的一般机制 各州。此外，我们将选择性地在延迟期内中断海马区的活动，以确定 根据人口激增和行为对未来选择进行编码是否会受到干扰。然后，Aim 2将执行 跨深层和浅层以及沿内嗅皮层背腹轴的记录以识别 MEC如何为WM做出贡献。最后，目标3将进行大规模的单单元和LFP组合记录 在海马区、mPFC和MEC揭示WM跨脑滞留机制的协调 地区。在研究补充中，我们还将研究MEC和背侧纹状体之间的协调。 综上所述，我们将确定种群爆发期间的神经元活动是否是一种普遍的机制 记忆保持与大脑状态无关，MEC是否支持持续活动的WM保持，以及 MPFC亚区如何与背侧腹侧的海马区和内嗅区协调 轴心。确定这些内存计算将是恢复治疗方法的基础 当神经和神经退行性疾病的大脑回路恶化时的记忆功能。

PROJECT SUMMARY A combination of entorhinal, hippocampal, and prefrontal pathology has a pivotal role in most neurological and neurodegenerative diseases and in the emergence of memory impairments that are associated with these diseases. Despite the knowledge that these brain regions are particularly vulnerable, the diversity of neural computations within and across these brain regions is only beginning to be revealed. For example, a key function of the hippocampus and medial entorhinal cortex (mEC) is to bridge events that are discontinuous in time, and entorhinal and hippocampal cells that are sequentially active (‘time cells’) have been proposed to be pivotal for memory retention over delay intervals of many seconds. In our previous work, we therefore investigated the firing patterns over the delay interval in a spatial working memory (WM) task. We unexpectedly found that hippocampal time cells were not a general mechanism for WM retention in hippocampus-dependent tasks. Rather, preliminary data indicate that information about past and future choices during the delay interval is evident during brief population bursts in hippocampus, while mEC cells may show memory-related activity that persists irrespective of brain state. We therefore hypothesize that memory retention does not require time-varying activity over the delay interval but is rather evident in sporadic population bursts in hippocampus and medial prefrontal cortex (mPFC) throughout the delay period and in firing patterns of entorhinal cells that provide continuity irrespective of brain state. To record activity during the delay period with varying brain states, we will – within each animal – use two variants of a spatial WM task, one with and one without forced running throughout the delay such that either theta or non-theta states are predominant. Aim 1 will focus on population bursts in hippocampus and determine whether they are only informative in non-theta states, as shown in our preliminary data, or a general mechanism across brain states. In addition, we will selectively interrupt hippocampal activity within the delay period to determine whether coding of future choices by population bursts and behavior are perturbed. Aim 2 will then perform recordings across deep and superficial layers and along the dorso-ventral axis of entorhinal cortex to identify how mEC contributes to WM. Finally, Aim 3 will carry out large-scale combined single-unit and LFP recordings in hippocampus, mPFC and mEC to reveal the coordination of mechanisms for WM retention across brain regions. In a research supplement, we will also investigate the coordination between mEC and dorsal striatum. Taken together, we will identify whether neuronal activity during population bursts is a general mechanism for memory retention irrespective of brain state, whether mEC supports WM retention with persistent activity, and how subregions of mPFC are coordinated with hippocampal and entorhinal subareas along the dorso-ventral axis. Identifying these memory computations will be the foundation for treatment approaches to restore memory functions when brain circuits deteriorate in neurological and neurodegenerative diseases.