ADVANCE Fellows Award: Theta phases of hippocampal place cell firing in REM sleep and waking

在REM睡眠中海马CA 1定位细胞的重放相位进动期间，Poe等人（Brain Res.，855：176-180，2000）观察到，在许多天内，随着大鼠变得更加熟悉相关的轨道环境，相对于海马体θ节律，放电的平均相位发生偏移。具体而言，在大鼠暴露于轨道的前两天，REM旋进期间的平均θ相位接近θ节律的去极化峰。 在接下来的几天里，平均theta相位在REM岁差期间转移到theta周期的超极化谷附近，但在跑道跑步期间保持在去极化峰附近。 这个项目的目标是研究快速眼动进动期间熟悉性产生这种相移的神经机制。PI是一位应用数学家，其研究领域是计算神经科学，他将直接与Gina Poe教授合作，Gina Poe教授目前正在进行实验，以记录海马CA 1区在活跃清醒和随后的REM睡眠期间的位置细胞放电。 合作者对平均放电相位偏移原因的工作假设是，报告的对CA 1锥体细胞的θ节律驱动中的体细胞-树突差异可以响应于不同位置的突触输入而差异地调节放电相位。 具体地，θ驱动的调制使近端树突输入优先在去极化θ峰附近产生激发，并且使远端树突输入优先在超极化θ谷处产生激发。相移将由来自内嗅皮层的直接突触通路携带的远端树突突触输入相对于来自内嗅皮层的Schaffer侧支和三突触环携带的近端树突突触输入的增强引起。 该项目通过在模拟轨道运行和REM睡眠的条件下，在现实的CA 1锥体细胞模型中模拟突触后反应，并通过分析实验数据来验证这一假设。 一般认为，海马位置细胞在特定的时间序列中放电的集合形成了大鼠相关环境记忆的海马表示。在探索环境后的睡眠事件中，位置细胞放电的重演被认为有助于巩固海马体中的记忆并将其转移到新皮层长期储存。当大鼠熟悉相关环境时，在REM睡眠中重放放电期间发生的位置细胞放电的平均θ相位的实验观察到的偏移可能是记忆转移的可观察指标，也可能表明海马体中REM睡眠的关键功能。 作为对产生这种转变的神经机制的调查的初始步骤，将进行神经元模拟和数据分析，其结果将确定对工作假设的约束，即转变是由细胞的不同突触输入的变化引起的。 研究结果将做出实验可验证的预测，并建议进一步的实验来研究REM睡眠和记忆处理之间的联系。

During replayed phase precession of hippocampal CA1 place cells in REM sleep, Poe et al. (Brain Res., 855:176-180, 2000) observed that over a number of days, as the rat became more familiar with the associated track environment, a shift occurred in the mean phase of firing relative to the hippocampal theta rhythm. Specifically, on the first two days the rat was exposed to the track, mean theta phase during REM precession was near the depolarizing peaks of the theta rhythm. Over following days, the mean theta phase shifted to near the hyperpolarizing troughs of the theta cycle during REM precession but remained near the depolarizing peaks during track running. The goal of this project is to investigate the neural mechanisms generating this phase shift that occurs with familiarity during REM precession. The PI, an applied mathematician whose research is in computational neuroscience, will work directly with Prof. Gina Poe, who is currently conducting experiments to record place cell firing in hippocampal region CA1 during active waking and subsequent REM sleep episodes. The collaborators' working hypothesis for the cause of the shift in mean firing phase is that the reported somato-dendritic differential in the theta rhythm drive to CA1 pyramidal cells can differentially modulate the firing phase in response to synaptic inputs at different locations. Specifically, the theta-driven modulation causes proximal dendritic inputs to preferentially generate firing near the depolarizing theta peaks and distal dendritic inputs to preferentially generate firing at the hyperpolarizing theta troughs. The phase shift would result from the potentiation of distal dendritic synaptic inputs, carried by the direct synaptic pathway from the entorhinal cortex, relative to proximal dendritic synaptic inputs carried by the Schaffer collaterals and tri-synaptic loop from the entorhinal cortex. The project tests this hypothesis through simulations of post-synaptic responses in realistic CA1 pyramidal cell models under conditions mimicking track-running and REM sleep, and through analysis of experimental data. It is generally assumed that an ensemble of hippocampal place cells firing in a specific temporal sequence forms the hippocampal representation of a memory of the associated environment for the rat. Replay of place cell firing during sleep episodes following exploration of an environment is thought to contribute to the consolidation of the memory in the hippocampus and to its transfer to neocortical long-term stores. The experimentally observed shift in mean theta phase of place cell firing that occurs during replayed firing in REM sleep as the rat becomes familiar with the associated environment may be an observable indicator of memory transfer and may also suggest a critical function for REM sleep in the hippocampus. As initial steps of the investigation into the neural mechanisms generating this shift, neuronal simulations and data analysis will be conducted whose results will identify constraints on the working hypothesis that the shift is caused by changes in distinct synaptic inputs to the cell. The results will make experimentally-testable predictions and suggest further experiments to investigate this link between REM sleep and memory processing.