A neuronal code for extended time in the hippocampal-entorhinal circuitry

描述（由申请人提供）：海马体的形成对自传式记忆的形成和检索至关重要，自传式记忆包括关于何时何地发生的事情的信息。我们已经知道，物体、环境和空间（什么、在哪里）是如何在海马体中表现出来的。最近有研究表明，时间（事件发生的时间）在秒到分钟的范围内是由海马体细胞的连续激活来表现的。在更长的时间尺度上，理论模型已经表明，时变神经编码适合于估计记忆事件的近时性。在最近发表的结果和作为初步数据呈现的结果中，我们确定了一种新颖的、随时间变化的海马体神经代码，它可以在小时和天的时间尺度上表示事件发生的时间。我们的数据首先确定了CA1细胞的神经元放电模式的特征是频率差异的单调积累，作为经历之间时间的函数。然而，我们证明了存储的信息不仅在CA1区域中退化，而且时间的代码可以与事件的其他方面的可靠编码共存，例如

DESCRIPTION (provided by applicant): The hippocampal formation is critical for the formation and retrieval of autobiographical memories, which consist of information about what happened when and where. It is known how objects, context and space (what, where) are represented in the hippocampus and it has recently been described that time (when events occur) on a scale of seconds to minutes is represented by the sequential activation of hippocampal cells. On a longer time scale, a time-varying neural code has previously been shown by theoretical models to be suitable for estimating the recency of a remembered event. In recently published results and results presented as preliminary data, we identify a novel, time-varying hippocampal neural code that can represent how long ago an event occurred on a time scale of hours and days. Our data first identified that the neuronal firing patterns of CA1 cells are characterized by a monotonic accumulation of rate differences as a function of time between experiences. However, we demonstrate that stored information does not simply deteriorate in the CA1 area, but that the code for time can co-exist with reliable coding for other aspects of an event, such as the spatial location or the context. We also found that CA3 contains an exquisitely precise code for context and space that does not vary over time. New preliminary data show an effect in CA2 that is opposite of CA3. CA2 cells represent elapsed time but no information about context. Based on these findings, we hypothesize that the neuronal code for extended time is combined with spatial and contextual information in the CA1 cell population to guide behavior in which the recency of a previous event is remembered. Using a combination of behavioral testing and single-unit recordings in awake behaving rodents, this hypothesis is tested in three aims that: (1) determine whether the neuronal code for extended time intervals is generated in the hippocampal CA2 neural network, (2) determine whether the input from the hippocampal CA3 subregion is necessary for maintaining the stable memory coding component in the CA1 neural network over hours and days, and (3) determine whether a time-varying neural code in hippocampal CA1 and CA2 subregions is correlated with remembering "how long ago". The first two aims address how different subregions contribute to the time-varying and stable components of the neural code. In addition to defining the function of CA2 for temporal coding and the function of CA3 in enabling stable memory representations, we will also ask whether the entorhinal cortex can represent time on an extended scale and is thus a brain region in which temporal coding over a large range of scales can be found. In the third aim, we will use a behavioral task in which it has been shown that rats remember "how long ago" over extended time periods. We will measure the similarity of activity patterns in place cell populations between two time points and determine whether the change in neuronal firing patterns corresponds to the rat's estimate of elapsed time. Taken together, these studies will be important for understanding the neural network mechanisms for long-term memory stability and temporal event coding in the brain structures that support episodic memory. Understanding the key mechanisms for memory processing will guide efforts to repair circuit dysfunction in psychiatric, neurological, and neurodegenerative diseases.