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

海马-内嗅回路中延长时间的神经元代码

• 批准号: 9198998
• 负责人: Jill K Leutgeb
• 金额: $ 37.32万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198998
• 关键词: Address; Alzheimer' s Disease; Animals; Area; Behavior; Behavioral; Biological Neural Networks; Brain; Brain region; Cells; Code; Data; Disease; Electrophysiology (science); Environment; Episodic memory; Event; Foundations; Functional disorder; Future; Hippocampal Formation; Hippocampus (Brain); Hour; Human; Impairment; Lateral; Lesion; Location; Measures; Medial; Memory; Memory Loss; Mental disorders; Neurodegenerative Disorders; Neurons; Pathology; Patients; Pattern; Population; Post-Traumatic Stress Disorders; Publishing; Radial; Rattus; Retrieval; Rodent; Schizophrenia; Structure; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Theoretical model; Time; Traumatic Brain Injury; Update; arm; awake; base; behavior test; entorhinal cortex; experience; experimental study; long term memory; memory process; nervous system disorder; novel; public health relevance; relating to nervous system; repaired; time interval; treatment strategy

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.

描述(申请人提供)：海马体结构对自传体记忆的形成和检索至关重要，自传体记忆由何时何地发生的信息组成。已知物体、背景和空间(什么、在哪里)在海马体中是如何表示的，最近已经描述了以秒到分钟的尺度上的时间(当事件发生时)由海马体细胞的顺序激活来表示。在更长的时间尺度上，理论模型已经表明，时变神经代码适合于估计记忆事件的新近性。在最近发表的结果和作为初步数据呈现的结果中，我们识别了一种新颖的、时变的海马神经代码，它可以表示事件发生在多长时间之前，时间尺度为小时和天。我们的数据首次确定了CA1细胞的神经元放电模式的特征是作为经历之间的时间函数的速率差异的单调累积。然而，我们证明了存储的信息不仅在CA1区域恶化，而且时间编码可以与事件的其他方面的可靠编码共存，例如 空间位置或上下文。我们还发现，CA3包含一种非常精确的上下文和空间代码，不会随着时间的推移而变化。新的初步数据显示，CA2的作用与CA3相反。CA2信元表示经过的时间，但没有关于上下文的信息。基于这些发现，我们假设延长时间的神经元编码与CA1细胞群体中的空间和上下文信息相结合，以指导记忆先前事件最近的行为。利用行为测试和清醒行为啮齿动物的单单位记录相结合的方式，这一假说得到了三个目标的检验：(1)确定延长时间间隔的神经元编码是否在海马CA2神经网络中产生，(2)确定来自海马CA3亚区的输入是否对于在几小时和几天内维持CA1神经网络中稳定的记忆编码成分是必需的，以及(3)确定海马CA1和CA2亚区的时变神经编码是否与记忆“多长时间前”相关。前两个目标解决了不同的子区域如何对神经编码的时变和稳定分量做出贡献。除了定义CA2的时间编码功能和CA3的稳定记忆表征功能外，我们还将询问内嗅皮层是否能够在扩展的尺度上表示时间，从而是一个可以在大范围尺度上发现时间编码的大脑区域。在第三个目标中，我们将使用一项行为任务，在该任务中，已经证明老鼠在延长的时间段内记得“多长时间以前”。我们将测量定位细胞群体中的活动模式的相似性 两个时间点，并确定神经元放电模式的变化是否符合大鼠对过去时间的估计。综上所述，这些研究对于理解支持情景记忆的大脑结构中长期记忆稳定性和时间事件编码的神经网络机制将是重要的。了解记忆处理的关键机制将指导修复精神、神经和神经退行性疾病的电路功能障碍的努力。