Cognitive and Physiological Mechanisms of Hippocampal Journey Dependent Coding

描述(申请人提供)：对自传性事件的记忆(情节记忆，EM)需要海马体功能，但其神经联系尚不清楚。在大鼠中，一种被称为情景式记忆的类似过程可以用来设计适合记录海马体活动的行为任务。我们先前发现，当大鼠执行具有情景样记忆方面的+迷宫任务时，CA1海马神经元的大部分空间选择性活动编码旅行的起点和目的地。这种类型的活动被称为海马体行程依赖编码(HJDC)，当对海马体依赖记忆的需求发生变化时，这种活动就会受到调节。因此，HJDC形成了可能有助于EM的时间扩展表示。为了证明HJDC和EM之间的直接联系，有必要在相关记忆任务中对HJDC进行实验操作。这种方法目前是不可能的，因为产生HJDC的机制尚不清楚。我们的长期目标是确定EM的神经生理基础。目前的提议是实现长期目标的第一步，其目的是了解CA1的空间选择性活动如何变得依赖于旅程，从而了解如何可能对HJDC进行实验性操作。我们的中心假设是HJDC是由来自内嗅皮层(EC)的输入和来自CA3海马神经元的输入相结合产生的。这项拟议研究的基本原理是，如果理解了HJDC的产生机制，并设计出程序，允许其在与行为相关的实验中进行选择性实验操作，就可以确定EM的神经基础。我们将通过追求两个特定目标来验证这一假说：1.评估EC和CA3活动在我们先前用来记录HJDC的+迷宫空间导航任务执行中的作用；2.表征同时记录的正常动物的CA1、EC和CA3活动，并将其与执行+迷宫空间导航任务的大鼠EC或CA3损伤后剩余区域的活动进行比较。在第一个目标下，我们将识别先前使用的海马依赖任务中EcoR CA3神经毒性损伤后的行为缺陷，并与在类似显性行为的海马非依赖任务中的表现进行比较。我们已经证明，这些损伤在我们的手中是可行的，将针对1)EC输入到所有的海马区；2)EC输入到CA1和下丘；以及3)CA3输入到CA1。在第二个目标下，我们将首先记录正常动物的CA1、CA3和EC活动，然后将其与上述三种损伤中的任何一种后记录的活动进行比较。这种方法是创新的，因为它涉及到行为范式中的高密度海马体记录，其神经生物学基础将被很好地理解。这项拟议的研究意义重大，因为除非我们了解HJDC是如何在CA1中产生的，否则我们无法通过实验操纵它来建立其行为相关性。反过来，如果没有这样的知识，我们就无法开发针对特定神经过程的记忆障碍的治疗方法。

DESCRIPTION (provided by applicant): Memory for autobiographic events (episodic memory, EM) requires hippocampal function, but its neural correlates are unknown. In rats, an analogous process referred to as episodic-like memory can be used to devise behavioral tasks suitable for recording hippocampal activity. We previously found that when rats perform a + maze task with episodic-like memory aspects, most of the spatially selective activity of CA1 hippocampal neurons encodes origin and destination of journeys. This type of activity, referred to as hippocampal journey-dependent coding (HJDC), is modulated when the demand for hippocampal-dependent memory changes. HJDC forms therefore temporally extended representations that could contribute to EM. To demonstrate a direct link between HJDC and EM, experimental manipulation of HJDC in relevant memory tasks is necessary. This approach is currently not possible because the mechanisms generating HJDC are not known. Our long-term goal is to identify the neurophysiological substrates of EM. The objective of the current proposal, which is the first step in attaining the long-term goal, is to understand how spatially-selective CA1 activity becomes journey-dependent and thus how experimental manipulation of HJDC might be possible. Our central hypothesis is that HJDC is generated by a combination of input from the entorhinal cortex (EC) with input from CA3 hippocampal neurons. The rationale underlying the proposed research is that if mechanisms generating HJDC are understood and procedures can be devised to allow its selective experimental manipulation in behaviorally relevant experiments, the neural underpinning of EM can be identified. This hypothesis will be tested by pursuing two specific aims: 1. Assess the role of EC and CA3 activity in performance of a + maze spatial navigation task with serial reversals we previously used to record HJDC; and 2. Characterize simultaneously recorded CA1, EC and CA3 activity in normal animals and compare it with activity in remaining areas after EC or CA3 lesions in rats performing the +maze spatial navigation task. Under the first aim, we will identify the behavioral deficits following ECor CA3 neurotoxic lesions in the hippocampal-dependent task previously used and compare with performance in a hippocampal-independent task similar in overt behavior. These lesions, which we have shown are feasible in our hands, will target 1)EC input to all hippocampal fields; 2) EC input to CA1 and subiculum only; and 3) CA3 input to CA1. Under the second aim, we will first record CA1, CA3, and EC activity in normal animals and then compare it to activity recorded after either of the three types of lesions described above. The approach is innovative because it involves high density hippocampal recording in a behavioral paradigm whose neurobiological substrate will be well understood. The proposed research is significant because unless we understand how HJDC is generated in CA1, we cannot manipulate it experimentally to establish its behavioral relevance. In turn, without such knowledge, we cannot develop treatments for memory disorders that would target specific neural processes.