Cognitive and Physiological Mechanisms of Hippocampal Journey Dependent Coding

描述（由申请人提供）：自传体事件的记忆（情景记忆，EM）需要海马功能，但其神经相关性尚不清楚。在老鼠身上，一个类似的过程被称为情景记忆，可以用来设计适合记录海马活动的行为任务。我们之前发现，当大鼠执行具有情景记忆方面的+迷宫任务时，大部分CA1海马神经元的空间选择性活动编码旅程的起点和目的地。这种类型的活动被称为海马体旅程依赖编码（HJDC），当对海马体依赖记忆的需求发生变化时，这种活动就会被调节。因此，HJDC形成了可以促进EM的时间扩展表征。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的神经生理底物。当前提案的目标是实现长期目标的第一步，即了解空间选择性CA1活性如何变得依赖于旅程，从而了解如何实验操纵HJDC。我们的中心假设是HJDC是由内嗅皮层（EC）和海马CA3神经元的输入组合产生的。这项研究的基本原理是，如果能够理解产生HJDC的机制，并且能够设计出在行为相关实验中允许其选择性实验操作的程序，则可以确定EM的神经基础。这一假设将通过追求两个具体目标来检验：1。评估EC和CA3活性在迷宫空间导航任务中的作用，我们之前使用了连续逆转来记录HJDC；和2。对正常动物同时记录的CA1、EC和CA3活性进行表征，并与大鼠执行+迷宫空间导航任务时EC或CA3损伤后剩余区域的活性进行比较。在第一个目标下，我们将在之前使用的海马体依赖任务中识别ECor CA3神经毒性病变后的行为缺陷，并将其与与显性行为相似的海马体独立任务中的表现进行比较。这些损伤，我们已经证明在我们手中是可行的，将针对1)EC输入到所有海马区；2) EC输入仅到CA1和耻骨下；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活性，然后将其与上述三种病变后记录的活性进行比较。这种方法是创新的，因为它涉及到一个行为范式的高密度海马记录，其神经生物学基础将得到很好的理解。提出的研究意义重大，因为除非我们了解CA1中HJDC是如何产生的，否则我们无法通过实验来操纵它以建立其行为相关性。反过来，如果没有这些知识，我们就无法开发针对特定神经过程的记忆障碍治疗方法。

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.