PROJECT 1-Neural encoding based on lateral and medial entorhinal information processing streams in behaviorally-characterized aged rats

海马和内侧颞叶结构在海马结构的形成和维持中起着重要作用 陈述性记忆一个共识正在形成，海马体接收一个基于自我运动的空间 来自内侧内嗅皮层（MEC）的信号和关于物体和物品的外部感觉信号。 外侧内嗅皮层（LEC）。它将这些输入组合起来以创建合取表示 在他们的时空背景下的离散经验。因为记忆丧失是 正常和病理性衰老的特征，一个关键的挑战是了解生理 海马体随着年龄的增长而发生的变化。最近的研究结果表明，LEC特别是 易受年龄相关功能障碍的影响。此外，用抗癫痫药物左乙拉西坦治疗， 改善一些与衰老相关的生理和认知障碍。 本研究提出了一系列的实验来验证LEC和MEC输入的具体假设 影响海马功能记忆力受损的老年大鼠的位置细胞显示出减少的控制 通过局部感觉线索（与LEC的神经表征相关），而它们仍然是 由全局空间线索（与MEC的表示相关联）控制。放置CA 3区域的单元格 将在下文中记录年轻大鼠和老年大鼠（有和无记忆障碍）的 实验(a)局部和全局空间参考框架将处于冲突状态。它是假设 老年受损大鼠将表现出异常的缺乏控制的本地参考框架，这一异常 用左乙拉西坦治疗可改善病情。(b)记录的几何形状和位置 房间将被改变。据推测，老年受损大鼠将表现出异常的稳定性， 当只有几何体被改变时（由于LEC输入的假设损失），但将显示正常位置时， 当位置改变时（由于假设的正常MEC输入），场改变。异常稳定 用左乙拉西坦治疗可改善模式。(c)新地点场的形成与 一种被称为头部扫描的解释行为将被研究。 大鼠将显示与该行为相关的新位置场的形成减少。治疗 左乙拉西坦将恢复这种神经可塑性现象。(d)MEC和LEC的记录将测试 假设老年受损大鼠的网格细胞、边缘/边界细胞和非空间细胞将是正常的， 与年轻和年老的未受损大鼠相比。这些实验将提供通用的强大测试， 假设LEC神经处理特别容易受到年龄相关功能障碍的影响， 左乙拉西坦治疗是恢复老年受损动物海马功能的潜在疗法。

The hippocampus and medial temporal lobe structures play critical roles in the formation and maintenance of declarative memories. A consensus is emerging that the hippocampus receives a self-motion-based, spatial signal from the medial entorhinal cortex (MEC) and an external sensory signal about objects and items in the world from the lateral entorhinal cortex (LEC). It combines these inputs to create conjunctive representations of discrete experiences within their spatiotemporal contexts. Because memory loss is one of the hallmark characteristics of both normal and pathological aging, a key challenge is to understand the physiological changes that occur in the hippocampus with aging. Recent results suggest that the LEC is particularly susceptible to age-related dysfunction. Moreover, treatment with the antiepileptic drug, levetiracetam, can ameliorate some of the physiological and cognitive impairments associated with aging. This project proposes a number of experiments to test specific hypotheses about how LEC and MEC inputs affect hippocampal function with aging. Place cells of aged rats with impaired memory show a reduced control by local sensory cues (associated with neural representations of the LEC), whereas they continue to be controlled by global spatial cues (associated with representations of the MEC). Place cells of the CA3 region will be recorded from young rats and from aged rats (with and without memory impairments) in the following experiments. (a) Local and global spatial reference frames will be placed in conflict. It is hypothesized that aged impaired rats will show an abnormal lack of control by the local reference frame, and that this abnormal condition will be ameliorated by treatment with levetiracetam. (b) The geometry and location of a recording chamber will be altered. It is hypothesized that aged impaired rats will show an abnormal stability of their place fields when only the geometry is altered (due to a hypothesized loss of LEC input) but will show normal place field changes when the location is altered (due to a hypothesized normal MEC input). The abnormal stability patterns will be ameliorated with levetiracetam treatment. (c) The formation of new place fields associated with an investigatory behavior known as head-scanning will be investigated It is hypothesized that aged impaired rats will show a reduction in the formation of new place fields associated with this behavior. Treatment with levetiracetam will restore this neural plasticity phenomenon. (d) Recordings from the MEC and LEC will test the hypothesis that grid cells, border/boundary cells, and nonspatial cells of aged impaired rats will be normal, compared to young and aged unimpaired rats. These experiments will provide robust tests of the general hypothesis that LEC neural processing is particularly susceptible to age-related dysfunction, and that levetiracetam treatment is a potential therapy to restore hippocampal function in aged-impaired animals.