Memory processing after neuron loss in the entorhinal cortex and hippocampus

描述（由申请人提供）：内侧颞叶神经元丢失和神经回路重组是创伤性脑损伤、颞叶癫痫、脑缺血和阿尔茨海默病的标志。不同程度的记忆障碍是这些疾病令人不安的症状之一，但组织病理学的确切模式因疾病而异。这些疾病中常见的记忆丧失被认为是由内海马功能障碍引起的。内嗅皮层和海马体作为一个反馈回路起作用，因此，当回路的任何部分受损时，破坏神经元处理可能会导致功能丧失。或者，回路中的每个亚区可能能够独立执行其特征功能，但内侧颞叶内不同模式的神经元损伤可能以一种共同的方式表现出来，因为内嗅皮层和海马只能不完全补偿彼此的功能。虽然关于神经功能障碍机制的问题可以在特定神经疾病的动物模型中研究，但对记忆问题来源的理解也可以从研究内侧颞叶内不同的损伤模式中获得。由于在内侧内嗅皮层（MEC）和海马体中已经描述了许多用于空间处理的细胞类型，因此我们建议首先关注这些大脑区域。我们已经开始研究大鼠海马和/或MEC损伤后空间记忆损伤的程度。我们的初步数据显示，中脑皮层损伤后的海马和海马中脑皮层损伤后的海马空间和时间加工存在明显的功能障碍。我们还发现，与综合损伤相比，单个脑区损伤后的记忆损伤不那么严重。基于我们的初步结果，我们假设空间功能可以部分地由MEC和海马体独立执行，但MEC和海马体神经元处理的时间方面需要整个回路完好无损。这一假设将在三个方面得到检验：(1)通过行为测试进一步表征MEC完全损伤后以及MEC与海马合并损伤后的记忆功能障碍；(2)通过行为过程中的单单元记录确定MEC损伤后海马神经元网络功能障碍的程度；(3)确定海马完全损伤后MEC中哪些神经元放电模式被破坏；确定脑刺激是否能恢复中皮层的神经元计算能力。识别不同损伤模式后的保留功能，并揭示剩余回路的操作如何补偿失去的功能，将为神经和神经退行性疾病中可以加强或恢复的网络机制提供见解。

DESCRIPTION (provided by applicant): Neuron loss and the reorganization of neural circuits in the medial temporal lobe are hallmarks of traumatic brain injury, temporal lobe epilepsy, brain ischemia, and Alzheimer's disease. Various degrees of memory impairments are among the troubling symptoms of each of these diseases, but the exact pattern of histopathology varies between diseases. The memory loss that is common to the diseases is thought to emerge from entorhino-hippocampal dysfunction. The entorhinal cortex and hippocampus function as a feedback loop and a loss of function could thus emerge by disrupting neuronal processing when damaging any part of the circuit. Alternatively, each subregion within the circuit may be able to independently perform its characteristic function, but different pattern of neuronal injury within the medial temporal lobe might nonetheless manifest in a common way because the entorhinal cortex and hippocampus can only incompletely compensate for each other's function. Although questions about the mechanisms of neural dysfunction can be studied in animal models that are specific for a neurological disease, an understanding of the sources for memory problems can also be obtained from investigating different patterns of injury within the medial temporal lobe. Because many cell types for spatial processing have been described in the medial entorhinal cortex (MEC) and hippocampus, we propose to initially focus on these brain regions. We have begun to investigate the extent of spatial memory impairments after lesions to the rat hippocampus and/or MEC. Our preliminary data show substantial dysfunction of spatial and temporal processing in the hippocampus after MEC lesions and in the MEC after hippocampal lesions. We also find that memory impairments are less severe after lesions to individual brain regions compared to combined lesions. Based on our preliminary results, we hypothesize that spatial functions can, in part, be independently performed by the MEC and the hippocampus, but that temporal aspects of MEC and hippocampal neuronal processing require that the entire loop be intact. This hypothesis will be tested in three aims: (1) further characterize memory dysfunction after complete MEC lesions and after combined lesions of the MEC and the hippocampus with behavioral testing, (2) determine the extent of neuronal network dysfunction in hippocampus after MEC lesions with single-unit recordings during behavior, and (3) determine which neuronal firing patterns in MEC are disrupted after complete hippocampal lesions and, additionally, identify whether neuronal computations in the MEC can be restored by brain stimulation. Identifying spared functions after different patterns of damage and revealing how manipulations of the remaining circuits can compensate for lost functions will provide insight into the network mechanisms that can be strengthened or restored in neurological and neurodegenerative diseases.