Memory processing after neuron loss in the entorhinal cortex and hippocampus

描述(申请人提供)：内侧颞叶的神经元丢失和神经回路的重组是创伤性脑损伤、颞叶癫痫、脑缺血和阿尔茨海默病的特征。不同程度的记忆障碍是这些疾病的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。这种疾病常见的记忆丧失被认为是由于内脏-海马体功能障碍造成的。内嗅皮层和海马体的功能就像一个反馈回路，因此，当破坏回路的任何部分时，通过扰乱神经元的处理可能会导致功能丧失。或者，回路中的每个区域可能能够独立地执行其特有的功能，但内侧颞叶内不同模式的神经元损伤可能仍以共同的方式表现出来，因为内嗅皮层和海马体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专门针对神经疾病的动物模型中进行研究，但也可以通过研究内侧颞叶的不同损伤模式来了解记忆问题的根源。由于许多用于空间处理的细胞类型在内侧内嗅皮层(MEC)和海马区已被描述，我们建议最初关注这些脑区。我们已经开始研究大鼠海马区和/或MEC损伤后空间记忆障碍的程度。我们的初步数据显示，在MEC损伤后的海马区和在MEC损伤后的MEC中，存在严重的空间和时间处理功能障碍。我们还发现，与联合损伤相比，单个大脑区域受损后的记忆损害没有那么严重。根据我们的初步结果，我们假设空间功能可以部分由MEC和海马体独立执行，但MEC和海马神经元处理的时间方面要求整个环路完整。该假说将被验证为三个目标：(1)通过行为测试进一步表征MEC完全性损伤后以及MEC与海马体联合损伤后的记忆功能障碍；(2)通过行为过程中的单单位记录，确定MEC损伤后海马区神经元网络功能障碍的程度；(3)确定MEC中的哪些神经元放电模式在海马完整损伤后被扰乱；以及(3)确定MEC中的神经元计算是否可以通过脑刺激恢复。识别不同损伤模式后的备用功能，并揭示对剩余电路的操作如何弥补丢失的功能，将有助于深入了解神经和神经退行性疾病中可以加强或恢复的网络机制。

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.