Memory processing after neuron loss in the entorhinal cortex and hippocampus

内嗅皮层和海马神经元丢失后的记忆处理

• 批准号: 8812021
• 负责人: Robert E Clark
• 金额: $ 32.83万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8812021
• 关键词: Acute; Address; Affect; Alzheimer' s Disease; Animal Model; Back; Behavior; Brain; Brain Ischemia; Brain region; Cells; Characteristics; Data; Disease; Episodic memory; Exhibits; Feedback; Functional disorder; Goals; Health; Hippocampal Formation; Hippocampus (Brain); Histopathology; Hour; Individual; Injury; Lead; Lesion; Medial; Memory; Memory Loss; Memory impairment; Neurodegenerative Disorders; Neuronal Injury; Neurons; Outcome; Pattern; Phase; Physiological; Process; Property; Rattus; Reporting; Semantic memory; Series; Source; Symptoms; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Theta Rhythm; Time; Traumatic Brain Injury; base; behavior test; cell type; combat; cost; dentate gyrus; entorhinal cortex; functional restoration; hippocampal subregions; improved; insight; loss of function; memory process; memory retention; nervous system disorder; network dysfunction; neural circuit; neuromechanism; neuron loss; place fields; prevent; research study; spatial memory

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.

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每种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。这些疾病常见的记忆丧失被认为是由内嗅海马功能障碍引起的。内嗅皮层和海马体起到反馈回路的作用，因此，当回路的任何部分受到损坏时，神经元处理就会受到干扰，从而可能会导致功能丧失。或者，回路内的每个子区域可能能够独立地执行其特征功能，但内侧颞叶内不同模式的神经元损伤可能以共同的方式表现出来，因为内嗅皮层和海马体只能不完全地补偿彼此的功能。尽管可以在神经系统疾病特有的动物模型中研究有关神经功能障碍机制的问题，但也可以通过研究内侧颞叶内不同的损伤模式来了解记忆问题的根源。由于内侧内嗅皮层（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 损伤后空间记忆障碍的程度。我们的初步数据显示，MEC 损伤后的海马以及海马损伤后的 MEC 中的空间和时间处理存在显着功能障碍。我们还发现，与联合损伤相比，单个大脑区域损伤后的记忆障碍不太严重。根据我们的初步结果，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保持完整。该假设将在三个目标上进行测试：（1）通过行为测试进一步表征完全MEC损伤后以及MEC和海马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，以及（3）确定MEC中哪些神经元放电模式在完全MEC损伤后被破坏。 此外，还确定 MEC 中的神经元计算是否可以通过脑刺激来恢复。识别不同模式的损伤后的备用功能，并揭示如何操纵剩余的电路来补偿丢失的功能，将有助于深入了解神经系统和神经退行性疾病中可以加强或恢复的网络机制。