Epilepsy related cell loss and cognitive dysfunction

项目摘要 颞叶癫痫通常与显著的认知功能障碍有关，但其机制 这种功能障碍的潜在原因尚不清楚。在人类颞叶癫痫及相关模型中， 神经元丢失发生在选定的海马神经元群体中，这种细胞丢失可能与 有学习和记忆缺陷。每一个最脆弱的神经元组的丧失的影响 这些神经元包括齿状回门部、门部的苔藓细胞 生长抑素(SOM)神经元和CA1层的SOM神经元，其中大部分是东方层 腔隙-分子(OLM)神经元。目前尚不清楚每种细胞类型的丧失是如何导致 突触连接的重组和改变体内海马体回路的功能。总的目标是 这项建议的目的是确定选择性消融对这三组患者的影响。 海马神经元及其相关轴突重组对电生理和行为的影响 认知功能的测量。为了确定每个细胞群丢失的影响，神经元将被 通过腺相关病毒(AAV)表达Cre依赖的白喉毒素A Cre细胞类型特异性表达的小鼠。特定目标1将检验选择性消融的假设 每一个脆弱的神经元群体都会导致剩余的独特的重组模式 成群的神经元。Cre依赖的EYFP在表达Cre的小鼠中的转染将被用于鉴定 残留神经元轴突分支的变化，并确定异常突触电路是否 已创建。特定目标2将测试苔藓细胞或肺门SOM神经元缺失的假设，但不是OLM 神经元缺失，会导致齿状回神经元在运动过程中放电的去同步化。硅探头 Theta振荡的记录和齿状脑门区神经元的多个单位记录将被用于 确定苔藓细胞、肺门SOM中间神经元或SOM OLM缺失是否导致这种去同步化 齿状的肺门神经元。特殊目标3将检验OLM缺失，但不是苔藓细胞或肺门 SOM神经元的缺失，将导致CA1锥体神经元位置相关放电的不精确(扩大)。 这些研究将使用钙成像对自由运动的动物的大量CA1神经元进行成像 定制的微型显微镜，以确定哪种细胞类型足以降低精度 设置野战射击位置。这项建议结合了两个实验室相互补充的专业知识 确定特定神经元组的丢失和相关的海马回路重组是否会导致 大量神经元如何同步和编码信息的变化，从而有助于 癫痫及相关疾病中的认知功能障碍。

Project Summary Temporal lobe epilepsy is often associated with significant cognitive dysfunction, but the mechanisms underlying such dysfunction are not understood. In both human temporal lobe epilepsy and related models, neuronal loss occurs in selected populations of hippocampal neurons, and this cell loss could be associated with the learning and memory deficits. The effects of loss of each of the most vulnerable groups of neurons are of particular interest, and these neurons include mossy cells in the hilus of the dentate gyrus, hilar somatostatin (SOM) neurons, and SOM neurons in stratum oriens of CA1, the majority of which are oriens lacunosum-moleculare (OLM) neurons. It remains unclear how the loss of each cell type contributes to the reorganization of synaptic connections and alters the in vivo function of hippocampal circuits. The broad goal of this proposal is to determine the effects of selective ablation of each of these three groups of hippocampal neurons and associated axonal reorganization on electrophysiological and behavioral measures of cognitive function. To determine the effects of loss of each cell population, the neurons will be ablated separately through adeno-associated virus (AAV) expression of Cre-dependent diphtheria toxin A in mice with cell-type specific expression of Cre. Specific Aim 1 will test the hypothesis that selective ablation of each of the vulnerable groups of neurons will lead to unique patterns of reorganization of remaining populations of neurons. Cre-dependent transfection of eYFP in Cre-expressing mice will be used to identify changes in the axonal arborizations of remaining neurons and determine if aberrant synaptic circuits are created. Specific Aim 2 will test the hypothesis that mossy cell or hilar SOM neuron deletion, but not OLM neuron deletion, will induce desynchronization of dentate hilar neuron firing during locomotion. Silicon probe recordings of theta oscillations and multiple single-unit recordings of dentate hilar neurons will be used to determine whether mossy cell, hilar SOM interneuron, or SOM OLM deletion induces this desynchronization of dentate hilar neurons. Specific Aim 3 will test the hypothesis that OLM deletion, but not mossy cell or hilar SOM neuron deletion, will cause less precise (broadened) place related firing of CA1 pyramidal neurons. These studies will use calcium imaging of large populations of CA1 neurons in freely moving animals with custom-made miniaturized microscopes to determine which cell type is sufficient for degrading the precision of place field firing. This proposal combines the mutually complementary expertise of two laboratories to determine if loss of specific groups of neurons and related reorganization of hippocampal circuits can lead to changes in how large groups of neurons become synchronized and encode information, and thus contribute to cognitive dysfunction in epilepsy and related disorders.