Epilepsy related cell loss and cognitive dysfunction

项目摘要 颞叶癫痫常伴有明显的认知功能障碍，但其机制尚不清楚。 这种功能障碍的根本原因尚不清楚。在人类颞叶癫痫和相关模型中， 神经元损失发生在海马神经元的选定群体中，并且这种细胞损失可能与 有学习和记忆缺陷每个最脆弱的神经元群体的损失的影响 这些神经元包括齿状回门部的苔藓细胞， 生长抑素（SOM）神经元，和SOM神经元在CA 1的oriens层，其中大多数是oriens 陷窝-分子神经元。目前尚不清楚每种细胞类型的丢失如何导致细胞凋亡。 突触连接的重组和改变海马电路的体内功能。广泛的目标 这项建议的目的是确定这三组中每一组的选择性消融的效果。 海马神经元及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损失的影响，将神经元 分别通过腺相关病毒（AAV）表达Cre依赖性白喉毒素A， Cre细胞类型特异性表达小鼠。具体目标1将检验选择性消融 每一个脆弱的神经元群体将导致剩余的神经元的独特的重组模式。 神经元群体。Cre表达小鼠中的Cre依赖性eYFP转染将用于鉴定 在剩余的神经元轴突分支的变化，并确定是否异常的突触回路， 创造具体目标2将检验苔藓细胞或肺门SOM神经元缺失，而不是OLM缺失的假设 神经元缺失将诱导运动期间齿状门神经元放电的去激活。硅探针 θ振荡的记录和齿状门神经元的多个单单位记录将用于 确定苔藓细胞，肺门SOM中间神经元，或SOM OLM缺失是否诱导这种去分化， 齿状门神经元具体目标3将检验OLM缺失，而不是苔藓细胞或肺门的假设。 SOM神经元缺失将导致CA1锥体神经元的不太精确（加宽）的位置相关放电。 这些研究将使用大量CA1神经元的钙成像，这些神经元是自由活动的动物， 定制的小型化显微镜，以确定哪种细胞类型足以降低 进行野外射击。该提案结合了两个实验室互补的专业知识， 确定特定神经元组的丢失和海马回路的相关重组是否会导致 大群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.