Cellular Mediators of Dentate Pattern Separation in Epilepsy

癫痫齿状模式分离的细胞介质

基本信息

批准号：
10752729
负责人：
Andrew Huang
金额：
$ 4.18万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752729
关键词：
Address Affect Axon Cell Death Cells Code Cognitive deficits Data Dendrites Distal Epilepsy Epileptogenesis Exhibits Failure Feedback Fire - disasters Generations Genetic Suppression Glutamates Hilar Hippocampus Impaired cognition Impairment Individual Injections Interneurons Knowledge Left Mediating Mediator Memory Memory impairment Modeling Molecular Mus Neurons Optics Output Parvalbumins Patients Pattern Physiology Pilocarpine Predisposition Probability Process Regulation Role Saline Signal Transduction Slice Somatostatin Source Status Epilepticus Stimulus Structure Synapses Synaptic plasticity Temporal Lobe Epilepsy Testing Training cell assembly cell type comorbidity connectome dentate gyrus designer receptors exclusively activated by designer drugs excitatory neuron granule cell in silico information processing insight nerve supply network models neural neural correlate neurochemistry novel novel strategies optogenetics receptive field spatiotemporal therapy development

项目摘要

Temporal lobe epilepsy (TLE) represents 60% of all epilepsy cases and involves the hippocampus resulting in memory and cognitive deficits. Within the hippocampus is the dentate gyrus (DG), a selectivity filter which generates unique representations of contextually similar inputs, a process known as pattern separation. Pattern separation relies on the coordinated activation of multiple types of interneurons (INs) which, in TLE, are susceptible to cell death and reorganize. Without proper inhibition, granule cells (GCs), the main projection neuron, fire imprecisely leading to failure in pattern separation. Two important IN subtypes in the DG are the parvalbumin (PV) INs, which modulates GC firing by delivering reliable perisomatic inhibition thus affecting output signals, and the somatostatin (SOM) INs, which modulates incoming signals by synapsing onto the distal dendrites. However, their individual contributions to pattern separation computation have yet to be determined. Recently, the semilunar granule cells (SGCs), an excitatory neuron identified by their wide dendrites, has been hypothesized to aid in maintaining suppression of the non-firing GCs. How SGCs and GCs differ in molecular and connectivity profiles is currently unknown. Interestingly, SGCs have been shown to be the primary source of perisomatic excitation onto PV-INs, potentially enhancing feedback inhibition onto local GCs. However, how SGCs affect network activity and their contribution to pattern separation in TLE is unknown. I hypothesize that SGCs will show reduced intrinsic pattern separation compared to GCs and that SGC driven PV-IN activity more robustly supports pattern separation than feedback dendritic inhibition by SOM-INs. Furthermore, experimental TLE will disrupt the precision of SGC to PV/SOM-IN mediated inhibition resulting in pattern separation deficits. This proposal will investigate the unique connectome of SGCs and, using an ex vivo temporal pattern separation paradigm as well as a in silico DG network model, to elucidate the contributions of PV-INs and SOM-INs to pattern separation in SGCs and GCs in healthy and epileptic circuits. Together, identification of the local circuit mechanisms underlying dentate pattern separation and how it is impaired during epileptogenesis will pave the way for novel strategies to manage memory related co-morbidities in epilepsy.

颞叶癫痫 (TLE) 占所有癫痫病例的 60%，涉及海马体，导致记忆和认知缺陷。海马体内有齿状回 (DG)，它是一种选择性过滤器，生成上下文相似输入的唯一表示，这一过程称为模式分离。图案分离依赖于多种类型中间神经元 (IN) 的协调激活，在 TLE 中，这些中间神经元是容易发生细胞死亡和重组。如果没有适当的抑制，颗粒细胞（GC），主要投射神经元，火不精确导致模式分离失败。 DG 中两个重要的 IN 亚型是小清蛋白 (PV) IN，通过提供可靠的体周抑制来调节 GC 放电，从而影响输出信号和生长抑素 (SOM) IN，它通过突触到远端来调节传入信号树突。然而，它们对模式分离计算的各自贡献尚未确定。最近，半月颗粒细胞（SGC）是一种通过其宽树突识别的兴奋性神经元，已被假设有助于维持对非发射 GC 的抑制。 SGC 和 GC 在分子上有何不同连接配置文件目前未知。有趣的是，SGC 已被证明是主要来源 PV-IN 的体周兴奋，可能增强对局部 GC 的反馈抑制。然而，如何 SGC 影响网络活动，并且它们对 TLE 中模式分离的贡献尚不清楚。我假设与 GC 相比，SGC 将表现出减少的内在模式分离，并且 SGC 更能驱动 PV-IN 活动与 SOM-IN 的反馈树突抑制相比，更强有力地支持模式分离。此外，实验 TLE 将破坏 SGC 对 PV/SOM-IN 介导的抑制的精确性，从而导致模式分离缺陷。该提案将研究 SGC 的独特连接组，并使用离体时间模式分离范例以及计算机 DG 网络模型，以阐明 PV-IN 和 SOM-IN 对健康和癫痫回路中 SGC 和 GC 的模式分离。一起，识别本地电路齿状模式分离的机制以及它在癫痫发生过程中如何受损将为研究铺平道路。管理癫痫记忆相关并发症的新策略的方法。