Progression of Entorhinal-hippocampal Spatial and Emotional Processing Deficits in a Mouse Model of Temporal Lobe Epilepsy

颞叶癫痫小鼠模型内嗅海马空间和情绪处理缺陷的进展

• 批准号: 10829101
• 负责人: Ivan Soler
• 金额: $ 4.71万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10829101
• 关键词: Address; Affinity Chromatography; Anhedonia; Animals; Anxiety; Automobile Driving; Award; Behavior; Behavioral; Biological Assay; Brain; Calcium; Chronic; Code; Cognitive deficits; Data; Data Analyses; Development; Disease; Dorsal; Emotional; Emotions; Epilepsy; Functional disorder; Future; Gene Expression; Genetic; Goals; Hippocampus; Image; Impairment; Intervention; Learning; Linear Models; Link; Location; Medial; Mediating; Memory; Memory impairment; Modeling; Molecular; Molecular Profiling; Mus; Neurons; Patients; Pharmacological Treatment; Phase; Pilocarpine; Population; Postdoctoral Fellow; Quality of life; Recurrence; Research; Research Personnel; Resistance; Ribosomes; Running; Scientist; Seizures; Signal Transduction; Site; Stress; Technical Expertise; Techniques; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Time; Training; Translating; Viral; Work; anxiety-like behavior; career; cell type; clinical phenotype; combinatorial; comorbidity; dentate gyrus; emotion regulation; emotional behavior; entorhinal cortex; experimental study; hippocampal pyramidal neuron; in vivo calcium imaging; in vivo imaging; insight; large scale data; molecular marker; mouse model; neural; neural circuit; novel; programs; psychiatric symptom; skills; spatial memory; stellate cell; targeted treatment; timeline; tool; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Temporal lobe epilepsy (TLE) is a debilitating disorder characterized by spontaneous and recurring seizures as well as pervasive memory and psychiatric impairments. These TLE-induced comorbidities do not respond to pharmacological treatment, and little is known about how specific brain circuits are altered by disease to drive these clinical phenotypes. Recent evidence suggests that these comorbidities are driven by deficits along the dorsoventral axis of the entorhinal-hippocampal circuit and that they are dissociable from seizures themselves. As such, it is imperative to study how epilepsy may detrimentally alter temporal lobe circuitry that is a key node in memory and emotion processing. In previous work, our lab and others have established CA1 of dorsal hippocampus (dCA1) as a site of poor spatial processing in epileptic mice. However, it remains unclear if upstream inputs to dCA1 are impaired which may be driving downstream changes in hippocampus. In the F99 phase, I will test the hypothesis that medial entorhinal cortex (MEC) has disrupted spatial coding in epileptic mice and will specifically test how distinct hippocampal inputs from layer 3 (MECIII) pyramidal neurons and layer 2 (MECII) stellate cells are altered. I will perform in vivo calcium imaging in these isolated subpopulations as epileptic and control mice perform spatial foraging and memory tasks, both before and after the onset of progressive memory impairments. This will allow me to determine the relationship between these spatial coding metrics and progressive memory deficits found in epileptic mice. During this phase I will receive technical training on in vivo calcium imaging and large-scale data analysis, as well as conceptual training on epilepsy models, learning and memory circuits, spatial coding, and integrating neural recordings with behavior. In the K00 phase, I plan to combine my previous expertise in stress-induced changes in entorhinal- hippocampal signaling with my current work in epilepsy circuits to determine how the ventral extent of this circuit contributes to altered emotional regulation in epilepsy. I will combine state-of-the-art mouse behavior, molecular assays, gene expression studies, calcium imaging, and virally mediated manipulation techniques to characterize ventral entorhinal-hippocampal circuit changes that drive psychiatric symptoms in epilepsy. Results from these studies will provide new insights into the neural and circuit mechanisms of epilepsy induced emotion deficits. Together, this training across F99 and K00 phases will support my successful transition to postdoctoral researcher and ultimately a career as an independent research scientist focusing on molecular, cellular, behavioral, and circuit-level signatures of behavioral dysfunction associated with epilepsy and stress.

项目概要 颞叶癫痫 (TLE) 是一种使人衰弱的疾病，其特征是自发性和反复发作： 以及普遍的记忆和精神障碍。这些 TLE 引起的合并症对 药物治疗，但人们对疾病如何改变特定的大脑回路来驱动汽车知之甚少。 这些临床表型。最近的证据表明，这些合并症是由沿途的缺陷引起的 内嗅海马回路的背腹轴，它们与癫痫发作本身是分离的。 因此，有必要研究癫痫如何有害地改变作为关键节点的颞叶电路 在记忆和情感处理中。在之前的工作中，我们实验室和其他人已经建立了背侧CA1 海马体（dCA1）是癫痫小鼠空间处理能力较差的部位。然而，目前尚不清楚是否 dCA1 的上游输入受损，这可能会驱动海马体的下游变化。在F99中 阶段，我将检验内侧内嗅皮层（MEC）破坏了癫痫患者的空间编码的假设 小鼠，将专门测试第 3 层 (MECIII) 锥体神经元的海马输入与 第 2 层 (MECII) 星状细胞发生改变。我将对这些孤立的亚群进行体内钙成像 当癫痫小鼠和对照小鼠在癫痫发作之前和之后执行空间觅食和记忆任务时 进行性记忆障碍。这将使我能够确定这些空间之间的关系 在癫痫小鼠中发现的编码指标和渐进性记忆缺陷。在此阶段我将收到 体内钙成像和大规模数据分析的技术培训以及概念培训 癫痫模型、学习和记忆回路、空间编码以及神经记录与行为的整合。 在 K00 阶段，我计划结合我之前在压力引起的内嗅变化方面的专业知识 海马信号传导与我目前在癫痫回路方面的工作，以确定这种情况的腹侧范围如何 电路有助于改变癫痫的情绪调节。我将结合最先进的鼠标行为， 分子测定、基因表达研究、钙成像和病毒介导的操作技术 表征导致癫痫精神症状的腹侧内嗅-海马回路变化。 这些研究的结果将为癫痫诱发的神经和回路机制提供新的见解 情绪缺陷。总之，这次跨 F99 和 K00 阶段的培训将支持我成功过渡到 博士后研究员，最终成为一名专注于分子、 与癫痫和压力相关的行为功能障碍的细胞、行为和回路水平特征。