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.

项目摘要 颞叶癫痫（TLE）是一种以自发性和反复发作为特征的衰弱性疾病， 以及普遍记忆和精神障碍。这些TLE诱导的合并症对 药物治疗，并且很少有人知道特定的大脑回路是如何被疾病改变的， 这些临床表型。最近的证据表明，这些合并症是由沿着 这一点与内鼻-海马回路的背腹轴有关，并且它们与癫痫发作本身无关。 因此，研究癫痫如何在精神上改变作为关键节点的颞叶回路是必要的。 在记忆和情绪处理方面。在以前的工作中，我们的实验室和其他人已经建立了背侧海马CA1区， 海马（dCA1）作为癫痫小鼠空间处理不良的部位。然而，目前尚不清楚， dCA 1的上游输入受损，这可能驱动海马体中的下游变化。在F99 阶段，我将测试的假设，内侧内嗅皮层（MEC）扰乱了空间编码癫痫 小鼠并将专门测试来自第3层（MECIII）锥体神经元的海马输入有何不同， 第2层（MECII）星状细胞被改变。我将在这些孤立的亚群中进行体内钙成像 当癫痫和对照小鼠在癫痫发作之前和之后进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度量和进行性记忆缺陷。在此期间，我将收到 关于体内钙成像和大规模数据分析的技术培训，以及关于 癫痫模型、学习和记忆回路、空间编码以及将神经记录与行为整合。 在K00阶段，我计划联合收割机结合我以前在压力诱导的内嗅变化方面的专业知识， 海马信号与我目前在癫痫电路的工作，以确定如何腹侧的程度， 回路有助于改变癫痫患者的情绪调节。我会将联合收割机最先进的老鼠行为 分子测定、基因表达研究、钙成像和病毒介导的操作技术， 描述腹侧内鼻-海马回路变化，驱动癫痫的精神症状。 这些研究结果将为癫痫的神经和电路机制提供新的见解 情感缺陷总之，F99和K00阶段的培训将支持我成功过渡到 博士后研究员，并最终成为一名独立的研究科学家， 与癫痫和压力相关的行为功能障碍的细胞、行为和电路水平特征。