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

基本信息

  • 批准号:
    10829101
  • 负责人:
  • 金额:
    $ 4.71万
  • 依托单位:
  • 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:
    2023-09-15 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

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.
项目总结 颞叶癫痫(TLE)是一种衰弱的疾病,以自发性和反复发作为特征,如 以及普遍存在的记忆力和精神障碍。这些由TLE引起的合并症对 药物治疗,关于疾病如何改变特定的大脑回路以驱动,我们知之甚少 这些临床表型。最近的证据表明,这些共病是由 内嗅觉-海马体回路的背腹轴,它们本身与癫痫发作无关。 因此,研究癫痫如何有害地改变作为关键节点的颞叶电路是非常必要的。 在记忆和情绪处理方面。在以前的工作中,我们实验室和其他人已经建立了背侧CA1 癫痫小鼠空间加工不良部位的海马区(DCA1)。然而,目前还不清楚是否 DCA1的上游输入受到损害,这可能是推动海马体下游变化的原因。在F99中 阶段,我将检验内侧内嗅皮层(MEC)扰乱癫痫患者空间编码的假设 并将专门测试来自第三层(MECIII)锥体神经元和 第二层(MECII)星状细胞改变。我将在这些孤立的亚群中进行活体钙成像 当癫痫患者和对照组小鼠在癫痫发作前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 在癫痫小鼠中发现了编码指标和进行性记忆缺陷。在此阶段,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、学习和记忆电路、空间编码,以及将神经记录与行为相结合。 在K00阶段,我计划结合我以前在压力诱导的内脏变化方面的专业知识- 用我目前在癫痫回路中工作的海马区信号来确定腹侧这一范围 电路有助于癫痫患者情绪调节的改变。我将结合最先进的鼠标行为, 分子分析、基因表达研究、钙成像和病毒介导的操纵技术 描述导致癫痫患者精神症状的腹侧内嗅觉-海马体回路改变。 这些研究的结果将为癫痫的神经和回路机制提供新的见解。 情绪缺陷。总而言之,这一跨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领域的独立研究科学家, 与癫痫和应激相关的行为功能障碍的细胞、行为和电路水平的特征。

项目成果

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