Circuits driving spatial coding deficits in epilepsy

驱动癫痫空间编码缺陷的电路

• 批准号: 10545083
• 负责人: Tristan Shuman
• 金额: $ 50.6万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10545083
• 关键词: Automobile Driving; Calcium; Cells; Chronic; Code; Cognitive deficits; Data; Disease; Epilepsy; Fire - disasters; Functional disorder; Head; Hippocampus; Image; Impairment; In Vitro; Interneurons; Intervention; Learning; Lesion; Medial; Mediating; Memory; Memory impairment; Microscope; Mus; Neurons; Pathway interactions; Patients; Pattern; Phase; Quality of life; Rodent Model; Role; Running; Silicon; Site; Source; Speed; Techniques; Temporal Lobe Epilepsy; Testing; Virus; active control; cell type; dentate gyrus; designer receptors exclusively activated by designer drugs; entorhinal cortex; insight; morris water maze; spatial memory; stellate cell; virtual; virtual reality

Project Summary/Abstract Temporal lobe epilepsy (TLE) is a debilitating disorder that includes pervasive memory impairments that significantly impact quality of life. In rodent models of TLE, my lab and others have found major deficits in learning and memory as well as in the precision and stability of CA1 place cells. However, it remains unclear whether impaired spatial coding in CA1 is primarily due to local processing deficits in hippocampus or rather is influenced by impaired spatial coding and synchronization from upstream inputs. In fact, there is significant evidence that upstream inputs into the hippocampus from the medial entorhinal cortex (MEC) may be altered in epilepsy. This proposal will test the hypothesis that both MEC inputs into the hippocampus have altered spatial coding and synchronization. To test this hypothesis, we will first use calcium imaging with miniature microscopes to characterize how chronic epilepsy alters spatial coding in MECII stellate cells and MECIII neurons, which directly input into hippocampus. Next, we will use silicon probes to record single unit firing and LFPs simultaneously in MECII, MECIII, DG, and CA1 and determine how synchronization throughout the entorhinal-hippocampal circuit is altered in epileptic mice. Finally, we will use excitatory and inhibitory DREADDs to modulate MEC neurons in control and epileptic mice and determine how each input into hippocampus alters synchronization of hippocampal circuits and spatial memory. Together, these aims will use state-of-the-art recording and manipulation techniques to determine precisely where and how spatial coding and synchronization breaks down in epileptic mice and gain new insights into the cause of cognitive deficits.

项目摘要/摘要 颞叶癫痫(TLE)是一种衰弱的疾病，包括广泛性记忆障碍， 显著影响生活质量。在TLE的啮齿动物模型中，我的实验室和其他人发现在 学习和记忆以及CA1定位细胞的精确度和稳定性。然而，目前仍不清楚 CA1的空间编码受损主要是由于海马区的局部处理缺陷，还是更确切地说是 受上游输入的空间编码和同步受损的影响。事实上，有意义的是 有证据表明，从内侧嗅觉皮质(MEC)进入海马体的上游输入可能在 癫痫。这一提议将检验海马区的两个MEC输入都改变了空间的假设 编码和同步。为了验证这一假设，我们将首先使用微型钙质成像。 显微镜研究慢性癫痫如何改变MECII星状细胞和MECIII细胞的空间编码 神经元，它直接输入到海马体。接下来，我们将使用硅探头来记录单个单位的发射和 MECII、MECIII、DG和CA1中同时存在的LFP，并确定整个 癫痫小鼠的内嗅觉-海马环路发生改变。最后，我们将使用兴奋性和抑制性 DREADDS调节对照组和癫痫小鼠的MEC神经元，并确定每个输入如何进入 海马体改变了海马体电路和空间记忆的同步性。综合起来，这些目标将使用 最先进的记录和操作技术，可准确确定空间编码的位置和方式 而癫痫小鼠的同步性被打破，并对认知缺陷的原因有了新的见解。