Closed-loop control of dentate inhibitory timing in healthy and epileptic mice

项目摘要/摘要 颞叶癫痫是一种衰弱和普遍的疾病，其特征不仅是癫痫发作，而且 通常出现在海马体中，但也会出现严重的记忆障碍。TLE患者报告说 他们最担心的是潜在的记忆问题。癫痫发作之间的关系 与颞叶癫痫相关的记忆缺陷是复杂和细微的。尽管 癫痫发作和记忆障碍的原因尚不清楚，可以用啮齿动物模型来研究这种复杂的情况 两性关系。这项提案将调查在一个子集的尖峰定时发生的故障 癫痫动物齿状回的中间神经元。以前的文献强烈支持这样一种观点，即 齿状回抑制可能导致癫痫发作和记忆障碍，但这还没有直接显示出来。在……里面 这一提议，我将检验这个假说，即这种齿状抑制时间的崩溃直接有助于 在癫痫和癫痫中出现的记忆缺陷分别导致癫痫发作。为了验证这一假设，我将在 活体硅探针同时记录CA1和齿状回的LFP和单个单位，并将应用 一种控制齿状小白蛋白表达的神经元间放电的闭环光遗传刺激方案。 这种闭环式光遗传刺激方案是创新和令人兴奋的，因为它将改变 齿状回中与CA1 theta周期不同阶段相关的特定抑制神经元，而不是 在癫痫发作时自己操纵细胞放电。这些手法将在癫痫患者和 使我们不仅能准确地确定健康动物中间神经元放电的病理效应 海马体，也存在于健康的海马体中。总之，这些AIMS将使用最先进的录音 和操纵技术，以获得对认知缺陷和癫痫发作原因的新见解。

Project Summary/Abstract Temporal lobe epilepsy is a debilitating and pervasive disorder that is characterized not only by seizures which typically emerge from the hippocampus but also by severe memory impairments. Patients with TLE report that the potential for memory problems is of greatest concern to them. The relationship between seizures themselves and the memory deficits associated with temporal lobe epilepsy is complex and nuanced. Though the cause of seizures and memory deficits is unknown, rodent models can be used to study this complicated relationship. This proposal will investigate a breakdown that occurs in the spike timing of a subset of interneurons in the dentate gyrus of epileptic animals. Prior literature strongly supports the notion that altered dentate inhibition may contribute to seizures and to memory deficits, but this has not been directly shown. In this proposal, I will test the hypothesis that this breakdown in dentate inhibitory timing contributes directly to the memory deficits seen in epilepsy and, separately, contributes to seizures. To test this hypothesis, I will use in vivo silicon probes to record LFPs and single-units simultaneously in CA1 and the dentate gyrus and will apply a closed-loop optogenetic stimulation protocol to control dentate parvalbumin-expressing interneuron firing. This closed-loop optogenetic stimulation protocol is innovative and exciting, as it will alter the firing patterns of specific inhibitory neurons in the dentate gyrus relative to various phases of the CA1 theta cycle, rather than manipulate cell firing at the time of seizures themselves. These manipulations will be done in epileptic and healthy animals so that we will not only determine the effects of precise interneuron firing in the pathological hippocampus, but also in the healthy hippocampus. Together, these aims will use state-of-the-art recording and manipulation techniques to gain new insights into the cause of cognitive deficits and seizures.