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

项目概要/摘要 颞叶癫痫是一种使人衰弱的广泛性疾病，其特征不仅在于癫痫发作， 通常是从海马体出现的，但也有严重的记忆障碍。TLE患者报告称， 他们最关心的是可能出现的记忆问题。癫痫发作与 与颞叶癫痫相关的记忆缺陷是复杂和微妙的。虽然 癫痫发作和记忆缺陷的原因尚不清楚，啮齿动物模型可用于研究这种复杂的 关系该提案将调查发生在一个子集的尖峰时间的故障， 癫痫动物齿状回的中间神经元。先前的文献强烈支持这一观点， 齿状抑制可能导致癫痫发作和记忆缺陷，但这还没有直接显示。在 这个建议，我将测试的假设，这种故障齿状抑制时间直接有助于 癫痫中出现的记忆缺陷，分别导致癫痫发作。为了验证这个假设，我将使用 体内硅探针记录LFP和单个单位同时在CA 1和齿状回，并将应用 闭环光遗传学刺激方案，以控制齿状小白蛋白表达的中间神经元放电。 这种闭环光遗传学刺激方案是创新和令人兴奋的，因为它将改变细胞的放电模式。 齿状回中与CA 1 θ周期的各个阶段相关的特定抑制性神经元，而不是 控制癫痫发作时的细胞放电这些操作将在癫痫患者和 因此，我们不仅可以确定病理组织中精确的中间神经元放电的影响， 海马体，但也在健康的海马体。总之，这些目标将使用最先进的记录 和操纵技术，以获得新的见解认知缺陷和癫痫发作的原因。

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.