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普遍性疾病，其特征不仅是癫痫发作， 通常是从海马体产生的，但也有严重的记忆障碍。 TLE 患者报告称 潜在的记忆问题是他们最关心的问题。发作之间的关系 颞叶癫痫本身以及与颞叶癫痫相关的记忆缺陷是复杂而微妙的。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情况 关系。该提案将调查一个子集的尖峰时序中发生的故障 癫痫动物齿状回的中间神经元。先前的文献强烈支持改变这一观点 齿状抑制可能导致癫痫发作和记忆缺陷，但这尚未得到直接证明。在 在这个提议中，我将测试这样的假设：齿状抑制时序的崩溃直接导致 癫痫症中出现的记忆缺陷会单独导致癫痫发作。为了检验这个假设，我将使用 体内硅探针可同时记录 CA1 和齿状回中的 LFP 和单个单元，并将应用于 一种闭环光遗传学刺激方案，用于控制表达齿状小白蛋白的中间神经元放电。 这种闭环光遗传学刺激方案是创新且令人兴奋的，因为它将改变 齿状回中特定的抑制性神经元相对于 CA1 theta 周期的各个阶段，而不是 在癫痫发作时操纵细胞放电。这些操作将在癫痫和 健康的动物，这样我们不仅可以确定病理学中精确的中间神经元放电的影响 海马体，而且还存在于健康的海马体中。这些目标将共同使用最先进的录音 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.