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

颞叶癫痫是一种使人衰弱且普遍存在的疾病，其特征不仅是通常出现在海马体的癫痫发作，而且还包括严重的记忆障碍。TLE患者报告说，潜在的记忆问题是他们最关心的问题。癫痫发作本身与颞叶癫痫相关的记忆缺陷之间的关系是复杂而微妙的。虽然癫痫发作和记忆缺陷的原因尚不清楚，但啮齿动物模型可以用来研究这种复杂的关系。本研究将研究癫痫动物齿状回中间神经元亚群的尖峰计时发生的故障。先前的文献强烈支持这样的观点，即改变的齿状抑制可能导致癫痫发作和记忆缺陷，但这并没有直接证明。在这个提议中，我将测试这样一个假设，即齿状抑制时间的崩溃直接导致癫痫中出现的记忆缺陷，并且单独导致癫痫发作。为了验证这一假设，我将使用体内硅探针同时记录CA1和齿状回中的lfp和单单元，并将应用闭环光遗传刺激方案来控制表达齿状小蛋白的中间神经元放电。这种闭环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特定抑制性神经元相对于CA1 θ周期的各个阶段的放电模式，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动物中进行，这样我们不仅可以确定病理海马中精确的中间神经元放电的影响，还可以确定健康海马中的影响。总之，这些目标将使用最先进的记录和操作技术来获得对认知缺陷和癫痫发作原因的新见解。

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.