Closed-Loop Control of Dentate Inhibitory Timing in Healthy and Epileptic Mice

健康小鼠和癫痫小鼠齿状抑制时间的闭环控制

• 批准号: 10397164
• 负责人: Zoé Christenson Wick
• 金额: $ 4.21万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-22 至 2023-04-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397164
• 关键词: Acute; Adult; Age; Animals; Behavioral; Brain; Cells; Chronic; Cognition; Cognitive deficits; Complex; Cues; Disease; Disease Progression; Epilepsy; Event; Experimental Designs; Faculty; Fire - disasters; Frequencies; Generations; Grant; Hippocampus; Impact Seizures; Impaired cognition; Impairment; Interneurons; Literature; Mediating; Memory; Memory impairment; Mus; Neuroanatomy; Neurons; Parvalbumins; Pathologic; Patients; Pattern; Performance; Persons; Phase; Physiological; Pilocarpine; Positioning Attribute; Postdoctoral Fellow; Protocols documentation; Reporting; Research; Rodent Model; Role; Seizures; Silicon; Techniques; Temporal Lobe Epilepsy; Testing; Time; Training; cognitive performance; comorbidity; dentate gyrus; experimental study; improved; in vivo; inhibitory neuron; innovation; insight; neuromechanism; novel; optogenetics

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.

颞叶癫痫是一种令人衰弱和普遍存在的疾病，不仅以癫痫发作的特征是通常从海马中出现的癫痫发作，而且还由严重的记忆障碍。 TLE患者报告说，记忆问题的潜力对他们来说是最大的关注。癫痫发作本身与与颞叶癫痫相关的记忆缺陷之间的关系是复杂而细微的。尽管癫痫发作和记忆缺陷的原因尚不清楚，但啮齿动物模型可用于研究这种复杂的关系。该提案将调查癫痫动物齿状回中间神经元子集的尖峰时机发生的分解。先前的文献强烈支持这样一种观念，即改变齿状抑制可能导致癫痫发作和记忆缺陷，但这并未直接显示。在此提案中，我将检验以下假设：齿状抑制时机的这种分解直接导致癫痫中看到的记忆缺陷，并分别有助于癫痫发作。为了检验这一假设，我将使用体内硅探针在CA1和齿状回中同时记录LFP和单个单位，并将应用闭环光遗传学刺激方案来控制表达表达牙齿的齿状膜中的间尿神经元。这种闭环光遗传学刺激方案是创新的和令人兴奋的，因为它会改变齿状回的发射模式相对于Ca1 Theta循环的各个阶段，而不是在癫痫发作本身时操纵细胞发射。这些操作将在癫痫和健康的动物中进行，因此我们不仅可以确定病理海马中精确的中间神经元射击的影响，还可以确定健康海马。这些目标共同使用最先进的记录和操纵技术来获得对认知缺陷和癫痫发作的原因的新见解。