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: 10316977
• 负责人: Zoé Christenson Wick
• 金额: $ 6.64万
• 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 2023-11-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316977
• 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 (Brain); Impact Seizures; Impaired cognition; Impairment; Interneurons; Literature; Mediating; Memory; Memory impairment; Mus; Neurons; Parvalbumins; Pathologic; Patients; Pattern; Performance; 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.

颞叶癫痫是一种衰弱和普遍的疾病，其特征不仅是典型的从海马体出现的癫痫发作，而且还有严重的记忆障碍。TLE患者报告说，他们最担心的是潜在的记忆问题。癫痫发作本身与与颞叶癫痫相关的记忆缺陷之间的关系是复杂和微妙的。虽然癫痫发作和记忆障碍的原因尚不清楚，但啮齿动物模型可以用来研究这种复杂的关系。这项提议将调查癫痫动物齿状回中的中间神经元子集的棘波计时发生的故障。以前的文献强烈支持这样的观点，即改变的齿状回抑制可能导致癫痫发作和记忆障碍，但这一点尚未被直接证明。在这项提案中，我将检验这样一种假设，即齿状回抑制时间的这种崩溃直接导致癫痫患者的记忆缺陷，并分别导致癫痫发作。为了验证这一假设，我将使用活体硅探针同时记录CA1和齿状回中的LFP和单个单位，并将应用闭合环光遗传刺激方案来控制表达小白蛋白的神经元间放电。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特定抑制性神经元相对于CA1 theta周期不同阶段的放电模式，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身上进行，这样我们不仅可以确定病理海马区精确的中间神经元放电的效果，而且还可以确定健康海马区的精确中间神经元放电的影响。总之，这些目标将使用最先进的记录和操纵技术来对认知缺陷和癫痫的原因获得新的见解。