Closed-Loop Control of Hippocampal Output During a Working Memory Task

描述（由申请人提供）：神经精神障碍、情感障碍和痴呆患者经常表现出异常的脑振荡，通过头皮电位测量。一个令人感兴趣的振荡波段是θ波段（4-10赫兹），它在从精神分裂症到阿尔茨海默氏症的各种疾病中都被破坏。行为测试显示，患有这些疾病的患者通常表现出工作记忆受损，这一过程已知与健康受试者的θ波振荡升高有关。中断的θ波振荡是这些损伤的潜在原因，还是它们的出现仅仅与认知缺陷有关？寻找潜在治疗方法的途径应该受到这个问题的答案的影响。对啮齿动物的广泛研究为θ波在认知任务中的重要性提供了进一步的证据，但是——直到现在——在不改变整个回路特性的情况下破坏θ波节律是不可能的。今天，光遗传学技术使我们能够在毫秒的时间尺度上随意地操纵基因定义的细胞群的活动。我将利用这种能力来破坏海马体中的θ波带活动，海马体是θ波产生的关键中枢。具体来说，我将在θ波产生的特定阶段阻断海马区的输出，这将使我能够观察到对工作记忆表现的试验对试验的影响。如果我观察到特定阶段的行为缺陷，它将表明，在单个teta周期内的尖峰隔离实际上对行为指导很重要。如果没有观察到特定阶段的中断，则表明θ波对于短期行为指导并不重要，至少在CA1背侧区域是如此。相反，这一结果有利于θ波在长期记忆存储中的作用，这可以在未来的实验中进行测试。这个提议代表了在theta时间尺度上与海马体相互作用的第一次尝试。要做到这一点，我需要接受训练，学习最有效的方法来在线读取海马体的状态，以便实施特定阶段的刺激。我在克里斯托弗·摩尔（Christopher Moore）的实验室（现在在布朗大学）工作时，已经有了光遗传学和电生理学的经验，但到目前为止，我所有的实验都涉及“开环”刺激。我的赞助人马修·威尔逊的实验室在“闭环”刺激方面有着丰富的经验，特别是与破坏海马体的振荡活动有关的经验。Kirschstein-NRSA奖学金为期两年，将为我的培训和完成实验提供必要的支持。我希望这些实验能够开创一个先例，将光遗传学与闭环反馈相结合，这是研究异常脑节律与异常认知之间关系的有力途径。

DESCRIPTION (provided by applicant): Patients with neuropsychiatric disorders, affective disorders, and dementias often display abnormal brain oscillations, as measured by electrical potentials on the scalp. One oscillatory band of interest is the theta band (4-10 Hz), which is disrupted in conditions ranging from schizophrenia to Alzheimer's. Behavioral tests reveal that patients with these disorders often display impaired working memory, a process known to be associated with elevated theta oscillations in healthy subjects. Are disrupted theta oscillations the underlying cause of these impairments, or is their appearance merely correlated with cognitive deficits? Routes toward potential therapies should be influenced by the answer to this question. Extensive studies in rodents provide further evidence for the importance of theta in cognitive tasks, but-until now-it was impossible to disrupt theta rhythms without changing the properties of the entire circuit. Today, optogenetic techniques allow us to causally manipulate the activity of genetically defined cell populations on the timescale of milliseconds. I will harnes this ability to disrupt theta-band activity in the hippocampus, a critical hub for theta generation Specifically, I will block the output of the hippo- campus at particular phases of theta, which wil allow me to observe trial-to-trial effects on working- memory performance. If I observe a phase-specific behavioral deficit, it will indicate that the segregation of spikes within an individual teta cycle is, in fact, important for behavioral guidance. If no phase- specific disruption is observed,it would suggest that theta is not important for short-term behavioral guidance, at least in the dorsal CA1 region. Instead, this result would favor the role of theta in long-term memory storage, something that could be tested in future experiments. This proposal represents the first attempt to interact with the hippocampus on the timescale of theta. To do so, I will need to receive training on the most efficient ways to read out the state of the hippocampus online, in order to implement phase-specific stimulation. I already have experience with optogenetics and electrophysiology from my work in the laboratory of Christopher Moore, now at Brown University, but so far all of my experiments have involved "open-loop" stimulation. The lab of my sponsor, Matthew Wilson, has a wealth of experience with "closed-loop" stimulation especially that related to disrupting oscillatory activity in the hippocampus. A Kirschstein-NRSA Fellowship lasting two years would provide the support necessary to fund my training and bring my experiments to completion. I hope these experiments will help set a precedent for combining optogenetics and closed-loop feedback, which represents a powerful approach to studying the relationship between abnormal brain rhythms and abnormal cognition.