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

描述（由申请人提供）：患有神经精神障碍、情感障碍和痴呆的患者通常表现出异常的脑振荡，如通过头皮上的电位所测量的。一个感兴趣的振荡带是θ带（4-10 Hz），其在从精神分裂症到阿尔茨海默氏症的条件下被破坏。行为测试显示，患有这些疾病的患者通常表现出受损的工作记忆，这一过程与健康受试者的θ振荡升高有关。θ波振荡中断是这些损伤的根本原因，还是它们的出现仅仅与认知缺陷有关？潜在的治疗途径应该受到这个问题的答案的影响。对啮齿类动物的广泛研究为theta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，不可能破坏theta节律。今天，光遗传学技术允许我们在毫秒的时间尺度上因果地操纵遗传定义的细胞群体的活动。我会利用哈内斯这种能力来破坏海马体中θ波的活动，这是θ波产生的关键枢纽具体来说，我会在θ波的特定阶段阻断海马体的输出，这将使我能够观察到试验对工作记忆表现的影响。如果我观察到特定阶段的行为缺陷，这将表明单个teta周期内尖峰的分离对于行为指导非常重要。如果没有观察到相位特异性干扰，这表明θ对于短期行为指导并不重要，至少在背侧CA 1区域是如此。相反，这一结果将有利于θ在长期记忆存储中的作用，这一点可以在未来的实验中进行测试。这个提议代表了第一次尝试在θ的时间尺度上与海马体相互作用。要做到这一点，我需要接受培训，学习在线读取海马体状态的最有效方法，以便实施特定阶段的刺激。我在布朗大学的克里斯托弗·摩尔实验室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（Matthew Wilson）的实验室在“闭环”刺激方面有着丰富的经验，尤其是与扰乱海马体振荡活动有关的经验。为期两年的Kirschstein-NRSA奖学金将提供必要的支持，以资助我的培训和完成我的实验。我希望这些实验将有助于为结合光遗传学和闭环反馈开创先例，这是研究异常脑节律和异常认知之间关系的有力方法。 公共卫生相关性：患有精神障碍的人不仅在思考和感受方面存在差异，而且在大脑产生的节奏活动方面也存在差异。没有人知道这些节律性活动的变化是他们认知差异的根源，因此也是治疗的潜在目标，还是仅仅是更深层次原因的无害副作用。使用新方法选择性地改变小鼠的这些节律，我将测试特定类型的节律活动如何影响行为，目的是了解大脑节律的变化如何解释各种疾病的症状，如阿尔茨海默氏症和精神分裂症。

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. PUBLIC HEALTH RELEVANCE: Individuals who suffer from mental disorders not only experience differences in the way they think and feel, but also have differences in the rhythmic activity generated by their brain. Nobody knows whether these changes in rhythmic activity are at the root of their cognitive differences-and, therefore, a potential target for therapies-or whether they are merely a harmless side-effect of a deeper underlying cause. Using new methods to selectively alter these rhythms in mice, I will test how a specific type of rhythmic activity contributes to behavior, with the goal of understanding how changes in brain rhythms might account for the symptoms of a variety of disorders, such as Alzheimer's and schizophrenia.