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

描述(申请人提供)：神经精神障碍、情感障碍和痴呆症患者经常表现出异常的脑振荡，通过头皮上的电位来测量。一个令人感兴趣的振荡频段是theta频段(4-10赫兹)，它在精神分裂症和阿尔茨海默氏症等疾病中会受到干扰。行为测试显示，患有这些障碍的患者经常表现出工作记忆受损，这一过程与健康受试者的theta振荡升高有关。这些损伤的根本原因是被扰乱的theta振荡，还是它们的出现仅仅与认知缺陷有关？通往潜在疗法的路线应该受到这个问题的答案的影响。对啮齿动物的广泛研究进一步证明了theta在认知任务中的重要性，但到目前为止，如果不改变整个回路的特性，就不可能扰乱theta的节奏。今天，光遗传技术使我们能够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。我将利用这种能力来扰乱海马体中的theta带活动，海马体是theta生成的关键中枢。具体地说，我将在theta的特定阶段阻止河马校园的输出，这将使我能够观察试验对工作记忆表现的影响。如果我观察到一个特定阶段的行为缺陷，它将表明在一个单独的TETA周期内尖峰的分离实际上对于行为指导是重要的。如果没有观察到特定阶段的干扰，这将表明theta对于短期行为指导并不重要，至少在CA1背侧区域是这样。相反，这一结果将有利于theta在长期记忆存储中的作用，这一点可能会在未来的实验中得到测试。这一提议代表了首次尝试在theta的时间尺度上与海马体相互作用。要做到这一点，我需要接受关于在线读取海马体状态的最有效方法的培训，以便实施特定阶段的刺激。我在克里斯托弗·摩尔的实验室已经有了光遗传学和电生理学方面的经验，但到目前为止，我所有的实验都涉及到“开环”刺激。我的赞助人马修·威尔逊的实验室在“闭环”刺激方面有丰富的经验，尤其是与扰乱海马体振荡活动有关的刺激。为期两年的Kirschstein-NRSA奖学金将提供必要的支持，以资助我的培训并完成我的实验。我希望这些实验将有助于开创光遗传学和闭环反馈相结合的先例，这是研究异常大脑节律和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.