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

描述（由申请人提供）：患有神经精神疾病、情感障碍和痴呆症的患者经常表现出异常的大脑振荡，这是通过头皮上的电位来测量的。一个令人感兴趣的振荡频带是 theta 频带（4-10 Hz），该频带在从精神分裂症到阿尔茨海默氏症等各种疾病中都会受到干扰。行为测试表明，患有这些疾病的患者经常表现出工作记忆受损，这一过程已知与健康受试者的 θ 振荡升高有关。 θ 振荡被破坏是这些损伤的根本原因，还是它们的出现仅仅与认知缺陷相关？潜在治疗的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 θ 在认知任务中的重要性提供了进一步的证据，但直到现在，不可能在不改变整个回路特性的情况下扰乱 θ 节律。如今，光遗传学技术使我们能够在毫秒的时间尺度上因果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 带活动，海马体是 θ 生成的关键枢纽。具体来说，我将在 θ 的特定阶段阻止海马体的输出，这将使我能够观察试验对工作记忆表现的影响。如果我观察到特定阶段的行为缺陷，则表明单个四周期内尖峰的分离实际上对于行为指导很重要。如果没有观察到特定阶段的破坏，则表明 θ 对于短期行为指导并不重要，至少在背侧 CA1 区域是这样。相反，这一结果有利于 θ 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。这一提议代表了在 theta 时间尺度上与海马体相互作用的首次尝试。为此，我需要接受有关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。我在布朗大学克里斯托弗·摩尔实验室的工作中已经积累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“开环”刺激。我的资助者马修·威尔逊的实验室在“闭环”刺激方面拥有丰富的经验，尤其是与破坏海马体振荡活动相关的经验。为期两年的 Kirschstein-NRSA 奖学金将为我的培训提供必要的支持，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，这代表了研究异常大脑节律和异常认知之间关系的有力方法。

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.