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

工作记忆任务期间海马输出的闭环控制

• 批准号: 8392517
• 负责人: Joshua H Siegle
• 金额: $ 4.22万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392517
• 关键词: Accounting; Adverse effects; Algorithms; Alzheimer' s Disease; Animals; Anxiety; Appearance; Behavior; Behavioral; Bilateral; Biological Models; Brain; Cells; Code; Cognition; Cognitive; Cognitive deficits; Cues; Custom; Decision Making; Dementia; Disease; Dorsal; Electrophysiology (science); Feedback; Fellowship; Fiber Optics; Fire - disasters; Funding; Future; Generations; Goals; Hippocampus (Brain); Human; Impairment; Implant; Individual; Information Retrieval; Interneurons; Laboratories; Lasers; Learning; Light; Location; Measures; Mental disorders; Methods; Mood Disorders; Mus; National Research Service Awards; Neocortex; Output; Patients; Performance; Periodicity; Phase; Physiologic pulse; Plant Roots; Population; Process; Property; Pyramidal Cells; REM Sleep; Reading; Retrieval; Rewards; Rodent; Role; Route; Scalp structure; Schizophrenia; Short-Term Memory; Specificity; Symptoms; Techniques; Testing; Thalamic structure; Theta Rhythm; Time; Training; Universities; Update; Work; awake; base; behavior test; cell assembly; cell type; electrical potential; experience; extracellular; interest; long term memory; millisecond; neuropsychiatry; novel; optogenetics; relating to nervous system; research study; response; segregation; tool

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.

描述（由申请人提供）：神经精神疾病，情感障碍和痴呆症患者通常表现出异常的脑振荡，如头皮上的电势测量。一个感兴趣的振荡带是Theta带（4-10 Hz），在从精神分裂症到阿尔茨海默氏症的条件下，该带被破坏。行为测试表明，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theta振荡升高有关。 theta振荡的破坏是这些障碍的根本原因，还是它们的外观仅仅与认知缺陷相关？潜在疗法的途径应受这个问题的答案的影响。对啮齿动物的广泛研究为theta在认知任务中的重要性提供了进一步的证据，但是直到现在就不可能破坏theta的节奏而不改变整个电路的性质。如今，光遗传学技术使我们能够因遗传定义的细胞群在毫秒的时间范围内而有因果操纵。我将这种能力破坏海马中的theta波段活动，这是Theta生成的关键枢纽，我将在Theta的特定阶段阻止Hippo-Campus的输出，这将使我能够观察到对工作记忆绩效的试验效果。如果我观察到特定相位的行为不足，它将表明单个TETA周期内的尖峰隔离实际上对于行为引导很重要。如果未观察到相位特异性破坏，则至少在背侧CA1区域中，Theta对于短期行为指导并不重要。取而代之的是，该结果将有利于Theta在长期记忆存储中的作用，这可以在将来的实验中进行测试。该提议代表了在Theta时期与海马相互作用的首次尝试。为此，我需要接受有关在线读取海马状态的最有效方法的培训，以实施特定阶段的刺激。我已经从现在在布朗大学（Brown University）的克里斯托弗·摩尔（Christopher Moore）实验室的工作中获得了光遗传学和电生理学的经验，但是到目前为止，我所有的实验都涉及“开环”刺激。我的赞助商马修·威尔逊（Matthew Wilson）的实验室在“闭环”刺激方面拥有丰富的经验，尤其是与破坏海马中振荡活动有关的经验。持续两年的Kirschstein-NRSA奖学金将为我的培训提供必要的支持，并使我的实验完成。我希望这些实验将有助于建立相结合光遗传学和闭环反馈的先例，这代表了研究异常脑节律与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会在他们的思维和感觉方式上经历差异，而且在大脑产生的节奏活动中存在差异。没有人知道节奏活动中的这些变化是否是其认知差异的根源，因此，疗法的潜在靶标或它们是否仅仅是深层根本原因的无害副作用。我将使用新的方法选择性地改变小鼠的这些节奏，我将测试特定类型的节奏活动如何有助于行为，目的是了解脑部节律的变化如何解释各种疾病的症状，例如阿尔茨海默氏症和精神分裂症。