Optogenetic control of attention through prefrontal synchrony

通过前额叶同步进行注意力的光遗传学控制

• 批准号: 7936928
• 负责人: Robert Desimone
• 金额: $ 49.45万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936928
• 关键词: Accounting; Address; Affect; American; Animal Behavior; Animals; Area; Attention; Attention deficit hyperactivity disorder; Behavior; Behavioral; Biological; Brain; Cells; Cognition; Communication; Complex; Coupled; Coupling; Data; Development; Disease; Etiology; Feedback; Fiber Optics; Frequencies; Functional disorder; Grant; Impaired cognition; Lead; Lesion; Location; Measurable; Mediating; Mediator of activation protein; Mental Depression; Mental disorders; Methods; Monkeys; National Institute of Mental Health; Nature; Neurons; Phase; Play; Prefrontal Cortex; Primates; Public Health; Pump; Recovery; Regulation; Relative (related person); Research; Rest; Role; Schizophrenia; Sensory; Sensory Process; Signal Transduction; Stimulus; Strategic Planning; Subfamily lentivirinae; Synapses; Technology; Testing; Time; Translational Research; United States National Institutes of Health; Variant; Virus; abstracting; area V4; association cortex; cognitive function; executive function; extrastriate; flexibility; frontal eye fields; frontal lobe; health science research; innovation; millisecond; neurophysiology; novel; postsynaptic; programs; public health relevance; receptive field; relating to nervous system; response; tool

DESCRIPTION (provided by applicant): Recovery Act Limited Competition: NIH Challenge Grants in Health and Science Research (RC1) RFA-OD-09-003 Broad Challenge Area: 15, Translational Science Research Area: 15-MH-109 Prefrontal cortex regulation of higher brain function and complex behaviors. Summary/Abstract The prefrontal cortex (PFC) plays an important role in executive function, including the control of attention. Lesions of PFC impair the ability to focus attention, ignore distracters, and switch attention in a flexible manner. The cognitive dysfunctions found in schizophrenia and other mental disorders likely involve some dysfunction of the PFC, and thus, understanding the functional circuitry that mediates cognitive function in PFC is consistent with the NIMH strategic plan. In spite of all the evidence that top-down feedback from PFC to the sensory association cortex is important for the control of attention and other cognitive functions, the nature of the PFC feedback is still unclear. We recently found that one key component of this mechanism may be phase-coupled gamma-frequency synchrony between PFC and the association cortex. Synchrony between the frontal eye field (FEF, within PFC) and area V4 (within association cortex) is strongly modulated by attention. Most importantly, the cross area synchrony is shifted in time by 8-12 ms, which appears to be just the right amount of time to allow for conduction and synaptic delays between the two areas. Thus, spikes from one area will begin to affect cells in the coupled area when they are maximally depolarized and prepared to receive new input. Such phase- coupled synchrony during attention may generally allow PFC to communicate effectively with other cortical areas. However, neurophysiological data such as these necessarily reveal only correlations between neural activity and behavior, not causality. The proposed studies will directly test whether the phase coupled oscillations between FEF and V4 cause firing rate changes and mimic the effects of attention on behavior. For these tests, we will use novel new optogenetic technology, which we have recently demonstrated can be used for stimulating primate neurons with millisecond precision. Using optogenetic tools, we will simultaneously stimulate FEF and record from area V4. We will stimulate FEF cells at gamma frequencies (~ 40 Hz), and we will dynamically adjust the phase of stimulation to maintain a time/phase delay of approximately 8-12 ms relative to the phase of local field potentials in V4. Stimulation with this time delay should maximize the response of V4 cells to a stimulus in the RF, thereby mimicking the effects of attention on V4 responses and the animal's behavior. Conversely, we will stimulate in V4 and test the effects of stimulation phase on the ability of bottom-up signals from V4 to drive cells in FEF. Positive evidence that phase-coupled synchrony between PFC and other cortical areas plays an important role in the regulation of attention would have a major impact on our understanding of PFC's role in cognition. More specifically, a dysfunction of neural synchrony in PFC may contribute to the cognitive dysfunctions in schizophrenia, and positive results from the present application would potentially provide an important lead in understanding the role of impaired cross-area communication. . PUBLIC HEALTH RELEVANCE: The proposed research seeks to understand the fundamental biological mechanisms of attention in prefrontal cortex. This research addresses a critical public health need, as disorders of attention are common in many mental disorders, including schizophrenia, depression, and ADHD. These disorders affect millions of Americans and current treatments remain inadequate for many people.

说明（由申请人提供）：《恢复法案》有限竞赛：NIH 健康与科学研究挑战资助 (RC1) RFA-OD-09-003 广泛挑战领域：15，转化科学研究领域：15-MH-109 前额皮质调节更高的大脑功能和复杂的行为。摘要/摘要 前额皮质（PFC）在执行功能中发挥着重要作用，包括注意力的控制。 PFC 损伤会损害集中注意力、忽略干扰因素以及灵活转移注意力的能力。精神分裂症和其他精神障碍中发现的认知功能障碍可能涉及 PFC 的某些功能障碍，因此，了解介导 PFC 认知功能的功能回路与 NIMH 战略计划是一致的。尽管所有证据表明从 PFC 到感觉关联皮层的自上而下的反馈对于注意力和其他认知功能的控制很重要，但 PFC 反馈的性质仍不清楚。我们最近发现这一机制的一个关键组成部分可能是 PFC 和关联皮层之间的相位耦合伽马频率同步。额叶视野（FEF，PFC 内）和 V4 区域（关联皮层内）之间的同步性受到注意力的强烈调节。最重要的是，跨区域同步在时间上移动了 8-12 毫秒，这似乎是允许两个区域之间的传导和突触延迟的正确时间量。因此，当耦合区域中的细胞最大程度去极化并准备好接收新输入时，来自一个区域的尖峰将开始影响耦合区域中的细胞。注意力过程中的这种相位耦合同步通常可以允许 PFC 与其他皮质区域进行有效的沟通。然而，诸如此类的神经生理学数据必然只能揭示神经活动和行为之间的相关性，而不是因果关系。拟议的研究将直接测试 FEF 和 V4 之间的相位耦合振荡是否会导致放电率变化并模拟注意力对行为的影响。对于这些测试，我们将使用新颖的光遗传学技术，我们最近证明该技术可用于以毫秒精度刺激灵长类动物神经元。使用光遗传学工具，我们将同时刺激 FEF 并从 V4 区域进行记录。我们将以伽马频率（约 40 Hz）刺激 FEF 细胞，并且动态调整刺激的相位，以保持相对于 V4 中局部场电位的相位大约 8-12 ms 的时间/相位延迟。延迟时间的刺激应最大限度地提高 V4 细胞对 RF 刺激的反应，从而模拟注意力对 V4 反应和动物行为的影响。相反，我们将在 V4 中进行刺激，并测试刺激阶段对来自 V4 的自下而上信号驱动 FEF 中的细胞的能力的影响。积极的证据表明 PFC 和其他皮质区域之间的相位耦合同步在注意力调节中发挥着重要作用，这将对我们对 PFC 在认知中的作用的理解产生重大影响。更具体地，PFC中的神经同步功能障碍可能导致精神分裂症的认知功能障碍，并且本申请的积极结果可能为理解受损的跨区域沟通的作用提供重要的线索。 。 公共健康相关性：拟议的研究旨在了解前额皮质注意力的基本生物学机制。这项研究解决了一个关键的公共卫生需求，因为注意力障碍在许多精神疾病中很常见，包括精神分裂症、抑郁症和多动症。这些疾病影响着数百万美国人，目前的治疗方法对许多人来说仍然不足。