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: 7809029
• 负责人: Robert Desimone
• 金额: $ 48.01万
• 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/7809029
• 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 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; depression; 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.

描述（由申请人提供）：恢复法案有限竞争：美国国立卫生研究院挑战赠款在健康和科学研究（RC 1）RFA-OD-09-003广泛的挑战领域：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：前额叶皮层（PFC）在执行功能中起着重要的作用，包括注意力的控制。前额叶皮层的损伤损害了集中注意力、忽视干扰物和灵活转换注意力的能力。在精神分裂症和其他精神疾病中发现的认知功能障碍可能涉及PFC的一些功能障碍，因此，了解PFC中介导认知功能的功能电路与NIMH战略计划一致。尽管所有的证据表明，从PFC到感觉联合皮层的自上而下的反馈对于控制注意力和其他认知功能很重要，但PFC反馈的性质仍然不清楚。我们最近发现，这一机制的一个关键组成部分可能是相位耦合的γ-频率PFC和联合皮质之间的同步。额叶眼场（FEF，PFC内）和V4区（联合皮层内）之间的同步性受到注意力的强烈调制。最重要的是，跨区域同步在时间上移动了8-12 ms，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，来自一个区域的尖峰将开始影响耦合区域中的细胞，此时它们被最大程度地去极化并准备接收新的输入。这种在注意过程中的相位耦合同步通常可以使PFC与其他皮层区域有效地交流。然而，像这样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引起放电率的变化，并模仿注意力对行为的影响。对于这些测试，我们将使用新的光遗传学技术，我们最近已经证明该技术可以用于以毫秒级的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区记录。我们将以伽马频率（~ 40 Hz）刺激FEF细胞，并且我们将动态地调整刺激的相位以相对于V4中的局部场电位的相位维持大约8-12 ms的时间/相位延迟。具有这种时间延迟的刺激应该使V4细胞对RF中的刺激的响应最大化，从而模仿注意力对V4响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中细胞的能力的影响。PFC和其他皮质区域之间的相位耦合同步在注意力调节中起着重要作用，这一积极证据将对我们理解PFC在认知中的作用产生重大影响。更具体地，PFC中的神经同步功能障碍可能导致精神分裂症中的认知功能障碍，并且来自本申请的积极结果将潜在地提供理解受损的跨区域通信的作用的重要线索。. 公共卫生相关性：拟议中的研究旨在了解前额叶皮层注意力的基本生物机制。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ADHD。这些疾病影响着数百万美国人，目前的治疗对许多人来说仍然不够。