Optogenetic control of attention through prefrontal synchrony

描述(由申请者提供)：Recovery Act Limited竞赛：NIH健康与科学研究挑战资助金(RC1)RFA-OD-09-003广泛挑战领域：15，翻译科学研究领域：15-MH-109大脑高级功能和复杂行为的前额叶皮质调节。前额叶皮质(PFC)在包括注意力控制在内的执行功能中起着重要作用。PFC的损害损害了集中注意力、忽视分心因素和灵活地切换注意力的能力。在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的一些功能障碍，因此，了解PFC中调节认知功能的功能回路符合NIMH的战略计划。尽管所有的证据表明，从PFC到感觉关联皮质的自上而下的反馈对于控制注意力和其他认知功能是重要的，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PFC和联合皮质之间的相位耦合伽马频率同步。前额眼场(PFC内的FEF)和V4区(关联皮质内)之间的同步性强烈地受到注意力的调节。最重要的是，跨区域的同步性在时间上移动了8-12ms，这似乎正好是允许两个区域之间的传导和突触延迟的时间。因此，当细胞被最大限度地去极化并准备接受新的输入时，来自一个区域的尖峰将开始影响耦合区域中的细胞。注意过程中的这种相位耦合同步通常允许PFC与其他皮质区域进行有效的通信。然而，诸如此类的神经生理学数据必然只揭示了神经活动和行为之间的相关性，而不是因果关系。这项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频率的变化，并模拟注意对行为的影响。在这些测试中，我们将使用新的光遗传学技术，我们最近证明，这种技术可以用来以毫秒级的精度刺激灵长类神经元。使用光遗传工具，我们将从V4区同时刺激FEF和记录。我们将以伽马频率(~40赫兹)刺激FEF细胞，我们将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约8-12ms的时间/相位延迟。这种时间延迟的刺激应该最大限度地提高V4细胞对射频刺激的反应，从而模仿注意力对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的自下而上信号在FEF中驱动细胞的能力的影响。积极的证据表明，PFC和其他皮质区域之间的相位耦合同步性在注意调节中发挥着重要作用，这将对我们理解PFC在认知中的作用产生重大影响。更具体地说，PFC的神经同步性障碍可能与精神分裂症的认知功能障碍有关，本研究的积极结果可能为理解跨区域沟通障碍的作用提供重要的线索。。 公共卫生相关性：这项拟议的研究试图了解前额叶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障碍中都很常见，包括精神分裂症、抑郁症和ADHD。这些疾病影响着数以百万计的美国人，目前的治疗方法对许多人来说仍然不够。

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.