Controlling Interareal Gamma Coherence by Optogenetics, Pharmacology and Behavior

描述（由申请人提供）：皮层区域之间的一致性涉及认知功能，包括注意力和工作记忆。连贯性可以动态地改变信息在大脑中的路径，为认知提供必要的灵活性。事实上，连贯性的中断与精神分裂症和自闭症谱系障碍等神经系统疾病有关。目前还没有系统的体内研究皮层间相干性是如何产生的。在这里，我们将测试当源区域的局部振荡传播到目标区域并与目标区域同步时，区域间皮质伽马（30-80 Hz）相干性发生的假设。计算模型预测，目标中预先存在的伽马的强度将影响其与传入振荡的相干性：“弱”的局部伽马振荡将很容易被携带，导致两个区域之间的相干性，而“强”的振荡抵抗外部输入，使相干性变得困难（除非输入在相位和频率上匹配）。为了验证这一假设，需要在体内对局部振荡进行因果控制，这是摩尔实验室最近利用光遗传学开发的一种技术。光遗传学与多区域记录的耦合将使我们能够发现振荡如何在区域之间凝聚的规则。我们将在源区域（初级体感皮层，SI）诱导局部伽马振荡，并测量其与目标区域（次级体感皮层，SII）的一致性。我们将通过三种方式操纵目标体内正在进行的伽马振荡的强度来检验我们的假设。在目标1中，我们将光遗传诱导目标中的伽马振荡，参数化地改变功率和相位，以确定它们对相干性的影响。胆碱能激动剂诱导新皮层的伽马振荡，乙酰胆碱可能是注意中观察到的区域间一致性的基础。因此，在Aim 2中，我们将通过增加局部胆碱能张力并测量其对相干性的影响来诱导目标中的伽马振荡。啮齿动物、猴子和人类的数据将伽马振荡与注意力联系起来。因此，在目标3中，我们将测试注意力对光遗传诱导局部伽马能力的影响，以及它对建立区域间一致性的影响。这些目标将直接检验关于区域间一致性机制的一个重要假设。此外，我将在Christopher Moore博士的指导下学习光遗传学、电生理学和小鼠行为学技术。我未来的职业目标是把我以前在灵长类动物身上的经验和这些在老鼠身上的新技术结合起来。我将在灵长类动物身上使用电生理学来训练它们执行复杂的行为，以产生关于认知背后的神经机制的假设。然后，这些提出的神经机制可以使用在小鼠身上可用的强大方法进行解剖。

DESCRIPTION (provided by applicant): Coherence between cortical regions has been implicated in cognitive functions including attention and working memory. Coherence may act to dynamically alter the routing of information through the brain, providing the flexibility that is necessary for cognition. Indeed, disruptions in coherence are linked to neural disorders such as schizophrenia and autism spectrum disorder. There has been no systematic, in vivo, study of how inter-cortical coherence arises. Here we will test the hypothesis that inter-area cortical gamma (30-80 Hz) coherence occurs when local oscillations in a source region propagate to, and synchronize with, a target region. Computational modeling predicts that the strength of pre-existing gamma in the target will affect its coherence with an incoming oscillation: 'weak' local gamma oscillations will be easily entrained, leading to coherence between the two regions, while 'strong' oscillations resist external input, making coherence difficult (unless the input matches in phase and frequency). Testing this hypothesis requires causal in vivo control of local oscillations, a technique that the Moore laboratory has recently developed utilizing optogenetics. Coupling optogenetics with multi-area recording will allow us to discover the rules of how oscillations cohere between areas. We will optogenetically induce local gamma oscillations in a source area (primary somatosensory cortex, SI) and measure their coherence with a target area (secondary somatosensory cortex, SII). We will test our hypothesis by manipulating the strength of ongoing gamma oscillations in the target in three ways. In Aim 1, we will optogenetically induce gamma oscillations in the target, parametrically varying the power and phase, in order to determine their effect on coherence. Cholinergic agonists induce gamma oscillations in the neocortex and acetylcholine may underlie the inter-areal coherence observed in attention. Therefore, in Aim 2, we will induce gamma oscillations in the target by increasing the local cholinergic tone and measuring its impact on coherence. Rodent, monkey and human data link gamma oscillations with attention. So, in Aim 3, we will test the impact of attention on the ability to optogenetically induce local gamma, and its impact on establishing coherence between areas. These aims will directly test an important hypothesis about the mechanism of inter-areal coherence. In addition, this proposal will allow me to learn optogenetic, electrophysiological, and behavioral techniques in mice, under the mentorship of Dr. Christopher Moore. My future career goals are to combine my previous primate experience with these new techniques in mice. I will use electrophysiology in primates trained to perform complex behaviors to generate hypotheses about the neural mechanisms underlying cognition. These proposed neural mechanisms can then be dissected using the powerful methods available in mice. PUBLIC HEALTH RELEVANCE: This project will investigate how brain regions achieve coherence with one another in the gamma oscillation band. Coherence is thought to aid in the communication between brain regions, and alterations in gamma expression and in inter-areal coherence are found in several mental and brain disorders, including schizophrenia and autism. Our work may, therefore, provide insight into these maladaptive changes.