Controlling Interareal Gamma Coherence by Optogenetics, Pharmacology and Behavior

描述（由申请人提供）：皮质区域之间的连贯性涉及认知功能，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，提供认知所需的灵活性。事实上，连贯性的破坏与精神分裂症和自闭症谱系障碍等神经疾病有关。 目前还没有系统的，在体内，皮层间的连贯性如何产生的研究。在这里，我们将测试的假设，即区域间皮层伽马（30-80 Hz）的相干性发生时，在源区域的本地振荡传播到，并与目标区域同步。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”局部伽马振荡将容易被夹带，导致两个区域之间的相干性，而“强”振荡抵抗外部输入，使得相干性困难（除非输入在相位和频率上匹配）。 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。将光遗传学与多区域记录相结合将使我们能够发现区域之间振荡如何连贯的规则。我们将在源区域（初级躯体感觉皮层，SI）中光遗传诱导局部伽马振荡，并测量它们与目标区域（次级躯体感觉皮层，SII）的一致性。我们将通过三种方式操纵目标中持续的伽马振荡的强度来测试我们的假设。在目标1中，我们将在目标中光遗传地诱导伽马振荡，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γ振荡的新皮层和乙酰胆碱可能是关注中观察到的区域间一致性的基础。因此，在目标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靶点中的伽马振荡。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学诱导局部伽马的能力的影响，以及它对建立区域之间的一致性的影响。 这些目标将直接检验关于地区间协调机制的一个重要假设。此外，这个建议将使我能够在克里斯托弗摩尔博士的指导下学习小鼠的光遗传学，电生理学和行为技术。我未来的职业目标是将我以前的灵长类动物经验与这些小鼠新技术结合起来。我将使用灵长类动物的电生理学训练来执行复杂的行为，以产生关于认知的神经机制的假设。这些提出的神经机制，然后可以解剖使用强大的方法在小鼠。 公共卫生相关性：该项目将研究大脑区域如何在伽马振荡带中实现相互一致。连贯性被认为有助于大脑区域之间的交流，伽马表达和区域间连贯性的改变在几种精神和大脑疾病中被发现，包括精神分裂症和自闭症。因此，我们的工作可能会为这些适应不良的变化提供洞察力。

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.