Controlling Interareal Gamma Coherence by Optogenetics, Pharmacology and Behavior

通过光遗传学、药理学和行为控制区域间伽玛相干性

• 批准号: 8208975
• 负责人: Timothy J. Buschman
• 金额: $ 8.48万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208975
• 关键词: Acetylcholine; Address; Affect; Animal Model; Area; Attention; Autistic Disorder; Axon; Behavior; Behavioral; Brain; Brain Diseases; Brain region; Cholinergic Agonists; Cognition; Cognitive; Communication; Complex; Computer Simulation; Coupled; Coupling; Disease; Electrophysiology (science); Equilibrium; Foundations; Frequencies; Future; Goals; Laboratories; Learning; Link; Measures; Mental disorders; Mentors; Mentorship; Methods; Modality; Monkeys; Mus; Muscarinic Agonists; Nature; Neocortex; Nicotinic Agonists; Optics; Parietal Lobe; Pharmacology; Phase; Primates; Protocols documentation; Reticular Formation; Rodent; Schizophrenia; Short-Term Memory; Somatosensory Cortex; Source; Techniques; Testing; Training; Transgenic Mice; Work; autism spectrum disorder; base; career; cholinergic; cognitive control; cognitive function; direct application; experience; flexibility; frontal lobe; human data; in vivo; insight; interest; neuromechanism; nonhuman primate; novel; optogenetics; public health relevance; relating to nervous system; response; skills; somatosensory

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.

描述（由申请人提供）：皮质区域之间的一致性与包括注意力和工作记忆在内的认知功能有关。连贯性可能会动态地改变信息通过大脑的路径，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。 目前还没有关于皮质间一致性如何产生的系统性体内研究。在这里，我们将测试以下假设：当源区域中的局部振荡传播到目标区域并与之同步时，会发生区域间皮质伽马 (30-80 Hz) 相干性。计算模型预测，目标中预先存在的伽马强度将影响其与传入振荡的相干性：“弱”局部伽马振荡将很容易被夹带，从而导致两个区域之间的相干性，而“强”振荡会抵制外部输入，从而使相干性变得困难（除非输入在相位和频率上匹配）。 检验这一假设需要对局部振荡进行体内因果控制，这是摩尔实验室最近利用光遗传学开发的一项技术。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协调的规则。我们将通过光遗传学诱导源区域（初级体感皮层，SI）中的局部伽马振荡，并测量它们与目标区域（次级体感皮层，SII）的一致性。我们将通过三种方式操纵目标中持续伽马振荡的强度来检验我们的假设。在目标 1 中，我们将以光遗传学方式在目标中诱发伽马振荡，以参数方式改变功率和相位，以确定它们对相干性的影响。胆碱能激动剂会诱导新皮质中的伽马振荡，而乙酰胆碱可能是注意力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音调并测量其对相干性的影响来诱发目标中的伽马振荡。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学诱导局部伽玛能力的影响，及其对建立区域之间一致性的影响。 这些目标将直接检验关于区域间一致性机制的重要假设。此外，这个提案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之前的灵长类动物经验与小鼠身上的这些新技术结合起来。我将在经过训练执行复杂行为的灵长类动物中使用电生理学，以生成有关认知基础神经机制的假设。然后可以使用小鼠中可用的强大方法来剖析这些提出的神经机制。 公共健康相关性：该项目将研究大脑区域如何在伽马振荡带中实现彼此的一致性。连贯性被认为有助于大脑区域之间的沟通，并且在多种精神和大脑疾病中发现了伽马表达和区域间连贯性的改变，包括精神分裂症和自闭症。因此，我们的工作可能会深入了解这些适应不良的变化。