Understanding the Neural Mechanisms Controlling Brain-wide Dynamics

了解控制全脑动态的神经机制

• 批准号: 10366350
• 负责人: Timothy J. Buschman
• 金额: $ 46.01万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366350
• 关键词: Address; Animals; Basal Ganglia; Behavior; Behavior Control; Behavioral; Brain; Brain region; Calcium; Cognitive; Corpus striatum structure; Crowding; Diagnostic; Disease; Dopamine; Dorsal; Electrophysiology (science); Environment; Evolution; Foundations; Frequencies; Friends; Image; Lead; Learning; Medial; Midbrain structure; Modeling; Motor; Motor Cortex; Movement; Mus; Neuromodulator; Neurons; Norepinephrine; Parietal Lobe; Pattern; Play; Population; Positioning Attribute; Prefrontal Cortex; Process; Rewards; Role; Route; Schizophrenia; Sensory; Sensory Process; Series; Signal Transduction; Techniques; Testing; Time; Ventral Tegmental Area; Work; autism spectrum disorder; base; behavior change; cognitive control; experience; improved; innovation; insight; learned behavior; locus ceruleus structure; memory process; memory recall; mind control; nervous system disorder; neural patterning; neuromechanism; neuropsychiatric disorder; neuroregulation; noradrenergic; novel; optogenetics; predictive modeling; recruit; relating to nervous system; response; sensory cortex; sensory input; spatiotemporal; stimulus processing

PROJECT SUMMARY/ABSTRACT Behavior emerges from the flow of information between brain regions. For example, finding a friend in a crowd requires the interaction of brain regions performing sensory processing, memory processing, and motor responses. Disrupting how neural activity flows through the brain is thought to lead to deficits in several neuropsychiatric and neurological disorders, including schizophrenia and autism spectrum disorder. However, the neural mechanisms controlling the flow of information through the brain are not well understood. To capture how information flows through the brain, we recently used mesoscale calcium imaging to record the dynamics of neural activity across the dorsal cortex of mice. Surprisingly, we found cortex-wide neural dynamics could be captured in 14 unique spatiotemporal patterns of neural activity. These ‘motifs’ of activity occurred repeatedly, were common to all mice, and were associated with specific behaviors. Importantly, identifying these motifs allows us to quantify how neural activity is flowing across cortex. Here, we will leverage this ability to understand the neural mechanisms that control the expression of different motifs and, thus, control the flow of neural activity across the brain. Our Aims will address three key components of control: First, information must be routed between brain regions. Activity from a brain region can flow to several possible downstream regions (to support different behaviors). Using mesoscale calcium imaging, we will quantify how activity is routed through the brain at each moment in time. Simultaneous electrophysiology and optogenetics will then test two prominent hypotheses that predict activity is routed differently depending on 1) how information is represented in the population of neurons and 2) the frequency of synchronous oscillations. Second, the brain must be able to control how neural activity flows through cortex. Prefrontal cortex and the basal ganglia are two regions thought to provide such control. However, their role in guiding cortex-wide neural dynamics has never been directly tested. Therefore, our second aim will combine mesoscale imaging, electrophysiology, and optogenetics to test whether neurons in prefrontal cortex or basal ganglia control the expression of different motifs and, thus, control how neural activity flows through the brain. Third, in order to learn a new behavior, one must learn the pattern of neural activity that supports that behavior. Neuromodulation is thought to be critical for such learning: current models propose norepinephrine explores new patterns while dopamine refines patterns. To test this, our third aim will combine mesoscale imaging with recording and stimulation of noradrenergic/dopaminergic midbrain neurons while animals learn new behaviors. In this way, we aim to understand how neuromodulation changes behavior and cortex-wide neural dynamics. Our innovative combination of mesoscale imaging, electrophysiology, and optogenetics will provide insight into how neural activity is routed (Aim 1) and how cortex-wide dynamics are controlled (Aim 2) and learned (Aim 3). By understanding these mechanisms, we hope to improve treatments for diseases disrupting cognitive control.

项目总结/摘要 行为产生于大脑区域之间的信息流动。例如，在人群中寻找朋友 需要大脑区域的相互作用，执行感觉处理，记忆处理和运动 应答扰乱大脑中的神经活动被认为会导致几个方面的缺陷。 神经精神和神经障碍，包括精神分裂症和自闭症谱系障碍。然而，在这方面， 控制大脑中信息流动的神经机制还没有得到很好的理解。 为了捕捉信息是如何在大脑中流动的，我们最近使用了中尺度钙成像来记录大脑中的钙离子。 小鼠背侧皮层神经活动的动力学。令人惊讶的是，我们发现大脑皮层神经 动态可以在14种独特的神经活动时空模式中捕获。这些活动的“主题” 重复发生，对所有小鼠都是共同的，并与特定的行为有关。重要的是， 识别这些图案使我们能够量化神经活动是如何流经大脑皮层的。在这里，我们将利用 这种理解控制不同图案表达的神经机制的能力，因此， 控制大脑中神经活动的流动。我们的目标将涉及控制的三个关键组成部分： 首先，信息必须在大脑区域之间传递。一个大脑区域的活动可以流向几个 可能的下游区域（以支持不同的行为）。使用中尺度钙成像，我们将 量化每时每刻大脑活动的路径。同步电生理学和 然后，光遗传学将测试两个突出的假设，预测活动的路线不同，这取决于1） 信息是如何在神经元群体中表达的; 2）同步振荡的频率。 其次，大脑必须能够控制神经活动如何流经皮层。前额叶皮层和 基底神经节是被认为提供这种控制的两个区域。然而，它们在引导整个皮层神经元 动力学从未被直接测试过。因此，我们的第二个目标将结合联合收割机中尺度成像， 电生理学和光遗传学来测试前额叶皮层或基底神经节中的神经元是否控制着大脑的活动。 不同图案的表达，从而控制神经活动如何流经大脑。 第三，为了学习一种新的行为，人们必须学习支持这种行为的神经活动模式。 神经调节被认为是这种学习的关键：目前的模型建议去甲肾上腺素探索 而多巴胺则提炼新的模式。为了验证这一点，我们的第三个目标将结合联合收割机中尺度成像与 记录和刺激去甲肾上腺素能/多巴胺能中脑神经元，同时动物学习新的行为。 通过这种方式，我们的目标是了解神经调节如何改变行为和皮层范围的神经动力学。 我们创新性地将中尺度成像、电生理学和光遗传学结合起来， 神经活动是如何路由的（目标1），以及皮层范围内的动态是如何控制的（目标2）和学习的（目标3）。 通过了解这些机制，我们希望改善对破坏认知控制的疾病的治疗。