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.

项目概要/摘要 行为是由大脑区域之间的信息流产生的。例如，在人群中寻找朋友 需要执行感觉处理、记忆处理和运动的大脑区域的相互作用 回应。扰乱神经活动流经大脑的方式被认为会导致多种功能缺陷 神经精神和神经系统疾病，包括精神分裂症和自闭症谱系障碍。然而， 控制大脑信息流的神经机制尚不清楚。 为了捕捉信息如何流经大脑，我们最近使用中尺度钙成像来记录 小鼠背皮质神经活动的动力学。令人惊讶的是，我们发现皮层范围的神经 可以通过 14 种独特的神经活动时空模式来捕捉动态。这些活动的“主题” 这种现象反复发生，对所有小鼠来说都很常见，并且与特定行为相关。重要的是， 识别这些基序使我们能够量化神经活动如何穿过皮层。在这里，我们将利用 这种理解控制不同基序表达的神经机制的能力，因此， 控制大脑中神经活动的流动。我们的目标将解决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。大脑某个区域的活动可以流向多个区域 可能的下游区域（以支持不同的行为）。使用介观钙成像，我们将 量化每个时刻的活动如何通过大脑进行。同时电生理学和 然后，光遗传学将测试两个重要的假设，这些假设预测活动的路由方式不同，具体取决于 1) 信息如何在神经元群体中表示以及 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。前额皮质和 基底神经节是被认为提供这种控制的两个区域。然而，它们在指导整个皮层神经元中的作用 动力学从未被直接测试过。因此，我们的第二个目标将结合介观成像， 电生理学和光遗传学来测试前额皮质或基底神经节中的神经元是否控制 不同主题的表达，从而控制神经活动如何流经大脑。 第三，为了学习一种新行为，我们必须学习支持该行为的神经活动模式。 神经调节被认为对于这种学习至关重要：当前模型提出去甲肾上腺素探索 新模式，而多巴胺则完善模式。为了测试这一点，我们的第三个目标是将介观成像与 当动物学习新行为时，记录和刺激去甲肾上腺素能/多巴胺能中脑神经元。 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。 我们将介观成像、电生理学和光遗传学创新结合起来，将提供以下方面的见解： 神经活动如何路由（目标 1）以及皮层范围的动态如何控制（目标 2）和学习（目标 3）。 通过了解这些机制，我们希望改进对破坏认知控制的疾病的治疗。