Quantifying the effect of brain state on the spatiotemporal dynamics of visual evoked responses

项目总结 令人惊讶的是，在麻醉下或在睡眠中，初级感觉皮质中的单个神经元可靠地代表 感官信息，即使在感觉缺失的情况下也是如此。这表明知觉的崩溃 由于初级感觉系统不能有效地将其活动与其他皮质的活动相结合 电路。一直以来，感知障碍，如精神分裂症和自闭症，都与 感觉诱发活动的时空整合中的扭曲4-7，14。然而，回路机制 允许感觉信息与潜在神经活动整合的机制在很大程度上仍是未知的。 自发的神经活动可以用电生理学记录下来，并通过以下方式分类为“大脑状态” 分解振荡模式15-17。在这里，我运用了神经生理学和光遗传学的结合 对视觉刺激引起的时空反应的显著特征进行量化。我们的预赛 植入高密度皮层脑电(ECoG)的小鼠实验表明，简单的视觉刺激 产生复杂的、可重现的、高度相干的行波(TGW)，这种行波几乎跨越整个 大脑皮层。我推测，这些存在于清醒和警觉的动物体内的TGW与 允许感知发生的特定且严格控制的传播模式。我会决定巡回 利用光遗传学产生远程诱发的TGW反应的潜在机制。在这里，我会 使用两种麻醉剂，异氟醚和氯胺酮，比较自然清醒状态下的视觉诱发活动 昏昏欲睡，被药物麻醉的动物。异氟醚引起丰富的Delta活动的光谱大脑状态 它模仿慢波睡眠，而氯胺酮刺激伽马活动和其他存在于 18-22岁的精神分裂症患者。在目标1中，我将量化大脑光谱状态对视觉诱发的TGW的影响 高密度表面脑电地形图(ECoG)在活体小鼠皮质中的反应。在《目标2》中，我会 量化大脑状态对这些视觉反应的层流时空组织的影响，使用 多个多通道深度探头。在目标3中，我将使用光遗传学来确定来自 视觉丘脑是产生和维持视觉诱发的高度一致的TGW所必需的 震荡。总而言之，这项工作的结果将提供进一步的见解，以理解如何感官 大脑的处理受到大脑整体光谱状态的影响。此外，我们的发现将告诉我们感官如何唤起 活动与正在进行的大脑皮层活动相结合，以创造感知可能和不可能的条件。 随之而来的洞察力也可能表明感觉处理在行为状态期间是如何改变的，例如 注意力不集中或睡眠不足，并可能有助于阐明精神分裂症等疾病的知觉是如何改变的。这 格兰特还将在卓越的环境中为有抱负的临床科学家提供不可或缺的支持 宾夕法尼亚大学佩雷尔曼医学院。她职业生涯的终极目标是 将基础神经科学转化为临床医学，以更好地了解健康和疾病状态。

PROJECT SUMMARY Surprisingly, under anesthesia or during sleep, individual neurons in primary sensory cortices reliably represent sensory information, even when perception is absent10–13. This suggests that the breakdown of perception is due to an inability of the primary sensory system to effectively integrate its activity with that of other cortical circuits. Consistently, disorders of perception, such as schizophrenia and autism, are associated with distortions in the spatial and temporal integration of sensory-evoked activity4–7,14. Yet, the circuit mechanisms that allow for integration of sensory information with the underlying neural activity remain largely unknown. Spontaneous neural activity can be recorded with electrophysiology and classified into “brain states” by decomposing the oscillatory patterns15–17. Herein, I deploy a combination of neurophysiology and optogenetics to quantify the salient features of spatiotemporal responses elicited by visual stimuli. Our preliminary experiments in mice implanted with high density electrocorticography (ECoG) show that simple visual stimuli elicit complex, reproducible, and highly coherent traveling gamma waves (TGW) that span nearly an entire hemicortex. I hypothesize that these TGWs, present in the awake and vigilant animal, are associated with specific and tightly controlled pattern of propagation that permit perception to occur. I will determine circuit mechanisms underlying the generation of long-range evoked TGW responses with optogenetics. Here, I will utilize two anesthetic agents, isoflurane and ketamine, and compare visual evoked activity in awake, naturally drowsy, and pharmacologically anesthetized animals. Isoflurane elicits spectral brain states rich in delta activity which mimic slow wave sleep, while ketamine stimulates gamma activity and other features present in schizophrenia18–22. In Aim 1, I will quantify the brain spectral state dependent effect on visual evoked TGW responses in mouse cortex in vivo using high density surface electrocorticography (ECoG). In Aim 2, I will quantify the effect of brain state on the laminar spatiotemporal organization of these visual responses, using multiple multichannel depth probes. In Aim 3, I will use optogenetics to determine whether projections from the visual thalamus are necessary for the generation and maintenance of visual evoked, highly coherent TGW oscillations. Collectively, the results of this work will provide further insights to understanding how sensory processing is affected by the global spectral brain state. Moreover, our findings will inform how sensory evoked activity integrates with ongoing cortical activity to create conditions in which perception is and is not possible. The ensuing insights may also suggest how sensory processing is altered during behavioral states such as inattention or sleep, and may shed light on how perception is altered in diseases such as schizophrenia23. This grant will also provide indispensable support for an aspiring clinician scientist in an outstanding environment at the University of Pennsylvania, Perelman School of Medicine. Her ultimate career goals are to infuse fundamental neuroscience into clinical medicine to better understand healthy and disease states.