Role of the Prefrontal Cortex in the Control of Arousal States

项目摘要/摘要 麻醉学领域的进步使得全身麻醉的管理和维持 这是一个相对安全和控制良好的手术。相比之下，从麻醉中苏醒是被动的，而且是糟糕的 神经生物学不明确的受控过程。我们最近发现，亚麻药剂量的氯胺酮 在吸入异氟醚的过程中，与直觉相反地加速了麻醉的恢复，增加了 前额叶皮质(PFC)中的乙酰胆碱，并恢复PFC与后皮质的连接。随后，我们 报道称，局部输注卡巴胆碱对PFC的胆碱能刺激恢复了觉醒，尽管 持续暴露于临床相关浓度的全身麻醉。这些数据表明 PFC中的胆碱能过程控制行为觉醒，并可用于加速康复 麻醉。然而，缺乏机械性的理解。我们的长期目标是了解 神经生物学过程，调节从生理、药理和病理状态中恢复 不省人事。拟议研究的总体目标是确定通过哪些神经回路 局部输注卡巴胆碱或全身注射亚麻药氯胺酮对PFC的刺激 加速从全身麻醉中恢复。我们的初步数据支持的核心假设是 PFC和基底前脑的相互回路调节行为唤醒，而亚麻醉剂 氯胺酮选择了这一途径来加速全身麻醉的恢复。建议的理由是 研究表明，它将产生有关唤醒和兴奋的神经通路的基本机械知识。 意识的恢复。为了验证我们的假设，我们将追求以下三个具体目标和 在大鼠模型中的方法：1)证明PFC通过基底前脑控制行为 唤醒-我们将通过局部输注卡巴胆碱并或不加河豚毒素(TTX)来刺激PFC- 介导的基底前脑失活或选择性抑制基底前脑胆碱能和 与觉醒有关的GABA能神经元，2)决定了基底前脑的作用 控制行为觉醒的前额叶投射--我们将通过化学遗传学刺激基底前脑 胆碱能或GABA能神经元，有或没有并发的TTX介导的PFC失活。要确认一个 乙酰胆碱在氯胺酮诱导的麻醉加速苏醒中在前额叶内的因果作用 在全麻下氯胺酮全身给药期间胆碱能拮抗剂进入PFC，以及3)确定 皮层连接性和复杂性在行为唤醒中的作用-我们将使用卡巴胆碱/氯胺酮- 以麻醉诱导复苏为模型系统来剖析麻醉状态与麻醉药物的影响 功能皮层连通性和时空复杂性。这项拟议的研究具有重要意义，因为 我们期望它能为PFC在行为唤醒中的作用提供基本的机械性理解 以及从麻醉中恢复，具有翻译意义。

PROJECT SUMMARY/ABSTRACT Advances in the field of anesthesiology have made the administration and maintenance of general anesthesia a relatively safe and well-controlled procedure. In contrast, emergence from anesthesia is passive and a poorly controlled process with an unclear neurobiology. We recently showed that a subanesthetic dose of ketamine during exposure to isoflurane counterintuitively accelerated the recovery from anesthesia, increased levels of acetylcholine in prefrontal cortex (PFC), and restored PFC connectivity to posterior cortex. Subsequently, we reported that cholinergic stimulation of PFC by local carbachol infusion restored wakefulness despite continuous exposure to clinically-relevant concentrations of general anesthesia. These data suggest that cholinergic processes in PFC control behavioral arousal and can be harnessed to accelerate recovery from anesthesia. However, mechanistic understanding is lacking. Our long-term goal is to understand the neurobiological processes that mediate recovery from physiologic, pharmacologic, and pathologic states of unconsciousness. The overall objective of the proposed studies is to identify the neural circuits through which PFC stimulation by local carbachol infusion or systemic delivery of subanesthetic ketamine produces accelerated recovery from general anesthesia. The central hypothesis, supported by our preliminary data, is that the reciprocal circuit of PFC and basal forebrain regulates behavioral arousal, and that subanesthetic ketamine co-opts this pathway to hasten recovery from general anesthesia. The rationale for the proposed research is that it will yield fundamental mechanistic knowledge of the neural pathways involved in arousal and recovery of consciousness. To test our hypothesis, we will pursue the following three specific aims and approaches in a rat model: 1) Demonstrate that PFC acts through basal forebrain to control behavioral arousal - we will stimulate PFC by local carbachol infusion with or without concurrent tetrodotoxin (TTX)- mediated inactivation of basal forebrain or selective chemogenetic inhibition of basal forebrain cholinergic and GABAergic neurons, which have been implicated in wakefulness, 2) Determine the role of basal forebrain projections to PFC in controlling behavioral arousal - we will chemogenetically stimulate basal forebrain cholinergic or GABAergic neurons, with or without concurrent TTX-mediated PFC inactivation. To confirm a causal role for acetylcholine in PFC in ketamine-induced accelerated recovery from anesthesia, we will infuse cholinergic antagonists into PFC during systemic delivery of subanesthetic ketamine, and 3) Determine the role of cortical connectivity and complexity in behavioral arousal - we will use carbachol/ketamine- induced recovery from anesthesia as a model system to dissect the state vs. anesthetic drug effects on functional cortical connectivity and spatiotemporal complexity. The proposed research is significant because we expect it to provide fundamental mechanistic understanding of the role of the PFC in behavioral arousal and recovery from anesthesia, with translational implications.