Role of the Prefrontal Cortex in the Control of Arousal States

前额叶皮层在控制唤醒状态中的作用

• 批准号: 10380066
• 负责人: George Alexander Mashour
• 金额: $ 38.01万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380066
• 关键词: Acetylcholine; Anesthesia procedures; Anesthesiology; Anesthetics; Area; Arousal; Attenuated; Behavior Control; Behavioral; Behavioral Mechanisms; Biological Models; Brain; Carbachol; Cardiovascular system; Cholinergic Antagonists; Cholinergic Receptors; Clinical; Conscious; Consciousness Disorders; Data; Dose; Electroencephalography; Exposure to; General Anesthesia; General anesthetic drugs; Goals; Image; Infusion procedures; Intervention; Intravenous; Isoflurane; Ketamine; Knowledge; Laboratories; Link; Maintenance; Mediating; Methods; Midbrain structure; Mission; Modeling; Neural Pathways; Neurobiology; Neurology; Neurons; Nicotine; Operative Surgical Procedures; Outcome; Pathologic; Pathway interactions; Patients; Perioperative; Pharmaceutical Preparations; Pharmacology; Physiological; Prefrontal Cortex; Procedures; Process; Public Health; Publishing; Rattus; Recovery; Reporting; Research; Research Proposals; Ritalin; Role; Safety; Site; Testing; Tetrodotoxin; Thalamic structure; Transgenic Organisms; Translating; Unconscious State; United States National Institutes of Health; Wakefulness; basal forebrain; cholinergic; cholinergic neuron; clinically relevant; cost; density; executive function; improved; innovation; neural circuit; neurobiological mechanism; neuromechanism; novel; novel strategies; off-label drug; preclinical study; public health relevance; reconstitution; sevoflurane; spatiotemporal; tool

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.

项目总结/摘要 麻醉学领域的进步使得全身麻醉的管理和维持 一个相对安全和控制良好的程序。相比之下，从麻醉中苏醒是被动的， 神经生物学不清楚的受控过程。我们最近发现亚麻醉剂量的氯胺酮 在暴露于异氟烷的过程中，与直觉相反， 乙酰胆碱在前额叶皮层（PFC），并恢复PFC连接到后皮质。后续我们 报告称，通过局部输注卡巴胆碱对PFC的胆碱能刺激可恢复觉醒， 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唤醒，并可用于加速从 麻醉然而，缺乏机械的理解。我们的长期目标是了解 神经生物学过程，介导从生理，药理学和病理状态的恢复， 昏迷拟议研究的总体目标是确定神经回路， 通过局部输注卡巴胆碱或全身递送亚麻醉剂氯胺酮刺激PFC产生 加速从全身麻醉中恢复我们的初步数据支持的中心假设是 PFC和基底前脑的相互回路调节行为唤醒， 氯胺酮选择该途径以加速从全身麻醉中恢复。建议的理由 研究的一个重要意义是，它将产生有关唤醒神经通路的基本机械知识， 恢复意识。为了检验我们的假设，我们将追求以下三个具体目标， 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（伴或不伴河豚毒素（TTX））刺激PFC- 介导的基底前脑失活或基底前脑胆碱能的选择性化学发生抑制， γ-氨基丁酸能神经元，这已经牵连在觉醒，2）确定基底前脑的作用 投射到PFC控制行为唤醒-我们将化学刺激基底前脑 胆碱能或GABA能神经元，伴或不伴同时的TTX介导的PFC失活。以确认 PFC中乙酰胆碱在氯胺酮诱导的麻醉加速恢复中的因果作用，我们将注入 胆碱能拮抗剂在全身递送亚麻醉氯胺酮期间进入PFC，和3）确定 皮层连接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- 麻醉诱导恢复作为一个模型系统，以解剖状态与麻醉药物对 功能性皮层连接和时空复杂性。这项研究意义重大，因为 我们希望它能为前额叶皮层在行为唤醒中的作用提供基本的机制性理解 以及从麻醉中恢复过来，以及翻译的影响。

项目成果

Estimating the Integrated Information Measure Phi from High-Density Electroencephalography during States of Consciousness in Humans.

• DOI: 10.3389/fnhum.2018.00042
• 发表时间: 2018
• 期刊: Frontiers in human neuroscience
• 影响因子: 2.9
• 作者: Kim H;Hudetz AG;Lee J;Mashour GA;Lee U;ReCCognition Study Group
• 通讯作者: ReCCognition Study Group

Dynamic reconfiguration of frequency-specific cortical coactivation patterns during psychedelic and anesthetized states induced by ketamine.

• DOI: 10.1016/j.neuroimage.2022.118891
• 发表时间: 2022-04-01
• 期刊: NeuroImage
• 影响因子: 5.7
• 作者: Li D;Vlisides PE;Mashour GA
• 通讯作者: Mashour GA

Consciousness, Anesthesia, and Acetylcholine.

• DOI: 10.1097/aln.0000000000003696
• 发表时间: 2021-04-01
• 期刊: Anesthesiology
• 影响因子: 8.8
• 作者: Pal D;Mashour GA
• 通讯作者: Mashour GA

A low-power band of neuronal spiking activity dominated by local single units improves the performance of brain-machine interfaces.

• DOI: 10.1038/s41551-020-0591-0
• 发表时间: 2020-10
• 期刊: Nature biomedical engineering
• 影响因子: 28.1
• 作者: Nason SR;Vaskov AK;Willsey MS;Welle EJ;An H;Vu PP;Bullard AJ;Nu CS;Kao JC;Shenoy KV;Jang T;Kim HS;Blaauw D;Patil PG;Chestek CA
• 通讯作者: Chestek CA

Inactivation of Prefrontal Cortex Delays Emergence From Sevoflurane Anesthesia.

• DOI: 10.3389/fnsys.2021.690717
• 发表时间: 2021
• 期刊: Frontiers in systems neuroscience
• 影响因子: 3
• 作者: Huels ER;Groenhout T;Fields CW;Liu T;Mashour GA;Pal D
• 通讯作者: Pal D