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.

Public Health Relevance

Public Health Relevance Statement: This research proposal is relevant to public health and the mission of the National Institutes of Health because it aims to understand the neurobiological mechanisms of behavioral arousal and the recovery of consciousness, which can ultimately have a positive impact on the fields of anesthesiology (recovery from general anesthesia) and neurology (recovery from disorders of consciousness).

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM111293-05
Application #
9961617
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Justinova, Zuzana
Project Start
2015-07-15
Project End
2023-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Hambrecht-Wiedbusch, Viviane S; Li, Duan; Mashour, George A (2017) Paradoxical Emergence: Administration of Subanesthetic Ketamine during Isoflurane Anesthesia Induces Burst Suppression but Accelerates Recovery. Anesthesiology 126:482-494
Avidan, Michael S; Maybrier, Hannah R; Abdallah, Arbi Ben et al. (2017) Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial. Lancet 390:267-275

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