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 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).
|Vaskov, Alex K; Irwin, Zachary T; Nason, Samuel R et al. (2018) Cortical Decoding of Individual Finger Group Motions Using ReFIT Kalman Filter. Front Neurosci 12:751|
|Vlisides, P E; Bel-Bahar, T; Nelson, A et al. (2018) Subanaesthetic ketamine and altered states of consciousness in humans. Br J Anaesth 121:249-259|
|Kim, Hyoungkyu; Moon, Joon-Young; Mashour, George A et al. (2018) Mechanisms of hysteresis in human brain networks during transitions of consciousness and unconsciousness: Theoretical principles and empirical evidence. PLoS Comput Biol 14:e1006424|
|Lee, UnCheol; Kim, Minkyung; Lee, KyoungEun et al. (2018) Functional Brain Network Mechanism of Hypersensitivity in Chronic Pain. Sci Rep 8:243|
|Mashour, George A; Hudetz, Anthony G (2018) Neural Correlates of Unconsciousness in Large-Scale Brain Networks. Trends Neurosci 41:150-160|
|Mashour, George A; Hudetz, Anthony G (2017) Bottom-Up and Top-Down Mechanisms of General Anesthetics Modulate Different Dimensions of Consciousness. Front Neural Circuits 11:44|
|Schroeder, Karen E; Irwin, Zachary T; Bullard, Autumn J et al. (2017) Robust tactile sensory responses in finger area of primate motor cortex relevant to prosthetic control. J Neural Eng 14:046016|
|Vlisides, Phillip E; Bel-Bahar, Tarik; Lee, UnCheol et al. (2017) Neurophysiologic Correlates of Ketamine Sedation and Anesthesia: A High-density Electroencephalography Study in Healthy Volunteers. Anesthesiology 127:58-69|
|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|
Showing the most recent 10 out of 15 publications