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University of Pennsylvania · Rehabilitation Medicine
Active 2013–2026
Andrew McKinstry-Wu, MD, is an Assistant Professor of Anesthesiology and Critical Care at the Hospital of the University of Pennsylvania. He is a faculty member at the Center for Sleep and Circadian Biology and the Neuroscience of Unconsciousness and Reanimation Research Alliance. His professional roles include attending anesthesiologist at the Hospital of the University of Pennsylvania and his academic focus is within the Department of Anesthesiology and Critical Care. His educational background includes a BA in Biology and History from Williams College, an MD from Columbia University, and studies at Exeter College, Oxford University.
bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-17
Abstract Introduction Here, we create a conditional Adra2a line and use it to show that sedative, hypnotic, and hypothermic effects of α 2 -agonists are neuronally mediated via the α 2A adrenergic receptor. Methods We generated mice with loxP sites flanking Adra2a using CRISPR/Cas9 gene targeting. This line was crossed with lines encoding Cre recombinase (Cre) under the control of the Vgat, Snap25, and Dbh promoters. Cell-specific knockout was confirmed using fluorescent in-situ hybridization demonstrating targeted reduction in Adra2a mRNA in the appropriate cell types. Mice were given intraperitoneal dexmedetomidine (0.3 or 1 mg/kg) or saline, and 20 minutes later righting reflex was assessed, followed by 3 rounds of rotarod testing, with fall time and end temperature recorded. Spontaneous activity was recorded using beam break for an hour after. Mice of each genotype were implanted with EEG leads and recorded while given 0.3 mg/kg IP dexmedetomidine. Results We created a conditional knockout and demonstrated cell-type specific reduction of Adra2a mRNA in crossed lines with cell-specific Cre. The pan-neuronal Adra2a knockout showed resistance to all temperature, sedative, and hypnotic effect endpoints in response to the α 2 -agonist dexmedetomidine. Adrenergic knockout demonstrated resistance to α 2 -agonist hypnosis and moderate resistance to hypothermia and impaired coordination with forced movement. GABAergic knockout showed resistance only to impairment of spontaneous movement by α 2 -agonists. Spectral analysis of the EEG showed an increase in proportion of delta power with a sedative dose of dexmedetomidine in all lines except the pan-neuronal Adra2a knockout. Discussion Future studies will pursue both the specific subtype(s) and location of neuronal populations responsible for sedative, hypnotic, and hypothermic effects of α 2 -agonists.
Reanimation of rodents: an animal model for cognitive recovery from anaesthesia
British Journal of Anaesthesia · 2025-08-01
Communications Biology · 2025-08-20 · 2 citations
Understanding the neurophysiological changes underlying conscious-unconscious transitions is a key goal in neuroscience. Using magnetic resonance neuroimaging, we investigate the network connectivity and neurovascular changes occurring as the human brain transitions from wakefulness to dexmedetomidine-induced hypnosis, and recovery. Hypnosis led to widespread decreases in functional connectivity strength and increased structure-function coupling, indicating functional patterns more constrained by the underlying anatomical connectivity. As individuals began to regain consciousness, both connectivity markers returned towards awake levels, with particularly prominent coupling changes across the cerebellum. Neurovascular dynamics were disrupted during hypnosis as well: cerebral blood flow decreased globally-most notably in the brainstem, thalamus, and cerebellum-and continued decreasing even as recovery commenced, except within the cerebellum. Notably, regions with higher functional connectivity strength during wakefulness exhibited greater blood flow reductions during hypnosis. Hypnosis also heightened the amplitude of low-frequency fluctuations in the hemodynamic signal, especially in visual and somatomotor regions. Critically, individuals who regained consciousness faster displayed higher baseline levels of both neurovascular, but not connectivity, markers. Together, these results reveal that the induction of, and emergence from, dexmedetomidine-induced unconsciousness involve widespread, coordinated changes in brain connectivity and neurovascular function; across our findings, we also highlight the recurrent role of cerebellum in conscious-unconscious transitions.
Dexmedetomidine directly binds to and inhibits Toll-like receptor 4
International Immunopharmacology · 2024-08-19 · 4 citations
bioRxiv (Cold Spring Harbor Laboratory) · 2024-10-07 · 1 citations
Understanding the neurophysiological changes that occur during loss and recovery of consciousness is a fundamental aim in neuroscience and has marked clinical relevance. Here, we utilize multimodal magnetic resonance neuroimaging to investigate changes in regional network connectivity and neurovascular dynamics as the brain transitions from wakefulness to dexmedetomidine-induced unconsciousness, and finally into early-stage recovery of consciousness. We observed widespread decreases in functional connectivity strength across the whole brain, and targeted increases in structure-function coupling (SFC) across select networks-especially the cerebellum-as individuals transitioned from wakefulness to hypnosis. We also observed robust decreases in cerebral blood flow (CBF) across the whole brain-especially within the brainstem, thalamus, and cerebellum. Moreover, hypnosis was characterized by significant increases in the amplitude of low-frequency fluctuations (ALFF) of the resting-state blood oxygen level-dependent signal, localized within visual and somatomotor regions. Critically, when transitioning from hypnosis to the early stages of recovery, functional connectivity strength and SFC-but not CBF-started reverting towards their awake levels, even before behavioral arousal. By further testing for a relationship between connectivity and neurovascular alterations, we observed that during wakefulness, brain regions with higher ALFF displayed lower functional connectivity with the rest of the brain. During hypnosis, brain regions with higher ALFF displayed weaker coupling between structural and functional connectivity. Correspondingly, brain regions with stronger functional connectivity strength during wakefulness showed greater reductions in CBF with the onset of hypnosis. Earlier recovery of consciousness was associated with higher baseline (awake) levels of functional connectivity strength, CBF, and ALFF, as well as female sex. Across our findings, we also highlight the role of the cerebellum as a recurrent marker of connectivity and neurovascular changes between states of consciousness. Collectively, these results demonstrate that induction of, and emergence from dexmedetomidine-induced unconsciousness are characterized by widespread changes in connectivity and neurovascular dynamics.
Hormonal basis of sex differences in anesthetic sensitivity
Proceedings of the National Academy of Sciences · 2024-01-08 · 56 citations
General anesthesia-a pharmacologically induced reversible state of unconsciousness-enables millions of life-saving procedures. Anesthetics induce unconsciousness in part by impinging upon sexually dimorphic and hormonally sensitive hypothalamic circuits regulating sleep and wakefulness. Thus, we hypothesized that anesthetic sensitivity should be sex-dependent and modulated by sex hormones. Using distinct behavioral measures, we show that at identical brain anesthetic concentrations, female mice are more resistant to volatile anesthetics than males. Anesthetic sensitivity is bidirectionally modulated by testosterone. Castration increases anesthetic resistance. Conversely, testosterone administration acutely increases anesthetic sensitivity. Conversion of testosterone to estradiol by aromatase is partially responsible for this effect. In contrast, oophorectomy has no effect. To identify the neuronal circuits underlying sex differences, we performed whole brain c-Fos activity mapping under anesthesia in male and female mice. Consistent with a key role of the hypothalamus, we found fewer active neurons in the ventral hypothalamic sleep-promoting regions in females than in males. In humans, we demonstrate that females regain consciousness and recover cognition faster than males after identical anesthetic exposures. Remarkably, while behavioral and neurocognitive measures in mice and humans point to increased anesthetic resistance in females, cortical activity fails to show sex differences under anesthesia in either species. Cumulatively, we demonstrate that sex differences in anesthetic sensitivity are evolutionarily conserved and not reflected in conventional electroencephalographic-based measures of anesthetic depth. This covert resistance to anesthesia may explain the higher incidence of unintended awareness under general anesthesia in females.
Neuroscience & Biobehavioral Reviews · 2023-10-05 · 14 citations
British Journal of Anaesthesia · 2023-11-23
Journal of Neuroscience · 2023-02-27 · 5 citations
Photoaffinity ligands are best known as tools used to identify the specific binding sites of drugs to their molecular targets. However, photoaffinity ligands have the potential to further define critical neuroanatomic targets of drug action. In the brains of WT male mice, we demonstrate the feasibility of using photoaffinity ligands in vivo to prolong anesthesia via targeted yet spatially restricted photoadduction of azi- m -propofol (aziPm), a photoreactive analog of the general anesthetic propofol. Systemic administration of aziPm with bilateral near-ultraviolet photoadduction in the rostral pons, at the border of the parabrachial nucleus and locus coeruleus, produced a 20-fold increase in the duration of sedative and hypnotic effects compared with control mice without UV illumination. Photoadduction that missed the parabrachial-coerulean complex also failed to extend the sedative or hypnotic actions of aziPm and was indistinguishable from nonadducted controls. Paralleling the prolonged behavioral and EEG consequences of on target in vivo photoadduction, we conducted electrophysiologic recordings in rostral pontine brain slices. Using neurons within the locus coeruleus to further highlight the cellular consequences of irreversible aziPm binding, we demonstrate transient slowing of spontaneous action potentials with a brief bath application of aziPm that becomes irreversible on photoadduction. Together, these findings suggest that photochemistry-based strategies are a viable new approach for probing CNS physiology and pathophysiology. SIGNIFICANCE STATEMENT Photoaffinity ligands are drugs capable of light-induced irreversible binding, which have unexploited potential to identify the neuroanatomic sites of drug action. We systemically administer a centrally acting anesthetic photoaffinity ligand in mice, conduct localized photoillumination within the brain to covalently adduct the drug at its in vivo sites of action, and successfully enrich irreversible drug binding within a restricted 250 µm radius. When photoadduction encompassed the pontine parabrachial-coerulean complex, anesthetic sedation and hypnosis was prolonged 20-fold, thus illustrating the power of in vivo photochemistry to help unravel neuronal mechanisms of drug action.
P331. Meta-Analysis of Functional Imaging Studies of Acute Administration of Psychedelics
Biological Psychiatry · 2022-04-28
Intersections of Sleep and Coma: Neural Pathways of Alpha-2 Adrenergic Hypnosis
NIH · $877k · 2017–2022
Max B. Kelz
California University of Pennsylvania
Roderic G. Eckenhoff
University of Pennsylvania
Weiming Bu
University of Pennsylvania
Brian P. Weiser
David Liang
National Institutes of Health
Longnecker LaboratoriesPI
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Wendy Lea
Ajit Jadhav
National Center for Advancing Translational Sciences
David J. Maloney