Max Kelz, MD, PhD

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				Max B. Kelz, M.D., Ph.D. Assistant Professor Department of Anesthesia Room 334 John Morgan Building 3620 Hamilton Walk (office) (215)-662-3713 (lab) (215)-898-8929 (fax) (215)-349-5078 email: kelzma@uphs.upenn.edu website: http://www.uphs.upenn.edu/dripps/research/kelz.html Click here for selected publications since Dr. Kelz's arrival at Penn RESEARCH INTERESTS Despite 150 years of widespread use, the mechanisms through which anesthetics reversibly inhibit consciousness remain obscure. Recent evidence suggests that several intravenous anesthetics "hijack" the endogenous neural circuitry that governs sleep-wake cycles, similar perhaps to the way in which opiates commandeer the endogenous reward system. My laboratory uses behavioral and electroencephalographic analysis to identify mice with altered sensitivity to the hypnotic properties of anesthetics. We are interested in applying mouse genetics along with classic pharmacology to understand the molecular mechanisms and neural pathways leading to anesthetic-induced unconsciousness. RESEARCH TECHNIQUES Loss of righting reflex and other behavioral analysis; EEG/EMG acquisition, sleep recording, and entropy analysis; Mouse surgery and anesthesia; Brightfield and Fluorescence Immunohistochemistry; Western blotting; In Situ Hybridization; Single Cell microdissection and RNA analysis; Microarrays; Real time PCR RESEARCH SUMMARY General Anesthesia is a behavioral state characterized by amnesia, unconsciousness/hypnosis, analgesia, blunted autonomic reflexes, and a degree of muscle relaxation. It is accompanied by altered thermoregulation, vasomotor tone, and minute ventilation. While much research over the past decade has focused on the molecular site(s) of anesthetic action, relatively little attention has been devoted to the critical areas of brain upon which general anesthetics exert their behavioral effects. I am interested in the neuroanatomic substrates that mediate specific behavioral features of general anesthesia. New research supports an old idea that general anesthetics act in part upon the endogenous neural circuitry that governs sleep-wake cycles (the reticular activating system) to produce hypnosis. Using mouse genetics as a tool, my laboratory seeks to better understand the molecular mechanisms through which anesthetics exert their sedative-hypnotic effects upon the reticular activating system. We have identified sleep mutants that are hypersensitive and will attempt to identify additional mutant mice that are either hypersensitive or resistant to inhaled anesthetics with two different measures. At the behavioral level, anesthetic sensitivity is measured with a loss of righting assay. As the dose of inhaled anesthetic increases, a mouse will eventually become obtunded and be unable to stand on all four limbs when placed in a rolling cylinder. By performing dose-response analysis on a population of genetically engineered mice and their wildtype sibling controls, it is possible to determine the minimum alveolar concentration at which 50% of the mice are obtunded, 'MACLORR.' A second approach for determining anesthetic sensitivity occurs with electrophysiological measurements. All anesthetics change the underlying raw EEG signal. By implanting mice with miniaturized transmitters, we simultaneously record mouse EEG and EMG waveforms. As mutant mice and sibling controls are exposed to increasing doses of inhaled anesthetics, the doses which produce the classic changes in the EEG signal are recorded. Additional vital signs that are studied include arterial blood pressure, pulse, and temperature. Within the mouse, we seek to reproduce the operating room's full suite of physiological measurements. Research in my laboratory is not limited to behavior and physiology. In addition, we are interested in characterizing the molecular adaptations that alter anesthetic sensitivity. Accordingly, we seek to understand the underlying biochemical and molecular modifications that occur within reticular activating nuclei of our mutant mice, which are responsible for altering the mouse's anesthetic sensitivity. With light and fluorescence microscopy we are able to identify specific neurons of the reticular activating system. We can then dissect these immunohistochemically identified neurons away from their neighbors in fixed slices. We utilize single-cell aRNA amplification as well as novel PCR based strategies to detect changes in mRNA levels that might account for our behavioral phenotypes. KEY WORDS: Anesthesia; Cognition; Sleep; Hypothalamus; Behavioral pharmacology; Mouse genetics; Single Cell and Systems Neurobiology