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Daniel K. Mulkey cellular and molecular mechanisms by which the brain controls breathing Breathing is essential for life. It provides the means to obtain the O 2 necessary for aerobic metabolism and to eliminate the CO 2 produced as a metabolic byproduct. In addition, via its effects on CO 2 levels, breathing serves a second critical function: rapid and dynamic regulation of acid-base balance. The importance of this latter function is underscored by the existence of an exquisitely sensitive homeostatic mechanism – socalled respiratory chemoreception – by which the rate and depth of breathing are controlled by arterial CO 2 / pH. The focus of my research is centered on the electrophysiological characteristics of mammalian neurons in brainstem regions associated with respiratory control, specifically defining properties unique to respiratory chemoreceptors. I am also interested in the cellular mechanisms by which chemoreceptors sense changes in CO 2 /pH. I first became interested in central chemoreception as a graduate student at Wright State University. As part of my thesis I showed that CO 2 -sensitive neurons in the solitary complex, a cardio-respiratory integration center, also respond to oxidative stress by a free radical dependent and pH independent mechanism. Later as a postdoctoral fellow in the laboratories of Douglas Bayliss and Patrice Guyenet at the University of Virginia I helped identify a population of neurons on the surface of the brainstem in a region called the retrotrapezoid nucleus (RTN) that appear to function as chemoreceptors. These neurons are highly CO 2 - sensitive in vivo (whole animal), intrinsically pH-sensitive in vitro (brain slice), are glutamatergic and send excitatory projections to the respiratory rhythm generator. We also determined that RTN chemoreceptors express an as of yet unidentified pH sensitive voltage independent K + current tha t likely confers pH sensitivity to these cells (see corresponding figure). Little else is known regarding the properties of cells in this region of the brainstem.
I joined this department in August of 2007 where I have continued to investigate the role of the RTN in respiratory control. We are currently using patch clamp techniques in brain slices to identify morphological and electrical properties that distinguish RTN chemoreceptors from non-chemosensitive neurons. In addition, it is well known that glial cells can modulate neuronal activity through control of the extracellular environment (e.g., pH buffering) or by releasing neurotransmitters. Therefore, we are using immunohistochemistry to identify the types of glial cells present in the RTN as well as a combination of pharmacological, electrophysiological and fluorescent imaging (e.g., Ca 2 + and intracellular pH and ATP) techniques to determine if glial cells modulate activity of RTN chemoreceptors. Finally, my earlier finding that free radicals affect CO 2 sensitive neurons in a cardio-respiratory region of the brain suggests that multiple signaling molecules can affect the output of chemoreceptors and consequently contribute to the drive for breathing. Therefore, we are investigating the mechanism by which nitric oxide, a neuromodulator released during sleep, contributes to the state dependent control of breathing. Selected Publications Mulkey, D. K, R. A. Henderson III, N.A. Ritucci, R. W. Putnam, J. B. Dean. (2004). Oxidative stress decreases intracellular pH and Na + /H + exchange and increases excitability of solitary complex (SC) neurons from rat brain slices. Am J Phyiol Cell Physiol 286:C940-C051, . Mulkey D. K., M. C. Weston, R. L. Stornetta, A. Parker, D. A. Bayliss, P. G. Guyenet. (2004). Respiratory control by ventral surface chemoreceptor neurons in rat. Nature Neurosci. 7:1360- 1369. Mulkey D. K., E. M. Talley, R. L. Stornetta, A. R. Siegel, G. H. West, N. Sen, M. M. Akshitkumar, P. G. Guyenet, D. A. Bayliss. (2007). TASK channels determine pH sensitivity in select respiratory neurons but do not contribute to central respiratory chemosensitivity. J Neurosci 27:14049-14058. Mulkey D. K., D. L. Rosin, G. H. West, A. C. Takakura, T. S. Moreira, D. A. Bayliss, P. G. Guyenet. (2007). Serotonergic neurons activate chemosensitive RTN neurons by a pH-independent mechanism. J Neurosci 27:14128-14138. Mulkey D. K., A. M. Mistry, P. G. Guyenet, D. A. Bayliss. (2006). Purinergic P2 receptors modulate excitability but do not mediate pH-sensitivity of RTN respiratory chemoreceptors. J Neurosci. 26:2730-2733.
Page 1 and 2: The college of liberal arts and sci
Page 3 and 4: The University About the Storrs Cam
Page 5 and 6: Graduate Program The Graduate Resea
Page 7 and 8: Faculty & Research Marie E. Cantino
Page 9 and 10: Selected Publications Cantino, M.E.
Page 11 and 12: Recently, I have become interested
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Page 15 and 16: a bioindicator of pollution exposur
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Page 23 and 24: We employ mouse (mus musculus) as t
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