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Research: The Neural Origins of Breathing Systems Neuroscience The College of Wi iiiam and Mary The most important issues in contemporary biology are interdisciplinary, spanning multiple levels of analysis from genes and molecules to the complex properties of networks. Nowhere is the interdisciplinary nature of modern-day life sciences more relevant than in neuroscience. Brain function underlies the vast repertoire of human behaviors and dysfunction of the brain and central nervous system causes many of society's most serious health problems. I am Professor Christopher A. Del Negro and my Systems Neuroscience laboratory in the Department of Applied Science provides a unique environment for neuroscience research and training at the graduate and postdoctoral level. My team and I have assembled state-of-the art experimental workstations for intracellular and patch-clamp electrophysiology combined with in vitro live-cell videomicroscopy and fluorescence imaging. We also have a vigorous computational neuroscience branch; we support parallel computing facilities for modeling and simulation. Our strategy to elucidate new knowledge in neuroscience blends theory and experiment: we use modeling to generate testable predictions, which are systematically evaluated via hypothesisdriven experimental studies. The masters and doctoral degree programs in Applied Science offer flexible curricula that are individually tailored by students, in consultation with their faculty advisors, to accomplish each student's unique and often interdisciplinary educational goals. Breathing behavior in mammals begins in utero and continues without lapse for the entire lifespan of the animal, which in humans can last up to, or exceed, 100 years. Diseases that affect the neural control of breathing can strike at any age, but newborns and premature babies are particularly susceptible to various forms of apnea and SIDS. We aim to provide new knowledge about how the neurons, synapses and networks of the brain stem assemble the rhythm-generating systems that drive breathing movements and control respiratory physiology. Breathing is an especially advantageous model system for this type of analysis because it is a behavior that can be studied under controlled conditions in vitro, using reduced brain stem 'slice' preparations. Our 'breathing slices' retain functional respiratory networks and generate spontaneous motor output during the inspiratory phase of the respiratory cycle. Figure 2. Students and faculty work together, using cutting-edge technology, to discover new principles in neuroscience at The College of William and Mary. One ongoing project in the laboratory examines calcium-activated nonspecific cationic membrane currents (i.e., 'CAN)' The ion channels underlying 'CAN are putatively from the transient receptor potential, or TRP, superfamily and have the unique ability to integrate voltage-dependent calcium influx with synaptically activated intracellular calcium release mechanisms. TRP channels can transform these In mammals, the rhythm for breathing originates in the brain stem nucleus called the preBotzinger Complex (preBotC). We isolate the preBotC and .A B 110 mV Figure 1. The 'breathing slice' preparation in vitro. Figure 3. Two preBotC neurons recorded in vitro using patch-clamp and fluorescent calcium imaging. its constituent rhythmogenic neurons in slice preparations (Fig. 1A). Rhythmic inspiratory motor activity can be measured via the hypoglossal cranial nerve output (Xlln) in vitro, while we examine cellular and synaptic properties in the context of network function. convergent calcium signals into high-amplitude, long-lasting neuronal activity states, which are suitable for driving inspiratory bursts and rhythm generation. During fictive inspiration, neurons in the preBotC generate robust bursts coincident with XII motor output (Fig. 1B). We aim to discover the cellular and synaptic mechanisms that produce rhythmic inspiratory bursts in preBotC neurons. Another thrust of our research examines the patterns of network connectivity among preBotC neurons. Here we use dual intracellular recordings to quantify synaptic coupling between preBotC neurons, as well as epifluorescence, confocal, and multi-photon imaging to measure calcium dynamics. Calcium imaging represents a convenient way to monitor the activity of many neurons simultaneously, which helps reveal network properties such as connectivity (Fig. 3). control 0.' 'oM" 1 ~ a~ _.. '00 . 0.0 "0 ~oo ~ -0.4 I ~ E .(J.B . ~ . .... .~ r- , O'"MSP'p' _./ ::t . :,~:: •• OmV +10mV -80mV Figure 4. Voltage-clamp analysis of preBtitC neuron sensitivity to neuropeptides such as substance P. Our efforts to unravel the neural basis for respiratory rhythm also emphasize mathematical modeling (Fig. 5). We are developing biophysically realistic models of preBotC neurons that account for morphology, the known complement of ion channels in preBotC neurons, as well as the novel biochemical signaling pathways that integrate synaptic and transmembrane calcium fluxes to evoke the burst-generating current ,CAN• Modeling at the cellular level forms the basis for network simulations that explore the role of connectivity: both the strength of coupling and the pattern of synaptic interconnections in the preBotC. CM • V = I NaF 17 - I K - I'eak = = Del Negro, CA et al. (2002) Biophysical Journal 82, 206-214. Del Negro, C.A., Morgado-Valle, C., & Feldman, J.L. (2002) Neuron 34, 821-830. Del Negro, C.A. et al. (2002) Journal of Neurophysiology 88, 2242-2250. Del Negro, C.A. et al. (2001) Journal of Neurophysiology 86, 59-74. Del Negro, C.A. et al. (1999) Journal of Neurophysiology 81, 1478-1485. Del Negro, C.A. et al. (1998) Biophysical Journal 75,174-182. Del Negro, C.A. & Chandler, S.H. (1998) Journal of Neuroscience 18, 9216-9226. Del Negro, C. A. & Chandler, S.H. (1997) Journal of Neurophysiology 77,537-553. Selected Recent Publications Applied Science at William and Mary Feldman, J.L. & Del Negro, C.A. (2006) Nature Reviews Neuroscience 7, 232-241. Del Negro, C.A. et al. (2005) Journal of Neuroscience 25, 446-453. I\")'" (noo(V) - n)' i,,(Vrl s = [(1- s)' Ca - I Ca - I AHP - I CAN - This intrinsic current (lCAN) amplifies synaptic excitation and allows for the creation of robust inspiratory bursts via a positive feedback process often called recurrent excitation, which is a form of self-organized behavior in biology. Inspiratory bursts end once all of the preBotC neurons have become fully excited: this extinguishes recurrent excitation, deactivates ,CAN' and leads to burst termination. Some preBotC neurons spike tonically at low rates and subsequently restart the cycle, leading to network rhythmicity (Fig. 6). Our overall goal is to evaluate the group-pacemaker hypothesis by determining its key mechanisms at the cellular and synaptic level, and then use mathematical models to test and refine our understanding. l s",(V) - k. s Contact i.,-I c' [-Ica + s(lp)) - kCa(Ca - Caoo)] Figure 5. Ordinary differential equations that describe membrane potential trajectory in preBtitC neurons during respiratory-like network activity. These equations are a subset of the full model. Our framework for analyzing respiratory rhythmogenesis is the group-pacemaker hypothesis which posits that 'CAN is a dendritically sited burst-generating current with an activation mechanism coupled to glutamatergic synapses. The College of William and Mary is the second oldest institution of higher education in the nation and has been repeatedly honored for its excellence by annual ran kings in US News & World Report. The Department of Applied Science is at the forefront of interdisciplinary research and its graduate students enjoy a flexible curriculum and yearly stipends of $20,040 plus tuition and health insurance. Finally, William & Mary is located in the town of Williamsburg, with its historic Colonial village and nearby tourist attractions like the Chesapeake bay and Atlantic beaches. Figure 6. An illustrated cycle of respiratory activity according to the group pacemaker hypothesis of rhythm generation. Panels 1 - 4 show the evolution of one inspiratory burst: from the onset of spontaneous activity (1), to the spread of excitation through the network (2-3), to the culmination of recurrent excitation, which evokes intrinsic currents and causes a robust network-wide inspiratory burst (4). Christopher A. Del Negro, Ph.D. Department of Applied Science The College of William and Mary Williamsburg, VA 23185 757 -221-7808 [email protected] http://people.wm.edu/-cadeln/ WILLIAM &MARY