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Senior Investigator

Jeffrey C. Smith, Ph.D.

Cellular and Systems Neurobiology Section

Building 49 Room 2A51
49 Convent Drive MSC 4479
Bethesda MD 20892-4479
Office: (301) 496-4960
Lab: (301) 451-0964
Fax: (301) 496-1339

Dr. Smith received his B.S. degree from the University of Maryland and his Ph.D. degree from Johns Hopkins University. After postdoctoral research in physiology at Harvard University, Northwestern University, and a Humboldt Fellowship at the University of Göttingen, Germany, in 1991 he became a faculty member in the Department of Physiological Science and Interdepartmental Program in Neuroscience at the University of California, Los Angeles. Dr. Smith moved to NINDS in 1994. His laboratory is studying the functional and computational properties of oscillatory motor networks in the mammalian brainstem and spinal cord.

Research in this section is directed toward understanding brain mechanisms underlying the generation and control of innate motor behavior in the mammalian CNS. One of the fundamental challenges in contemporary neuroscience is to explain the generation of behavior in terms of the cellular and neural network properties of neural systems. Networks generating movement, particularly those producing innate rhythmic motor behaviors such as breathing and locomotion, provide important model systems to address this problem. We study brainstem networks producing rhythmic breathing movements. Our long-range goal is to explain the neurogenesis of respiratory movements at the molecular, biophysical, synaptic, and network levels. The respiratory network is one of the few neural systems that can generate behaviorally relevant patterns of neural activity in highly reduced preparations of the mammalian CNS. This attribute has enabled us to develop unique in vitro preparations (e.g. see Koshiya and Smith, 1999), including brain slice preparations, that retain active respiratory networks, allowing concurrent measurements at cellular, synaptic, and network levels in the context of behaviorally meaningful network activity.

Our current in vitro studies focus mainly on mechanisms generating the neural oscillation underlying the rhythm of breathing. We are conducting interrelated studies to determine biophysical properties, morphology, network architecture, and synaptic interactions of the rhythm-generating neurons in the pre-Botzinger complex, the brainstem locus of rhythm generation (Smith et al., Science 254: 726-729, 1991). Our experimental techniques include whole-cell patch-clamp recording for studies of biophysical and synaptic properties, infrared and fluorescence videomicroscopy for real-time imaging of single cell and neuron population activity with calcium-sensitive dyes (Koshiya and Smith, 1999), and computational modeling of neurons, synapses, and networks (Butera et al., 1999).

Staff Image
  • Yonghua Chen, M.D., Ph.D.
    Guest Researcher

  • Noriyuki Hama, Ph.D.
    Guest Researcher

  • Tibin John, B.A.
    IRTA Fellow

  • Hidehiko Koizumi, Ph.D.
    Senior Research Fellow

  • Naohiro Koshiya, Ph.D.
    Research Scientist

  • Ruli Zhang, M.D.
    Research Fellow
    (301) 402-2534

  • Sami Znati, B.S.
    IRTA Fellow

  • 1) Koizumi, H., B. Mosher, M. F. Tariq, R. Zhang, N. Koshiya, and J. C. Smith. (2016)
  • Voltage-dependent rhythmogenic property of respiratory pre-Bötzinger complex glutamatergic, Dbx1-derived and somatostatin-expressing neuron populations revealed by graded optogenetic inhibition.
  • eNeuro, 3
  • 2) Marchenko, V., H. Koizumi, B. Mosher, N. Koshiya, M. F. Tariq, T. G. Bezdudnaya, Ruli Zhang, Yaroslav I. Molkov, I. A. Rybak, and J.C. Smith (2016)
  • Perturbations of respiratory rhythm and pattern by disrupting synaptic inhibition within pre-Bötzinger and Bötzinger complexes.
  • eNeuro, 3
  • 3) Bacak, B.J., T. Kim, J.C. Smith, J.E. Rubin, and I.A. Rybak (2016)
  • Mixed-mode oscillations and population bursting in the pre-Bötzinger complex
  • eLife, 2016;5:e13403.
  • 4) Abdala, A. P., J.F.R. Paton, and J. C. Smith. (2015)
  • Defining inhibitory neuron function in respiratory circuits: opportunities with optogenetics?
  • J. Physiology (London), 593, 3033-3046
  • 6) Molkov, Y, I., N. A. Shevtsova, C. Park, A. Ben-Tal, J. C. Smith, J. E. Rubin, and I. A. Rybak. (2014)
  • A closed-loop model of the respiratory system: focus on hypercapnia and active expiration.
  • PloS ONE, 9, 1-15
  • 7) Shevtsova, N.A., D. Büsselberg, Y. I. Molkov, A. M. Bischoff. J.C. Smith, D.W. Richter, and I.A. Rybak (2014)
  • Effects of glycinergic inhibition failure on respiratory rhythm and pattern generation. In Neural Control of Respiration, Eds. Holstege, G. and H. Subramanian.
  • Prog. Brain Res. , 209, 25-38
  • 8) Rybak, I.A., Y. I. Molkov, P. E. Jasinski, N. A. Shevtsova, and J. C. Smith (2014)
  • Rhythmic bursting in the pre-Bötzinger complex: mechanisms and models. In Neural Control of Respiration, Eds. Holstege, G. and H. Subramanian.
  • Prog. Brain Res., 209, 1-23
  • 9) Corcoran, A.E, K.G. Commons, J.C. Smith, M.B. Harris, and G. B. Richerson (2014)
  • Dual effects of 5-HT1a receptor activation on breathing in neonatal mice.
  • J. Neurosci., 34, 51-59
  • 10) Richter, D.W. and J.C. Smith. (2014)
  • Respiratory rhythm generation in vivo
  • Physiology, 29, 58-71
  • 11) Smith, J.C., A.P.L. Abdala, A. Borgmann, I.A. Rybak, and J.F.R. Paton (2013)
  • Brainstem respiratory networks: Building blocks and microcircuits.
  • Trends in Neurosciences, 36, 152-162
  • 12) Koizumi, H., N. Koshiya, J. Chia, F. Cao, J. Nugent, R. Zhang, and J.C. Smith (2013)
  • Structural-functional properties of identified excitatory and inhibitory interneurons within pre-Bötzinger complex respiratory microcircuits.
  • J. Neurosci., 33, 2994-3009
  • 13) Jasinski, P.E., Y. I. Molkov, N.A. Shevtsova, J.C. Smith, and I.A. Rybak (2013)
  • Sodium and calcium mechanisms of rhythmic bursting in excitatory neural networks of the pre-Bötzinger complex: a computational modeling study
  • Euro. J. Neurosci., 37, 212-230
  • 14) Lindey, B., I.A. Rybak, and J.C.Smith. (2012)
  • Computational models and emergent properties of respiratory neural networks.
  • Comprehensive Physiology , 2, 1619-1670
  • 15) Shevstova, N.A., Manzke, T., Molkov, Y.I., Bischoff, A., Smith, J.C., Rybak, I.A., and D.W. Richter. (2011)
  • Computational modelling of 5-HT receptor-mediated reorganization of the brainstem respiratory network
  • Eur. J. Neurosci., 34, 1276-1291
  • 16) Rubin, J. E., B.J. Bacak, Y.I. Molkov, N.A. Shevtsova, J.C. Smith, and I.A. Rybak (2011)
  • Interacting oscillations in neural control of breathing: modeling and analysis.
  • J. Comput. Neurosci., 30, 607-632
  • 17) Marina, N., A.P. Abdala, S. Trapp, A. Li, E.E. Nattie, J. Hewinson, J.C. Smith, J.F.R. Paton, and A.V. Gourine. (2010)
  • Essential role of Phox2b-expressing ventrolateral brainstem neurons in chemosensory control of inspiration and expiration.
  • J. Neurosci., 30, 12466-12473
  • 18) Molkov, Y.I., A.P.L. Abdala, B.J. Bacak, J.C. Smith, J.F.R. Paton, and I.A. Rybak (2010)
  • Late-expiratory activity: emergence and interactions with the respiratory CPG.
  • J. Neurophysiol, 30, 2713-2729
  • 19) Milescu, L.S., T. Yamanishi, K. Ptak, and J.C. Smith. (2010)
  • Kinetic properties and functional dynamics of sodium channels during repetitive spiking in a slow pacemaker neuron
  • J. Neurosci., 30, 12113-12127
  • 20) Ben-Tal, A. and J.C. Smith (2010)
  • Control of breathing: two types of delays studied in an integrated model of the respiratory system
  • Respir Physiol Neurobiol, 170, 103-112
  • 21) Koizumi, H., S. Smerin, T. Yamanishi, B. Moorjani, R. Zhang, and J.C. Smith (2010)
  • TASK channels contribute to the K+-dominated leak current regulating respiratory rhythm generation in vitro
  • J. Neurosci. , 30, 4273-4284
  • 22) Rubin, J.E., N.A, Shevtsova, G.B. Ermentrout, J.C. Smith, and I.A. Rybak. (2009)
  • Multiple rhythmic states in a model of the respiratory CPG
  • J. Neurophysiol. , 101, 2146-2165
  • 23) Ptak, K., T. Yamanishi, J. Aungst, L. Milescu, R. Zhang, G.B. Richerson, and J.C. Smith (2009)
  • Raphe neurons stimulate respiratory circuit activity by multiple mechanisms via endogenously released serotonin and substance P
  • J. Neurosci., 29, 370-3737
  • 24) Smith, J.C., A.P.L. Abdala, I. A. Rybak, and J.F.R. Paton (2009)
  • Structural and functional architecture of respiratory networks in the mammalian brainstem
  • Phil. Trans. Royal Soc. B , 364, 2577-2587
  • 25) Hodges, M., M. Wehner, J. Aungst, J.C. Smith, and G.B. Richerson (2009)
  • Transgenic mice lacking serotonin neurons have severe apnea and high mortality during development
  • J. Neurosci. , 29, 10341-10349
  • 26) Koizumi, H., C.G. Wilson, S. Wong, T. Yamanishi, N. Koshiya, and J.C. Smith (2008)
  • Functional imaging, spatial reconstruction, and biophysical analysis of a respiratory motor circuit isolated in vitro
  • J. Neurosci. , 28, 2353-2365
  • 27) Milescu, L. S., T. Yamanishi, K. Ptak, M.Z. Mogri, and J.C. Smith (2008)
  • Real-time kinetic modeling of voltage-gated ion channels using dynamic clamp
  • Biophys. J. , 95, 66-87
  • 28) Ben-Tal. A. and J.C. Smith (2008)
  • A model for control of breathing in mammals: coupling neural dynamics to peripheral gas exchange and transport
  • J. Theor. Biol. , 251, 480-497
  • 29) Koizumi, H. and J.C. Smith (2008)
  • Persistent Na+ and K+-dominated leak currents contribute to respiratory rhythm generation in the pre-Botzinger complex in vitro
  • J. Neurosci. , 28, 1773-1785
  • 30) Smith, J.C., A.P.L. Abdala, H. Koizumi, I.A. Rybak, and F.F.R. Paton (2007)
  • Spatial and functional architecture of the mammalian brainstem respiratory network: a hierarchy of three oscillatory mechanisms
  • J. Neurophysiol. , 98, 3370-3387
  • 31) Purvis, L., J.C. Smith, H. Koizumi, and R.J. Butera (2007)
  • Intrinsic bursters increase the robustness of rhythm generation in an excitatory network
  • J. Neurophysiol. , 97, 1515-1526
  • 32) Rybak, I.A., A.P.L. Abdula, S.N. Markin, J.F.R. Paton, and J.C. Smith (2007)
  • Spatial organization and state-dependent mechanisms for respiratory rhythm and pattern generation
  • Progress in Brain Research, 165, 201-220
  • 33) Paton, J.F.R., A.P.L. Abdala, H. Koizumi, J.C. Smith, and W. M. St-John (2006)
  • Respiratory rhythm generation during gasping depends on persistent sodium current
  • Nature Neurosci. , 9, 311-313
  • 34) Yuste, R., J.N. McClean, J. Smith, and A. Lansner (2005)
  • The cortex as a central pattern generator
  • Nature Rev. Neurosci. , 6, 477-483
  • 35) Del Negro, C., R.J. Butera, C.G. Wilson, and J.C. Smith (2002)
  • Periodicity, mixed-mode oscillations, and quasiperiodicity in a rhythm-generating neural network
  • Biophysical Journal, 82, 206-214
  • 36) Del Negro, C., N. Koshiya, R.J. Butera, and J.C. Smith (2002)
  • Persistent sodium current, membrane properties, and bursting behavior of pre-Bötzinger complex inspiratory neurons in vitro
  • J. Neurophysiology, 88, 2242-2250
  • 37) Johnson, S.M., N. Koshiya, and J.C. Smith (2001)
  • Isolation of the kernel for respiratory rhythm generation in a novel in vitro preparation: the pre-Bötzinger complex “island”
  • J. Neurophysiology, 85, 1772-1776
  • 38) Butera, R.J., C.G. Wilson, C. Del Negro, and J.C. Smith (2001)
  • A methodology for achieving high-speed rates for artificial conductance injection in electrically excitable biological cells
  • IEEE Transactions on Biomedical Engineering, 48, 1460-1470
  • 39) Del Negro, C., S.M. Johnson, R.J. Butera, and J.C. Smith (2001)
  • Models of respiratory rhythm generation in the pre-Bötzinger complex. III. Experimental tests of model predictions
  • J. Neurophysiology, 86, 59-74
  • 40) Johnson, S.M., N. Koshiya, and J.C. Smith (2001)
  • Isolation of the kernel for respiratory rhythm generation in a novel in vitro preparation: the pre-Botzinger complex island
  • J. Neurophysiology, 85, 1772-1776
  • 41) Smith, J.C., R.J. Butera, N. Koshiya, C. Del Negro, G.G. Wilson, ans S.M. Johnson (2000)
  • Respiratory rhythm generation in neonatal and adult mammals: the hybrid pacemaker-network model
  • Respiration Physiology, 122, 131-148
  • 42) Koshiya, N. and J.C. Smith (1999)
  • Neuronal pacemaker for breathing visualized in vitro
  • Nature, 400, 360-363
  • 43) Butera, R.J., Jr., J. Rinzel, and J.C. Smith (1999)
  • Models of respiratory rhythm generation in the pre-Bötzinger complex. II. Populations of coupled pacemaker neurons
  • J. Neurophysiology, 81, 398-415
  • 44) Butera, R.J., Jr., J. Rinzel, and J. C. Smith (1999)
  • Models of respiratory rhythm generation in the pre-Bötzinger complex. I. Bursting pacemaker neurons
  • J. Neurophysiology, 81, 382-397
  • 45) Smith, J.C., H.H. Ellenberger, K. Ballanyi, D.W. Richter, and J.L. Feldman (1991)
  • Pre-Botzinger Complex: A brainstem region that may generate respiratory rhythm in mammals
  • Science, 254, 726-729
  • 46) Smith, J.C., J.J. Greer, G. Liu, and J.L. Feldman (1990)
  • Neural mechanisms generating respiratory pattern in mammalian brain stem-spinal cord in vitro. I. Spatiotemporal patterns of motor and medullary neuron activity
  • J. Neurophysiology, 64, 1149-1169
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