The Ramirez Lab

Jan-Marino (Nino) Ramirez, PhD is a Professor of Neurological Surgery and Director of the Center for Integrative Brain Research at the Seattle Children’s Research Institute.

Dr. Ramirez has a general research interest in the neural control of rhythmic activity. He studies neural mechanisms involved in the generation of respiratory rhythms, neocortical activity, and epilepsy. He is also interested in the neuronal mechanisms underlying erratic breathing in Rett syndrome, familial dysautonomia, congenital hypoventilation syndrome, traumatic brain injury, and pediatric epilepsy, as well as burst firing in dopaminergic neurons, possibly linked to ADHD. Dr. Ramirez’s current work is focused on hypoxic effects on mammalian respiratory neural networks. His work is supported by multiple National Institutes of Health (NIH) awards.

Lab worker in Ramirez lab
Investigators/ Researchers
Research Questions

With the introduction of molecular approaches into the field of neuroscience, an unexpected variety of receptor and ion channel subtypes have been discovered that are developmentally regulated within the central nervous system.

The relevance of these findings for the function of neuronal networks is still unclear. In a close combination of studies at the cellular and systems level Dr. Ramirez's laboratory examines how diversity at the cellular level may lead to ontogenetic changes at the network level.

Research Methods
  1. Over the past decade, Dr. Ramirez has analyzed cellular mechanisms in neuronal networks that generate rhythmic motor activity in invertebrates and vertebrates. His current work focuses on the analysis of the in-vitro respiratory network in mice. For this purpose, he isolates acutely the respiratory network in a transverse plane of the mouse medulla. This brainstem slice preparation contains the essential medullary structures involved in cardio-respiratory control and even after the in vitro isolation, generates rhythmic activity in rats and mice of all developmental stages (up to an age of 25 postnatal days). This approach permits a direct comparison of the neuronal mechanisms of rhythmogenesis in newborn and more mature mammals.

  2. In order to analyze the cellular mechanisms in rhythm generating neural networks, Dr. Ramirez employs the currently available electrophysiological and immunohistochemical techniques. The great advantage of the brainstem slice preparation is that single neurons can be visualized that are embedded in a functional neuronal network using infrared-Normarski optics in conjunction with upright microscopes. Thus, voltage-gated and synaptic whole cell currents, properties of single channels as well as second messenger pathways can be investigated in a functional context to characterize changes in postnatal development of the respiratory network.

  3. In the future this slice preparation will enable Dr. Ramirez to further obtain systems and cellular data from functionally identified respiratory neurons. In combination with cell culture and modern molecular techniques (e.g. expression of channel subtypes obtained from respiratory neurons in oocytes) we expect to gain new insights into principal mechanisms of respiratory rhythm generation and the hypoxic response in mammals.

Bibliography of Selected Publications
  1. Thoby-Brisson, M., Telgkamp, P. Ramirez, J.M. (2000). The role of the hyperpolarization-activated current in modulating rhythmic activity in the isolated respiratory network of mice. J. Neuroscience. 20 (8): 2994-3005.

  2. Lieske, S.P. Thoby-Brisson, M., Telgkamp, P. Ramirez, J.M. (2000). Reconfiguration of the neural network controlling multiple breathing patterns: eupnea, sighs and gasps. Nature Neuroscience 3: 600-7.

  3. Wilken, B., Ramirez, J.M., Probst, I., Richter, D.W., Hanefeld, F. (2000). Anoxic ATP depletion in neonatal mice brainstem is prevented by creatine supplementation. Arch. Diseases in Childhood, Fetal Neonatal Ed. 82: F224-7.

  4. Wilken B, Ramirez JM, Hanefeld F, Richter DW. (2000). Aminophylline modulation of the mouse respiratory network changes during postnatal maturation. Journal of Applied Physiology 89: 2015-2022.

  5. Thoby-Brisson, M., Ramirez, J.M. (2000). Role of inspiratory pacemaker neurons in mediating the hypoxic response of the respiratory network in vitro. J. Neuroscience 20: 5858-66.

  6. McCrimmon, D.R., Ramirez, J.M., Alford, S., Zuperku, E.J. (2000). Unraveling the mechanisms for respiratory rhythm generation. BioEssays 22: 6-9.

  7. Thoby-Brisson, M, Ramirez, J.M. (2001). Two types of inspiratory pacemaker neurons in the isolated respiratory network of mice. J. Neurophysiol: 86 (1):104-12.

  8. Lieske, S.P., Thoby-Brisson, M., Ramirez, J.M. (2001). Reconfiguration of the central respiratory network under normoxic and hypoxic conditions. Adv Exp Med Biol. 2001; 499: 171-8

  9. Kelty, J.D., Noseworthy, P.A., Feder, M.E., Robertson, R.M., Ramirez, J.M. (2002). Thermal Preconditioning and HSP72 protect synaptic transmission during thermal stress. J. Neuroscience. Jan 1; 22(1): C193

  10. Koch, L.E., Koch, H., Stolle, D., Ramirez, J.M., Saternus, K.S. (2002). Heart rate changes in response to mild mechanical irritation of the high cervical spinal cord region in infants. Forensic Science International. In press.

  11. Blitz, D.M., Ramirez, J.M. (2002). Long-term Modulation of Respiratory Network Activity Following Anoxia in Vitro. J. Neurophysiol. 87: 2964-2971.

  12. Ramirez, J.M., Zuperku, E.J., Alheid, G., Lieske S.P., Ptak, C., McCrimmon, D.R. (2002). Respiratory Rhythm Generation.Converging Concepts from In Vitro and In Vivo Approaches? Resp. Physiol. and Neurobiol. 131: 43-56.

  13. Telgkamp P. Ramirez, J.M. (2002). The Role of Substance P in the Control of respiratory Activity under Normoxic and Hypoxic Conditions In Vitro. J. Neurophysiol. 88: 206-213.

  14. Tryba, A.K, Ramirez, J.M. (2002). The hyperthermic response of the isolated respiratory network of mice. Journal of Neurophysiology: 89 (6): 2975-2983.

  15. Pena, F., Ramirez, J.M. (2002). Endogenous activation of serotonin 2A receptors is required for normal respiratory rhythm generation in vitro. J. Neuroscience; 22(24): 11055-64.

  16. Van Drongelen, W., Koch H., Marcuccilli C.J., Pena, F. Ramirez, J.M. (2003). Synchrony levels during evoked seizure like bursts in mouse neocortical slices, J. Neurophysiology: 90 (3): 1571-1580.

  17. Van Drongelen, W. Koch, H., Marcuccilli, C.J., Hecox, K., Ramirez, J.M. (2003). Is burst activity in cortical slices a representative model for epilepsy? Neurocomputation. 52-54: 963-968.

  18. Tryba A.K., Pena, F., Ramirez J.M. (2003). Stabilization of bursting in respiratory pacemaker neurons. J. Neuroscience 23 (8): 3538-3546.

  19. Moseley, A.F., Lieske S.P., Wetzel R.K., James P.F., He S., Shelly D.A., Paul R.J., Boivin, G.P., Witte D.P., Ramirez, J.M., Sweadner, K.J., Lingrel, J.B., (2003).

  20. The Na k-AtPase, alpha 2 isoform is expressed in neurons, and its absence disrupts neuronal activity in newborn mice. J. Biol. Chem. 14 278 (7): 5317-5324.

  21. Ramirez, J.M. (2004). Adaptive properties of motor behavior: The response to changes in developmental and environmental conditions. In: Biedermann H. (editor). Chiropractic Therapy in Infants. Elsevier.

  22. Tryba, A.K., Ramirez, JM (2004). Hyperthermia modulates respiratory pacemaker bursting properties. J. Neurophysiology 92(5):2844-52.

  23. Tryba, A.K., Ramirez, JM (2004). Background sodium current stabilizes bursting in respiratory pacemaker neurons. J. Neurobiology, 60: 481-489.

  24. Pena, F., Parkis M.A., Ramirez J.M. (2004). Differential contribution of pacemaker properties to the generation of respiratory rhythms during normoxia and hypoxia. Neuron, 43: 105-117.

  25. Peña, F.P., Ramirez, J.M. (2004). Substance P mediated modulation of pacemaker properties in the mammalian respiratory network. J. Neuroscience, 24: 7549-7556. Ramirez, JM, Tryba, AK, Peña, FP (2004). Pacemaker neurons: An integrative view. Cur. Opin. Neurobiol, 14(6):665-74.