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Respiratory and Arousal Mechanisms (NS090414)

Specific Aims and Tasks

Post-ictal respiratory depression has been proposed to contribute to SUDEP, and this may be particularly dangerous when combined with impaired arousal that commonly occurs after generalized tonic-clonic seizures. The combination of arousal and respiratory defects could explain why many SUDEPs occur with patients in bed in the prone position. This proposal has the following Specific Aims:
1 - Characterize interictal and ictal respiratory control and arousal in Dravet Syndrome patients and Dravet Syndrome mice.
2 - Identify the anatomical pathway from the forebrain that inhibits the respiratory control network during seizures.
3 - Determine which brainstem neurons are involved in peri-ictal inhibition of breathing and depressed arousal during seizures.
The proposed work is expected to help define the mechanisms underlying post-ictal hypoventilation and depression of arousal; identify biomarkers of SUDEP, and; discover preventive interventions for SUDEP.

Principal Investigator

Core Personnel

Rup Sainju, MD - Neurology
Brian Gehlbach, MD – Pulmonary Medicine
Brian Dlouhy, MD – Neurosurgery
Mark Granner, MD – Neurology
Marcus Nashelsky, MD – Pathology
Gordon Buchanan, MD, PhD – Neurology
Eduardo Bravo, PhD – Postdoctoral Fellow
YuJaung Kim – Biomedical Engineering PhD Student
Katherine Proch – MSTP Student
Frida Teran – MSTP Student
Anthony Marincovich – M2 Medical Student
Ryan Lechtenberg – M2 Medical Student
Hassan Ahamed – Biomedical Engineering Undergraduate Student
Lori Smith – Laboratory Manager
Deidre Dragon – Research Assistant
Harold Winnike – Pulmonary Technician

Publication Links

  • Cerpa, V.J., Y. Wu, E.U. Bravo, F.A. Teran, R.S. Flynn & G.B. Richerson. Medullary 5-HT neurons: Switch from respiratory drive to chemoreception during postnatal development. Neurosci (in press), 2016.
  • Buchanan, G.F. & G.B. Richerson. Epilepsy: A dietary supplement for SUDEP prevention? Nature Rev Neurol 12(9):495-6, 2016. PMID 27514288.
  • Devinsky, O., D.C. Hesdorffer, D. Thurman, S. Lhatoo, G.B. Richerson. Sudden Unexpected Death in Epilepsy: Epidemiology, Mechanisms & Prevention. Lancet Neurology, 15(10):1075-88, 2016. PMID 27571159.
  • Zhan, Q., G. Buchanan, J. Motelow, J. Andrews, P. Vitkovskiy, W. Chen, F. Serout, A. Gummadavelli, A. Kundishora, M. Furman, W. Li, X. Bo, G.B. Richerson, and H. Blumenfeld. Impaired serotonergic brainstem function during and following seizures. J Neurosci, 36(9):2711-22, 2016. PMID 26937010.
  • Richerson, G.B., D. Boison, C. Faingold & P. Ryvlin. SUDEP: From unwitnessed fatality to witnessed rescue: pharmacological intervention. Epilepsia, 57(Suppl 1):35-45, 2016. PMID 26749015.
  • Lhatoo, S., J. Noebels, V. Whittemore, and The NINDS Center for SUDEP Research. Sudden Unexpected Death in Epilepsy (SUDEP): Identifying Risk and Preventing Mortality. Epilepsia 56(11):1700-6, 2015. PMID 26494436.
  • Murray, N.M., G.F. Buchanan & G.B. Richerson. Sleep disruption caused by serotonin depletion is due to hypothermia. Sleep, 38(12):1985-93, 2015. PMID: 26194567.
  • Dlouhy, B.J., B.K. Gehlbach & G.B. Richerson. Sudden unexpected death in epilepsy (SUDEP): basic mechanisms and clinical implications for prevention. J Neurol Neurosurg Psych, 87(4):402-13, 2015. PMID 26979537.
  • Cerpa, V.J., M.L. Aylwin, S. Beltrán-Castillo, E.U. Bravo, I.R. Llona, G.B. Richerson & J.L. Eugenín. Alteration of neonatal raphe neurons by prenatal-perinatal nicotine: Meaning for Sudden Infant Death Syndrome. Am J Respir Cell Mol Biol, 53(4):489-99, 2015. PMID 25695895.
  • Dlouhy, B.J., B.K. Gehlbach, C.J. Kreple, H. Kawasaki, H. Oya, C. Buzza, M.A. Granner, M.J. Welsh, M.A. Howard III, J.A. Wemmie and G.B. Richerson. Breathing inhibited when seizures spread to the amygdala and upon amygdala stimulation. J Neurosci, 35(28):10281-9, 2015. PMID 26180203.
  • Buchanan, G.F., H. Smith, A. MacAskill & G.B. Richerson. 5-HT2A receptor activation is necessary for CO2-induced arousal. J Neurophysiol, 114(1):233-43, 2015. PMID 25925320.
  • Corcoran, A.E., G.B. Richerson & M.B. Harris. Functional link between the hypocretin and serotonin systems in the neural control of breathing and central chemosensitivity. J Neurophysiol, 114(1):381-9, 2015. PMID 25878157.
  • McGlashon, J.B., A. Kozlowski, M. Gorecki, C. Thirnbeck, K. Markan, M.E. Kotas, M.J. Potthoff, G.B. Richerson & M.P. Gillum. Central serotonergic neurons activate and recruit thermogenic brown and beige fat and regulate glucose and lipid homeostasis. Cell Metabolism, 21(5):692-705, 2015. PMID 25955206.
  • Massey, C.A., K.E. Iceman, S.L. Johansen, Y. Wu, M.B. Harris & George B. Richerson. Isoflurane abolishes spontaneous firing of serotonin neurons and masks their pH/CO2 chemosensitivity. J Neurophysiol, 113(7):2879-88, 2015. PMID 25695656.
  • Richerson, G.B & L.M. Bateman. Partners Against Mortality in Epilepsy Conference Summary. Epilepsy Currents, 14(6) Supplement:16-18, 2014.
  • Brust, R.D., A.E. Corcoran, G.B. Richerson, E.E.Nattie, S.M. Dymecki. Functional and developmental identification of a molecular subtype of brain serotonergic neuron specialized to regulate breathing dynamics. Cell Reports, 9(6):2152-65, 2014. PMID: 25497093 .
  • Buchanan, G.F., N.M. Murray, M.A. Hajek & G.B. Richerson. Serotonin neurones have anticonvulsant effects and reduce seizure-induced mortality. J Physiol, 592(19):4395-4410, 2014. PMID: 25107926 .
  • Massey, C.A., L.P. Sowers, B.J. Dlouhy & G.B. Richerson. Mechanisms of sudden unexpected death in epilepsy: The pathway to prevention.Nature Rev Neurol, 10:271-282, 2014. PMID 24752120.
  • Teran, F.A., C.A. Massey & G.B. Richerson. Serotonin neurons and central respiratory chemoreception: Where are we now? Prog Brain Res, 209:207-233, 2014. PMID: 24746050 .
  • Ray, R., A. Corcoran, R. Brust, J. C. Kim, G.B. Richerson, E.E. Nattie & S. M. Dymecki. Homeostatic imbalance upon acute in vivo serotonergic neuron inhibition. Science 333(6042): 637-642, 2011. PMID: 21798952 (Science Editor’s Choice). (Faculty of 1000).
  • Richerson, G.B. & G.F. Buchanan. The serotonin axis: Shared mechanisms in seizures, depression, and SUDEP. Epilepsia 52 (Suppl 1):28-38, 2011. PMID: 21214537 .
  • Buchanan, G.F. & G.B. Richerson. Central serotonin neurons are required for arousal to CO2. PNAS 107(37): 16354-9, 2010. PMID 20805497.
  • Hodges, M.R., M. Wehner, J. Aungst, J.C. Smith & G.B. Richerson. Transgenic mice lacking serotonin neurons have severe apnea and high mortality during development.J Neurosci 29(33):10341-10349, 2009. PMID 19692608.
  • Buchanan, G.F. & G.B. Richerson. Role of chemoreceptors in mediating dyspnea. Respir Physiol Neurobiol 167(1):9-19, 2009.
  • Ptak, K., T. Yamanishi, J. Aungst, L.S. Milescu, R. Zhang, G.B. Richerson & J.C. Smith. Raphé neurons stimulate respiratory circuit activity by multiple mechanisms via endogenously released serotonin and substance P.J Neurosci 29(12): 3720-37, 2009. PMID 19321769.
  • Kinney, H.C., G.B. Richerson, S.M. Dymecki, R.A. Darnall & E.E. Nattie. The brainstem and serotonin in the sudden infant death syndrome.Annual Rev Pathol 4: 517-550, 2009. PMID 19400695.
  • Hodges, M.R., G.J. Tattersall, M.B. Harris, S. McEvoy, D.N. Richerson, E.S. Deneris, R.L. Johnson, Z.F. Chen & G.B. Richerson. Defects in breathing and thermoregulation in mice with near-complete absence of central serotonin neurons. J Neurosci 28(10): 2495-2505, 2008. PMID 18322094.
  • Wu, Y., W. Wang, A. Diez-Sampedro & G.B. Richerson. Hippocampal nonvesicular neurotransmission via reversal of the GABA transporter GAT-1.Neuron 56(5): 851-65, 2007. PMID 18054861.
  • Du, W., J.F. Bautista, H. Yang, A. Diez-Sampedro, S.A. You, L. Wang, P. Kotagal, H.O. Lüders, J. Shi, J. Cui, G.B. Richerson & Q. Wang. Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder.Nature Genetics 37(7): 733-738, 2005. PMID 15937479.
  • Richerson, G.B. Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis.Nature Reviews Neuroscience 5:449-461, 2004.PMID 15152195.
  • Severson, CA, W Wang, VA Pieribone, CI Dohle & GB Richerson. Midbrain serotonergic neurons are central pH chemoreceptors.Nature Neurosci 6(11):1139-1140, 2003. PMID 14517544.
  • Bradley, S. Risso, V. A. Pieribone, W. Wang, C.A. Severson, R. A. Jacobs & G. B. Richerson. Chemosensitive serotonergic neurons are closely associated with large medullary arteries. Nature Neurosci 5(5): 401-402, 2002.
  • Wang, W., S. Risso Bradley & G.B. Richerson. Quantification of the response of rat medullary raphe neurones to independent changes in pHo and PCO2. J Physiol (Lond) 540(3): 951-970, 2002.PMID 2290275.
  • Wang, W., A.V. Zaykin, J.K. Tiwari, S. Risso Bradley & G.B. Richerson. Acidosis-stimulated neurons of the medullary raphe are serotonergic. J Neurophysiol 85:2224-2235, 2001.PMID 3402849.
  • Wang, W., J. Pizzonia, & G.B. Richerson. Chemosensitivity of rat medullary raphe neurones in primary tissue culture. J Physiol (Lond) 511(2):433-450, 1998. PMID: 2231124.
  • Richerson, G.B. Response to CO2 of neurons in the rostral ventral medulla in vitro. J Neurophysiol 73(3):933-944, 1995.PMID: 7608778.
  • Dekin, MS, GB Richerson & PA Getting. Thyrotropin-releasing hormone induces rhythmic bursting in neurons of the nucleus tractus solitarius. PMID 3925552.