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Respiratory and Arousal Mechanisms (NS090414)

Specific Aims and Tasks

Cardiac arrhythmias and respiratory depression are both proposed to be mechanisms that lead to SUDEP; however respiratory mechanisms have not been studied as extensively as cardiac causes. SUDEP is a major cause of death in patients with epilepsy, by some estimates accounting for up to 50% of mortality in patients with chronic refractory epilepsy. Cardiac arrhythmias and respiratory depression are both proposed to be mechanisms that lead to SUDEP, however respiratory mechanisms have not been studied as extensively as cardiac causes. This proposal seeks: 1) to investigate the mechanisms underlying hypoventilation and post-ictal coma; 2) to identify biomarkers; 3) to aid forensic diagnosis, and; 4) to discover preventive interventions to decrease SUDEP.
  • This project seeks to identify anatomical pathways by which cortical seizures can invade the midbrain and brainstem and cause depressed cardiorespiratory function and arousal

Principal Investigator


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.
  • Dekin, MS, GB Richerson & PA Getting. Thyrotropin-releasing hormone induces rhythmic bursting in neurons of the nucleus tractus solitarius. PMID 3925552.
  • Bradley, SR, VA Pieribone, W Wang, CA Severson, RA Jacobs & GB Richerson. Chemosensitive serotonergic neurons are closely associated with large medullary arteries. PMID 11967547.
  • Severson, CA, W Wang, VA Pieribone, CI Dohle & GB Richerson. Midbrain serotonergic neurons are central pH chemoreceptors. PMID 14517544.
  • Richerson, G.B. Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis.PMID 15152195.
  • 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. PMID 15937479.
  • Wu, Y., W. Wang, A. Diez-Sampedro & G.B. Richerson. Hippocampal nonvesicular neurotransmission via reversal of the GABA transporter GAT-1. PMID 18054861.
  • 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 PMID 18322094.
  • 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. PMID 19692608.
  • 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. PMID 19400695.
  • 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. PMID 19321769.
  • Buchanan, G.F. & G.B. Richerson. Central serotonin neurons are required for arousal to CO2. PMID 20805497.
  • Richerson, G.B. & G.F. Buchanan. The serotonin axis: Shared mechanisms in seizures, depression, and SUDEP. PMID 21214537.
  • 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. PMID 21798952.
  • Richerson, G.B., G. Aston-Jones & C.B. Saper. Brainstem modulation of brain function. In: Principles of Neural Science, Fifth edition. Edited by Kandel, E.R., J.H. Schwartz, T.M. Jessel, A.J. Hudspeth & S.A. Siegelbaum, 2012.
  • Sowers, L.P., C.A. Massey, B.K. Gehlbach, M.A. Granner & G.B. Richerson. Sudden unexpected death in epilepsy: Fatal post-ictal respiratory and arousal mechanisms. PMID: 23707877.
  • Corcoran, A.E., K.G. Commons, J.C. Smith, M.B. Harris & G.B. Richerson. Dual effects of 5-HT1a receptor activation on breathing in neonatal mice. PMID 24381267.
  • Massey, C.A., L.P. Sowers, B.J. Dlouhy & G.B. Richerson. Mechanisms of sudden unexpected death in epilepsy: The pathway to prevention. PMID 24752120.