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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 Investigators

Publication Links

  • 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.