Sudden infant death syndrome (SIDS) is the most common cause of post neonatal infant death in the U.S. The mechanisms are unknown, but abnormalities in the serotonin system have been consistently found in autopsy studies. Thus, defining the role of serotonin neurons in normal brain function, which is also an important scientific goal, may help to understand SIDS. We have proposed that serotonin neurons of the raphe nuclei are sensors of arterial carbon dioxide that respond to hypercapnia by inducing arousal, an increase in breathing, and other changes aimed at restoring pH/CO2 homeostasis. This is consistent with the epidemiology of SIDS, because a defect in CO2 chemoreception could lead to loss of the normal ventilatory response to airway obstruction or rebreathing during sleep. We now plan to use two lines of genetically altered mice in which there is a defect in development of serotonin neurons to directly test the hypothesis that serotonin neurons are CO2 chemoreceptors. One line of mouse lacks Pet1, and has only 30% of the normal number of serotonin neurons. Our preliminary data indicate that male Pet1 KO mice have a defect in the hypercapnic ventilatory response as adults. The other line of mouse is a tissue specific knockout of Lmx1 b in cells that co-express Pet1. These mice have a selective loss of >99% of serotonin neurons. They live to adulthood with relatively few abnormalities. However, they have a severe defect in CO2 chemoreception. We will expose adult and neonatal mice to hypercapnia and hypoxia, and measure ventilation, heart rate, motor activity and EEG. We will also examine the effect on wild-type and mutant mice of prenatal exposure to cigarette smoke. We will then use the perfused brain preparation and brain slices to determine whether there is an alteration of respiratory rhythm generation or decreased response of the respiratory network to CO2. Finally, using in vivo, perfused brain and brain slice preparations, we will determine whether serotonin or thyrotropin releasing hormone can restore normal breathing in adult Lmxlb conditional knockout mice. These experiments will help define the normal role of serotonin neurons in control of breathing, autonomic function and arousal, and may explain how a defect in the serotonin system could lead to death while sleeping during a critical developmental period. This may provide a specific neurobiological mechanism for the association between SIDS and defects in the serotonin system.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
7R01HD052772-06
Application #
8393631
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Willinger, Marian
Project Start
2007-02-15
Project End
2013-01-31
Budget Start
2011-07-01
Budget End
2013-01-31
Support Year
6
Fiscal Year
2011
Total Cost
$239,050
Indirect Cost
Name
University of Iowa
Department
Neurology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Cerpa, Veronica J; Wu, Yuanming; Bravo, Eduardo et al. (2017) Medullary 5-HT neurons: Switch from tonic respiratory drive to chemoreception during postnatal development. Neuroscience 344:1-14
Richerson, George B; Boison, Detlev; Faingold, Carl L et al. (2016) From unwitnessed fatality to witnessed rescue: Pharmacologic intervention in sudden unexpected death in epilepsy. Epilepsia 57 Suppl 1:35-45
Massey, Cory A; Iceman, Kimberly E; Johansen, Sara L et al. (2015) Isoflurane abolishes spontaneous firing of serotonin neurons and masks their pH/CO? chemosensitivity. J Neurophysiol 113:2879-88
Buchanan, Gordon F; Smith, Haleigh R; MacAskill, Amanda et al. (2015) 5-HT2A receptor activation is necessary for CO2-induced arousal. J Neurophysiol 114:233-43
Murray, Nicholas M; Buchanan, Gordon F; Richerson, George B (2015) Insomnia Caused by Serotonin Depletion is Due to Hypothermia. Sleep 38:1985-93
Cerpa, Verónica J; Aylwin, María de la Luz O; Beltrán-Castillo, Sebastián et al. (2015) The Alteration of Neonatal Raphe Neurons by Prenatal-Perinatal Nicotine. Meaning for Sudden Infant Death Syndrome. Am J Respir Cell Mol Biol 53:489-99
Corcoran, Andrea E; Richerson, George B; Harris, Michael B (2015) Functional link between the hypocretin and serotonin systems in the neural control of breathing and central chemosensitivity. J Neurophysiol 114:381-9
Teran, Frida A; Massey, Cory A; Richerson, George B (2014) Serotonin neurons and central respiratory chemoreception: where are we now? Prog Brain Res 209:207-33
Corcoran, Andrea E; Commons, Kathryn G; Wu, Yuanming et al. (2014) Dual effects of 5-HT(1a) receptor activation on breathing in neonatal mice. J Neurosci 34:51-9
Buchanan, Gordon F; Murray, Nicholas M; Hajek, Michael A et al. (2014) Serotonin neurones have anti-convulsant effects and reduce seizure-induced mortality. J Physiol 592:4395-410

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