Based on observations from brainstem tissue of SIDS cases, we hypothesize, as a program, that an important subset of SIDS result from medullary defects in serotonin (5-HT)-producing neurons and related neurotransmitter systems such as GABA. Evidence suggests that these defects arise during gestation and affect specific subtypes of, as opposed to all, 5-HT neurons. From this, we reason that SIDS is an embryonic developmental disorder affecting specific subtypes of 5-HT and/or GABA neurons of the medulla. Towards understanding the differential basis for SIDS, we propose experiments designed to decode the developmental and molecular origins of different neuron subtypes within the medullary 5-HT and GABA neural systems in the mouse, and determine the specific properties of these subtypes as relates to homeostatic control. These experiments are made possible via recent, powerful advances: 1) a developmental map of the mature brainstem 5-HT system that, for the first time, resolves the system into molecularly separable, and therefore genetically accessible, 5-HT neuron subtypes;2) the identification of embryonic genetic programs that are instructive for different GABAergic fates and which are likely employed in the developing medulla;and 3) tools with sufficient specificity to perturb the activity of (for example, """"""""silence"""""""") select 5-HT or GABA subtypes in the living mouse. Using these tools, we will plot cellular functions and electrophysiological properties onto the developmental maps of medullary 5-HT and GABA neuron subtypes (Aims 1 and 3, respectively). Because our goal is to identify neuron subtypes most relevant pathophysiologically to SIDS, we will focus on 5-HT and GABA neuron subtypes of the medulla and their properties as relates to sensing acidosis and/or hypoxia (in collaboration with Project 4) and their functions as relates to control of breathing, heart rate, blood pressure and reflex apnea (in collaboration with Project 2). These are functions which, if impaired, might plausibly contribute to sudden death. Further, we propose investigating a possible mechanism for regulating 5-HT neuron production, our goal being to decipher the basis for the increased number of 5-HT neurons in SIDS cases. The ability to redefine medullary 5-HT and GABA neuron subtypes and their production based on a constellation of criteria - molecular, developmental, electrophysiological, and functional- is a major strength and innovation of this proposal and program.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD036379-15
Application #
8376691
Study Section
Special Emphasis Panel (ZHD1-MCHG-B)
Project Start
Project End
2013-09-23
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
15
Fiscal Year
2012
Total Cost
$338,557
Indirect Cost
$23,191
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Edlow, Brian L; McNab, Jennifer A; Witzel, Thomas et al. (2016) The Structural Connectome of the Human Central Homeostatic Network. Brain Connect 6:187-200
Hefti, Marco M; Kinney, Hannah C; Cryan, Jane B et al. (2016) Sudden unexpected death in early childhood: general observations in a series of 151 cases: Part 1 of the investigations of the San Diego SUDC Research Project. Forensic Sci Med Pathol 12:4-13
Commons, Kathryn G (2016) Ascending serotonin neuron diversity under two umbrellas. Brain Struct Funct 221:3347-60
Goodstein, M H; Hauck, F R; Darnall, R A et al. (2016) Swaddling is not contraindicated in the newborn period. J Perinatol 36:160
Barrett, Karlene T; Dosumu-Johnson, Ryan T; Daubenspeck, J Andrew et al. (2016) Partial Raphe Dysfunction in Neurotransmission Is Sufficient to Increase Mortality after Anoxic Exposures in Mice at a Critical Period in Postnatal Development. J Neurosci 36:3943-53
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
Cerpa, Veronica J; Wu, Yuanming; Bravo, Eduardo et al. (2016) Medullary 5-HT neurons: Switch from tonic respiratory drive to chemoreception during postnatal development. Neuroscience :
Darnall, Robert A; Schneider, Robert W; Tobia, Christine M et al. (2016) Eliminating medullary 5-HT neurons delays arousal and decreases the respiratory response to repeated episodes of hypoxia in neonatal rat pups. J Appl Physiol (1985) 120:514-25
Goldstein, Richard D; Trachtenberg, Felicia L; Sens, Mary Ann et al. (2016) Overall Postneonatal Mortality and Rates of SIDS. Pediatrics 137:
Hefti, Marco M; Cryan, Jane B; Haas, Elisabeth A et al. (2016) Hippocampal malformation associated with sudden death in early childhood: a neuropathologic study: Part 2 of the investigations of The San Diego SUDC Research Project. Forensic Sci Med Pathol 12:14-25

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