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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Special Emphasis Panel (ZHD1)
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Children's Hospital Boston
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Dosumu-Johnson, Ryan T; Cocoran, Andrea E; Chang, YoonJeung et al. (2018) Acute perturbation of Pet1-neuron activity in neonatal mice impairs cardiorespiratory homeostatic recovery. Elife 7:
Babb, Jessica A; Linnros, Sofia E; Commons, Kathryn G (2018) Evidence for intact 5-HT1A receptor-mediated feedback inhibition following sustained antidepressant treatment in a rat model of depression. Neuropharmacology 141:139-147
Ehlinger, Daniel G; Commons, Kathryn G (2017) Altered Cav1.2 function in the Timothy syndrome mouse model produces ascending serotonergic abnormalities. Eur J Neurosci 46:2416-2425
Panzini, Chris M; Ehlinger, Daniel G; Alchahin, Adele M et al. (2017) 16p11.2 deletion syndrome mice perseverate with active coping response to acute stress - rescue by blocking 5-HT2A receptors. J Neurochem 143:708-721
Commons, Kathryn G; Cholanians, Aram B; Babb, Jessica A et al. (2017) The Rodent Forced Swim Test Measures Stress-Coping Strategy, Not Depression-like Behavior. ACS Chem Neurosci 8:955-960
Haynes, Robin L; Frelinger 3rd, Andrew L; Giles, Emma K et al. (2017) High serum serotonin in sudden infant death syndrome. Proc Natl Acad Sci U S A 114:7695-7700
Guo, Yue-Ping; Commons, Kathryn G (2017) Serotonin neuron abnormalities in the BTBR mouse model of autism. Autism Res 10:66-77
Hennessy, Morgan L; Corcoran, Andrea E; Brust, Rachael D et al. (2017) Activity of Tachykinin1-Expressing Pet1 Raphe Neurons Modulates the Respiratory Chemoreflex. J Neurosci 37:1807-1819
Darnall, Robert A; Chen, Xi; Nemani, Krishnamurthy V et al. (2017) Early postnatal exposure to intermittent hypoxia in rodents is proinflammatory, impairs white matter integrity, and alters brain metabolism. Pediatr Res 82:164-172
Tenpenny, Richard C; Commons, Kathryn G (2017) What Gene Mutations Affect Serotonin in Mice? ACS Chem Neurosci 8:987-995

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