The Sudden Infant Death Syndrome (SIDS) remains the leading cause of death between 1 month and 1 year of age. SIDS cases display more apnea as well as sleep abnormalities, including increased amounts of active sleep (?AS?; i.e. rapid eye movement sleep), a state characterized by unstable breathing. Ultimately, many SIDS cases die from cardiorespiratory collapse during an episode of severe hypoxia (failed autoresuscitation). The underlying pathophysiology of these abnormalities is unclear. Most SIDS victims have defects in the brainstem 5-HT system, including reduced serotonin (5-HT) and inhibitory 5-HT1A receptors. Neonatal rodents lacking central 5-HT have phenotypes reminiscent of SIDS, including apnea and failed autoresuscitation. Our long-term goal is to illuminate the mechanisms by which 5- HT prevents apnea during AS and facilitates autoresuscitation. The overarching hypothesis driving our research is that brainstem 5-HT acts as a negative regulator of acetylcholine neurons in the pons and GABAergic neurons in the medulla, leading to apnea during prolonged periods of AS and compromised autoresuscitation, respectively. These hypotheses will be explored with the following Specific Aims:
Specific Aim 1 : To determine the mechanisms by which a loss of central 5-HT leads to apnea during prolonged periods of AS. Our working hypothesis is that signaling through 5-HT1A receptors located in the LDT and/or PPT reduces drive to cholinoreceptive regions of the pons, including the Kolliker Fuse (KF) nucleus, thereby terminating AS and mitigating apnea and respiratory instability in AS.
Specific Aim 2 (SA2): To determine mechanistically how a loss of central 5-HT compromises autoresuscitation. Our working hypothesis is that signaling through 5-HT1A receptors helps to promote autoresuscitation by reducing GABAergic drive within the ventrolateral medulla (VLM). Our research will reveal that 5-HT maintains cardiorespiratory homeostasis in infancy through cholinergic and GABAergic pathways. It will be impactful as it will show how 5-HT signaling can 1) reduce the chances of an infant becoming hypoxic during sleep, and 2) facilitate cardiorespiratory recovery when hypoxia becomes severe. This mechanistic insight will be crucial for developing new pharmacological, prophylactic strategies aimed at reducing SIDS incidence within at-risk populations.
The Sudden Infant Death Syndrome (SIDS) remains the leading cause of infant death between 1 month and 1 year of age, with SIDS victims dying following apnea (no breathing), a failure to wake up from sleep, and inability to restore heat rate and blood pressure when hypoxia (low oxygen) becomes severe. Most SIDS victims have reduced amounts of the neurotransmitter serotonin in the brain. The ultimate goal of this research is to help reduce the incidence of SIDS by revealing how serotonin deficiency leads to a baby?s breathing ceasing during sleep, leading to severe hypoxia and eventually death following cardiovascular collapse.