The role of central 5-HT in heart rate and blood pressure regulation during sleep in the neonatal period

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Project Summary/Abstract The Sudden Infant Death Syndrome (SIDS) occurs during sleep. Most SIDS cases have major defects in the brainstem serotonin (5-hyrdoxytryptamine, 5-HT) system, including reduced 5-HT and tryptophan hydroxylase 2 (TPH2), the rate limiting enzyme in central 5-HT synthesis. In addition, rare recordings captured from SIDS cases indicate that death is preceded by bradycardia and hypotension, suggesting failure of autonomic mechanisms governing heart rate (HR) and blood pressure (BP). However, how reduced 5-HT could compromise heart rate and blood pressure regulation during sleep is unresolved. My proposed research directly addresses this knowledge gap. We hypothesize that during the neonatal period, 5-HT is important in the maintenance of BP and HR predominantly during quiet sleep (QS), when 5-HT neurons are active, and not during active sleep (AS), when these neurons are silent. Our over-arching hypothesis is that the bradycardia and hypotension displayed by 5-HT-deficient neonatal rodents occurs primarily in QS, due to enhanced cholinergic drive to the heart and associated defects in the cardiac baroreflex. To test this hypothesis, we will measure HR, BP and sleep state in freely-behaving 2 week-old rats deficient in TPH2 (TPH2-/-) and wild-type controls. A femoral arterial catheter will be used to monitor HR and BP across AS and QS, determined using nuchal electromyogram and behavioral observation. Drugs will be administered intravenously to determine autonomic tone to the heart under resting conditions, and the strength of the cardiac baroreflex in AS and QS. Immunohistochemistry against Fos will be used to assess the extent to which the activity of barosensitive autonomic nuclei is influenced by 5- HT deficiency. These findings will therefore give new insight into how a specific loss of serotonergic signaling could increase the risk of sudden death in a sleeping infant, and provide the knowledge needed for new translational studies in infants.