Role of central serotonin in sleep architecture and arousal in infant rat pups

Sudden Infant Death Syndrome (SIDS) occurs during sleep and is the leading cause of infant death in the post‐neonatal period. SIDS cases have more active sleep (AS), a sleep state associated with apnea and cardiovascular instabilities. It is also thought that SIDS involves a failure to arouse from an apneic event during sleep. Defects within the brainstem serotonin (5‐hydroxytryptamine, 5‐HT) system (including a loss of 5‐HT content) are associated with SIDS, and a causal role 5‐HT deficiency is suggested by recent studies using rodents deficient in central 5‐HT. However, how a specific loss of central 5‐HT in neonatal life affects sleep, respiratory control across sleep states and arousal from sleep has not been investigated. We hypothesized that 5‐HT deficiency increases the amount of active sleep (AS), compromises breathing mostly during quiet sleep (QS) when 5‐HT neurons still fire, and blunts the arousal response to hypercapnia. We monitored sleep and breathing over ~2hrs in two groups of unanaesthetized, 2 week‐old rat pups deficient in tryptophan hydroxylase‐2 ( TPH2 − / − ) and wild‐type controls (WT). One group (n=6 WT, 5 TPH2 − / − ) was kept in normoxic conditions and the other group (n=10 WT, 8 TPH2 − / − ) was given intermittent challenges of 5% CO 2 at the beginning of episodes of AS and QS until arousal. Sleep state was determined using nuchal electromyography and behavioral observation. Breathing was monitored using whole body plethysmography. We measured the duration of AS and QS episodes ( i.e. latency to arousal) in normocapnia and hypercapnia, and in normocapnia measured respiratory variables in each sleep state: frequency (f B ), tidal volume (V T ), ventilation (V E ) and the co‐efficient of variation of the respiratory period (CV%). While the duration of QS episodes was not influenced by 5‐HT deficiency, TPH2 − / − pups experienced episodes of AS that were ~2‐times longer than those of controls (~190 vs 90 sec; p=0.003). In AS, hypercapnia had no effect on the latency to arousal of either WT or TPH2 − / − pups. In QS, hypercapnia reduced the arousal latencies of WT pups (from ~108 sec to 72 sec), but had no influence on the latencies of TPH2 − / − pups (state × gas × genotype: p=0.02). 5‐HT deficiency significantly reduced f B and V E in both sleep states (p<0.001 for both). Breathing stability was significantly compromised by 5‐HT deficiency, but only in AS (genotype × state: p<0.001). We conclude that at an age close to infancy, central 5‐HT deficiency increases the duration of AS episodes, destabilizes breathing during AS, and delays arousal from hypercapnia during QS. These findings lend support the hypothesis that reduced 5‐HT signaling alters sleep architecture and breathing in a way that increases SIDS risk. Support or Funding Information Funding for this research was provided by the American Physiological Society Undergraduate Student Research Fellowship Program (to J.Y.) and by an American Heart Association Scientist Development Grant (14SDG18560022; PI: KJC).