Severe spontaneous bradycardia associated with respiratory disruptions in rat pups with fewer brain stem 5-HT neurons

Abstract

Cummings KJ, Commons KG, Fan KC, Li A, Nattie EE. Severe spontaneous bradycardia associated with respiratory disruptions in rat pups with fewer brain stem 5-HT neurons. Am J Physiol Regul Integr Comp Physiol 296: R1783-R1796, 2009. First published April 15, 2009 doi:10.1152/ajpregu.00122.2009.-The medullary 5-HT system has potent effects on heart rate and breathing in adults. We asked whether this system mitigates the respiratory instability and bradycardias frequently occurring during the neonatal period. 5,7-Dihydroxytryptamine (5,7-DHT) or vehicle was administered to rat pups at postnatal day 2 (P2), and we then compared the magnitude of bradycardias occurring with disruptions to eupnea in treated and vehicle control littermates at P5-6 and P10 -12. We then used a novel method that would allow accurate assessment of the ventilatory and heart rate responses to near square-wave challenges of hypoxia (10% O 2), hypercapnia (5 and 8% CO2 in normoxia and hyperoxia), and asphyxia (8% CO 2-10% O2), and to the induction of the HeringBreuer inflation reflex (HBR), a potent, apnea-inducing reflex in newborns. The number of 5-HT-positive neurons was reduced ϳ80% by drug treatment. At both ages, lesioned animals had considerably larger bradycardias during brief apnea; at P5-6, average and severe events were ϳ50% and 70% greater, respectively, in lesioned animals (P ϭ 0.002), whereas at P10 -12, events were ϳ 23% and 50% greater (P ϭ 0.018). However, lesioning had no effect on the HR responses to sudden gas challenge or the HBR. At P5-6, lesioned animals had reduced breathing frequency and ventilation (V E), but normal V E relative to metabolic rate (V E/V O2). At P10 -12, lesioned animals had a more unstable breathing pattern (P ϭ 0.04) and an enhanced V E response to moderate hypercapnia (P ϭ 0.007). Within the first two postnatal weeks, the medullary 5-HT system plays an important role in cardiorespiratory control, mitigating spontaneous bradycardia, stabilizing the breathing pattern, and dampening the hypercapnic V E response. neonate; CO 2; breathing; SIDS; Hering-Breuer; chemoreflex SPORADIC APNEA AND BRADYCARDIA are hallmarks of early postnatal life (20). Although progress has been made toward characterizing inhibitory neurotransmitters responsible for this cardiorespiratory instability [e.g., GABA, adenosine (1)], there is little information regarding the role of serotonin (5-HT). This is of interest because 5-HT not only projects to multiple brain stem loci participating in cardiorespiratory control, but also interacts extensively with GABA and adenosine signaling within these loci (1, 10, 11). Apnea, bradycardia, and the resulting desaturation are highly associated with an increase in morbidity and mortality (12,22). Infants also display overt apnea and bradycardia shortly before succumbing to the sudden infant death syndrome (SIDS) (26,35), an affliction that is strongly associated with disorders within the medullary 5-HT system, located predominantly in the raphé nuclei (32).Accumulating data obtained from a...

Bradycardia in serotonin-deficientPet-1−/−mice: influence of respiratory dysfunction and hyperthermia over the first 2 postnatal weeks

“…Previous data from our laboratory and others have demonstrated respiratory instability and a propensity for large, spontaneous bradycardias associated with these hypopneas in neonatal rodents deficient in medullary 5-HT neurons (7,11). Our results extend these findings, suggesting that a prenatal loss of medullary 5-HT neurons not only enhances spontaneous bradycardias until P12, but also that 1) Pet-1 Ϫ/Ϫ animals display respiratory instability at P4 -5 and P14 -15, but are only susceptible to hypoxia at P14 -15, owing to a relative suppression of V O 2 at P4 -5; 2) contrary to our original hypothesis, neither greater hypoxia nor greater concomitant hypopnea explain the augmentation of bradycardias in Pet-1 Ϫ/Ϫ neonates; and 3) at approximately P12, hyperthermia augments the bradycardias Pet-1 deficiency and potential for respiratory-related hypoxia over development.…”

“…Our results extend these findings, suggesting that a prenatal loss of medullary 5-HT neurons not only enhances spontaneous bradycardias until P12, but also that 1) Pet-1 Ϫ/Ϫ animals display respiratory instability at P4 -5 and P14 -15, but are only susceptible to hypoxia at P14 -15, owing to a relative suppression of V O 2 at P4 -5; 2) contrary to our original hypothesis, neither greater hypoxia nor greater concomitant hypopnea explain the augmentation of bradycardias in Pet-1 Ϫ/Ϫ neonates; and 3) at approximately P12, hyperthermia augments the bradycardias Pet-1 deficiency and potential for respiratory-related hypoxia over development. Similar to other rodent models with medullary 5-HT disruption (including rat pups with pharmacological lesions, tryptophan hydroxylaseϪ2 Ϫ/Ϫ mice, and adult lmx-1b Ϫ/Ϫ mice) Pet-1 Ϫ/Ϫ neonates have a lower f B and are prone to apnea (2,7,16,17). Importantly, these new data suggest that P4 -5 Pet-1 Ϫ/Ϫ animals do not hypoventilate (and are thus not hypoxic), as their reduced f B and V E are matched appropriately to a reduced V O 2 .…”

“…We have previously demonstrated that the magnitude of spontaneous bradycardias is augmented until at least postnatal days (P) 11-12 in rat pups when the medullary 5-HT system is chemically lesioned shortly after birth (7). Here we extend these original observations and ask if hypoxia or greater concomitant hypopnea could contribute to bradycardia that might occur in Pet-1-deficient neonatal mice.…”

Altered ventilatory and thermoregulatory control in male and female adult Pet-1 null mice

“…For example, Pet-1 knockout ( Pet-1 null) mice, which lack ~70% of 5-HT neurons throughout the classically-described B nuclei (Hendricks et al 2003), display respiratory dysfunction (Erickson et al 2007) and spontaneous bradycardias during early development (Cummings et al 2009), as well as several abnormal behaviors as adults (Hendricks et al 2003; Lerch-Haner et al 2008). Neonatal mice with genetic deletion of Lmx1b in neurons expressing Pet-1 ( Lmx1b f/f/p ), which have a selective and severe deficit (>99%) in 5-HT neurons (Zhao et al 2006), show frequent and severe apnea and high mortality (Hodges et al 2009).…”

Intermittent hypercapnia enhances CO2 responsiveness and overcomes serotonergic dysfunction

“…Abnormal serotonergic brainstem mechanisms may contribute to infant vulnerability to Sudden Infant Death Syndrome (SIDS), and that vulnerability may result in part from chemosensory dysfunction (Cummings et al, 2009; Duncan et al, 2010; Hodges and Richerson 2010; Kinney et al, 2009; Paterson et al, 2006; Richerson, 2004). If induced reflex plasticity is sufficient to overcome or reverse ventilatory chemosensitivity dysfunctions similar to those thought to contribute to SIDS, then interventions that induce plasticity could be therapeutic in augmenting chemoresponsiveness and decreasing infant vulnerability to SIDS.…”