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Arousal is an important defense against hypoxia during sleep. Rat pups exhibit progressive arousal impairment (habituation) with multiple hypoxia exposures. The mechanisms are unknown. The medullary raphe (MR) is involved in autonomic functions, including sleep, and receives abundant GABAergic inputs. We hypothesized that inhibiting MR neurons with muscimol, a GABA(A) receptor agonist, or preventing GABA reuptake with nipecotic acid, would impair arousal and enhance arousal habituation and that blocking GABA(A) receptors with bicuculline would enhance arousal and attenuate habituation. Postnatal day 15 (P15) to P25 rat pups were briefly anesthetized, and microinjections with aCSF, muscimol, bicuculline, or nipecotic acid were made into the MR. After a ∼30-min recovery, pups were exposed to four 3-min episodes of hypoxia separated by 6 min of normoxia. The time to arousal from the onset of hypoxia (latency) was determined for each trial. Latency progressively increased across trials (habituation) in all groups. The overall latency was greater after muscimol and nipecotic acid compared with aCSF, bicuculline, or noninjected controls. Arousal habituation was reduced after bicuculline compared with aCSF, muscimol, nipecotic acid, or noninjected pups. Increases in latency were mirrored by decreases in chamber [O2] and oxyhemoglobin saturation. Heart rate increased during hypoxia and was greatest in muscimol-injected pups. Our results indicate that the MR plays an important, not previously described, role in arousal and arousal habituation during hypoxia and that these phenomena are modulated by GABAergic mechanisms. Arousal habituation may contribute to sudden infant death syndrome, which is associated with MR serotonergic and GABAergic receptor dysfunction.

The brainstem development of infants born between 33 and 38 weeks' gestation is less mature than that of a full-term infant. During late gestation, there are dramatic and nonlinear developmental changes in the brainstem. This translates into immaturity of upper airway and lung volume control, laryngeal reflexes, chemical control of breathing, and sleep mechanisms. Ten percent of late preterm infants have significant apnea of prematurity and they frequently have delays in establishing coordination of feeding and breathing. Unfortunately, there is a paucity of clinical, physiologic, neuroanatomic, and neurochemical data in this specific group of infants. Research focused on this group of infants will not only further our understanding of brainstem maturation during this high risk period, but will help develop focused plans for their management.

We have reached a conundrum in assigning cause of death for sudden unexpected infant deaths. We summarize the discordant perspectives and approaches and how they have occurred, and recommend a pathway toward improved consistency. This lack of consistency affects pediatricians and other health care professionals, scientific investigators, medical examiners and coroners, law enforcement agencies, families, and support or advocacy groups. We recommend that an interdisciplinary international committee be organized to review current approaches for assigning cause of death, and to identify a consensus strategy for improving consistency. This effort will need to encompass intrinsic risk factors or infant vulnerability in addition to known environmental risk factors including unsafe sleep settings, and must be sufficiently flexible to accommodate a progressively expanding knowledge base. [ABSTRACT FROM AUTHOR]

Abstract: Arousal from sleep is a major defense mechanism in infants against hypoxia and/or hypercapnia. Arousal failure may be an important contributor to SIDS. Areas of the brainstem that have been found to be abnormal in a majority of SIDS infants are involved in the arousal process. Arousal is sleep state dependent, being depressed during AS in most mammals, but depressed during QS in human infants. Repeated exposure to hypoxia causes a progressive blunting of arousal that may involve medullary raphe GABAergic mechanisms. Whereas CB chemoreceptors contribute heavily to arousal in response to hypoxia, serotonergic central chemoreceptors have been implicated in the arousal response to CO2. Pulmonary or chest wall mechanoreceptors also contribute to arousal in proportion to the ventilatory response and decreases in their input may contribute to depressed arousal during AS. Little is known about specific arousal pathways beyond the NTS. Whether CB chemoreceptor stimulation directly stimulates arousal centers or whether this is done indirectly through respiratory networks remains unknown. This review will focus on arousal in response to hypoxia and CO2 in the fetus and newborn and will outline what we know (and do not know) about the involvement of the carotid body in this process. [Copyright &y& Elsevier]

Serotonergic receptor binding is altered in the medullary serotonergic nuclei, including the paragigantocellularis lateralis (PGCL), in many infants who die of sudden infant death syndrome (SIDS). The PGCL receives inputs from many sites in the caudal brainstem and projects to the spinal cord and to more rostral areas important for arousal and vigilance. We have shown previously that local unilateral nonspecific neuronal inhibition in this region with GABAA agonists disrupts sleep architecture. We hypothesized that specifically inhibiting serotonergic activity in the PGCL would result in less sleep and heightened vigilance. We analyzed sleep before and after unilaterally dialyzing the 5-HT1A agonist (±)-8-hydroxy-2-(dipropylamino)-tetralin (8-OH-DPAT) into the juxtafacial PGCL in conscious newborn piglets. 8-OH-DPAT dialysis resulted in fragmented sleep with an increase in the number and a decrease in the duration of bouts of nonrapid eye movement (NREM) sleep and a marked decrease in amount of rapid eye movement (REM) sleep. After 8-OH-DPAT dialysis, there were decreases in body movements, including shivering, during NREM sleep; body temperature and heart rate also decreased. The effects of 8-OH-DPAT were blocked by local pretreatment with N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane-carboxamide, a selective 5-HT1A antagonist. Destruction of serotonergic neurons with 5,7-DHT resulted in fragmented sleep and eliminated the effects of subsequent 8-OH-DPAT dialysis on REM but not the effects on body temperature or heart rate. We conclude that neurons expressing 5-HT1A autoreceptors in the juxtafacial PGCL are involved in regulating or modulating sleep. Abnormalities in the function of these neurons may alter sleep homeostasis and contribute to the etiology of SIDS. [ABSTRACT FROM AUTHOR]