The Emerging Role of Hypocretin (Orexin-A) in the Developing Central Nervous System

The normal values for cerebrospinal fluid (CSF) hypocretin-1 in adults are predictable and stay within a range of 280 ± 33 pg/mL.¹ Levels below 110 pg/mL are typically observed in patients with narcolepsy-cataplexy. Reference values for hypocretin during the neonatal period and early infancy have, however, not been standardized, and it is not known if they change with gestational age or maturation.

In this issue of SLEEP, Aran and colleagues² report on cerebrospinal fluid (CSF) levels of hypocretin-1 (orexin-A) measured during early infancy. They gathered an initial pool of 284 infants (preterm and full term) and 35 older children aged 0.5-13 years of age who had undergone lumbar puncture for presumed sepsis. Of those younger than 4 months of age, 43 were preterm (28-34 weeks post-conceptional age), while 52 had been born at full term. From this pool, 108 neurologically intact subjects were selected for further study—there were 95 infants less than 4 months age, while 13 were older children. In order to be categorized as “neurologically intact,” the patient had to have no medical problem other than being premature, possess a normal neurological examination, have normal blood and cerebrospinal fluid laboratory tests, and maintain a normal examination at 48 hours post-lumbar puncture. Forty-nine of the 108 subjects had lumbar punctures performed during the first 24 hours after birth, with 19/49 having undergone the procedure within the first hour. Cerebrospinal fluid hypocretin-1 levels were measured by radioimmunoassay. For infants of 28-34 weeks gestation, the hypocretin-1 levels were 314 ± 65 pg/ mL, increasing linearly to 476 ± 72 pg/mL by 2-4 months after age, and being higher than those in the 0.5-13 year age group (353 ± 78 pg/mL; P = 0.0001).

Aran and colleagues² are to be commended for helping extend into infancy our knowledge base concerning hypocretin CSF levels. The strengths of the study include a reasonably large sample size and the inclusion of both healthy preterm and full-term infants. Since 19/108 subjects had levels sampled within the first hour after birth, one wonders about the possibility of the stress of labor and delivery having contributed to elevation of hypocretin levels. Sampling from the latter half of the first week of life would therefore also have been helpful. The mean level of hypocretin observed by Aran et al. in infants below 4 months of age (476 pg/mL) is higher than that reported by Kanbayashi et al.,¹ who had evaluated CSF hypocretin levels in 7 Japanese infants below the age of 4 months using similar methodology, with 1/7 having infantile spasms. They found a mean level 264 pg/mL. I am unable to explain the discrepant results of the two studies but am hopeful that further studies will help resolve the issue.

Newborns of other species also exhibit well-developed hypo-cretin (orexin) pathways. Dickinson et al.³ found that fetal lambs of 127-135 days gestational age, those near full term (145 days old), and two-week-old baby lambs all showed orexin-A positive cells in the hypothalamus on immunocytochemical studies. There was a steady increase in density of orexin-carrying fibers into the brainstem with maturation. Further, levels of hypocretin were measurable in the plasma and cerebrospinal fluid.

Plentiful hypocretin in the newborn, but then why so much sleep?

In older children and adults, the alertness enhancing property of hypocretin-1 is substantiated by the loss of hypocretin secreting cells correlating with the development of narcolepsycataplexy.⁴ It seems counterintuitive, therefore, that newborns, despite manifesting levels of hypocretin that are higher than at any other time in life, tend to sleep 16-18 hours per day. There are no clear explanations for this paradox. Some newborn neuronal networks do, however, exhibit paradoxical function. For example, gamma aminobutyric acid (GABA), a major inhibitory neurotransmitter, shows a predominantly depolarizing (excitatory) rather than hyperpolarizing (inhibitory) effect in the immature cortical neurons.⁵ Kirmse et al. explain that at the cellular level, excitability and excitation-inhibition ratios are determined by the balance between intrinsic (e.g., voltage dependent and independent conductances) and extrinsic factors such as depolarizing and hyperpolarizing inputs, and that these patterns of inhibition and excitation show significant and continuous evolution during neurodevelopment.⁵ Similarly, therefore, whether the hypocretin pathway in healthy newborns is more sleep promoting than wakefulness promoting needs further study.

What other roles might hypocretin play in the newborn?

Feeding is physiologically suppressed in the fetus, but becomes active after birth in order to sustain growth.³ It is a survival skill that healthy but prematurely born infants start to learn by 30-32 weeks of post-conceptional age. The maturation of feeding behavior requires the coordination of processes such as activation of appetite and maturation of perioral rooting responses as well as their coordination with sucking and swallowing. As pointed out by Aran et al.,² hypocretin plays a major role in feeding, energy homeostasis, and gastrointestinal motility, and hypocretin pathways mature significantly during the third trimester of pregnancy. Feeding problems are exceedingly common in prematurely born infants, with many needing to be fed via nasogastric tubes. The role of hypocretin in the possible regulation of newborn feeding is ripe for further study.

Sudden infant death syndrome (SIDS) is a complex, multifactorial disorder that peaks in incidence during the first 2-3 months after birth. Interestingly, its age of occurrence coincides with peaking of levels of CSF hypocretin reported by Aran et al. One of the agonal key events leading up to SIDS is the inability to arouse in response to hypoxia and hypercarbia, likely from impaired development of the medullary serotonergic network.^6,7 Since hypocretin mediates central arousal mechanisms, can it be implicated in the pathogenesis of SIDS? It is known that orexins depolarize rostral ventrolateral medullary neurons and increase heart rate and arterial pressure in rats, mainly via orexin-2 receptors.⁸ Additionally, a recent study by Dergacheva et al.⁹ suggests that hypocretin-1 prevents the effects of hypoxia/hypercapnia and enhances GABAergic pathways that project from the lateral paragigantocellular nucleus to cardiac vagal neurons located in the nucleus ambiguus. These are projections that might influence cardiac arrhythmias, bradycardia, and sudden cardiac death.⁹

There is a progressive decrease in total sleep time over the first year with a corresponding increase in time spent staying awake, which is essential for enabling cognitive, language, and social development during infancy. Does hypocretin play a role in the consolidation of sleep during infancy? Blumberg et al.¹⁰ have studied sleep wake patterns and their consolidation in wild-type infant mice and their hypocretin knockout counterparts. They noticed that by the age of three weeks, the wild-type infant mice had consolidated their sleep, which was not the case in the hypocretin knockout model.

The above examples underscore the importance of hypo-cretin pathways in the developing brain. It is to be hoped that impetus from the studies of Aran et al.² and Kanbayashi et al.¹ with regard to CSF hypocretin normative data in newborns and infants will serve as a stepping stone for both clinicians and basic science researchers towards improved understanding of many complex physiological and pathological phenomena in this age group.

DISCLOSURE STATEMENT

Dr. Kotagal has indicated no financial conflicts of interest.

CITATION

Kotagal S. The emerging role of hypocretin (orexin-A) in the developing central nervous system. SLEEP 2012;35(2):171-172.