The perifornical‐lateral hypothalamic area (PF‐LHA) has been implicated in the regulation of behavioural arousal. The PF‐LHA contains several cell types including neurones expressing the peptides, hypocretin (HCRT; also called orexin) and melanin‐concentrating hormone (MCH). Evidence suggests that most of the PF‐LHA neurones, including HCRT neurones, are active during waking and quiescent during non‐rapid eye movement (non‐NREM) sleep. The PF‐LHA contains local GABAergic interneurones and also receives GABAergic inputs from sleep‐promoting regions in the preoptic area of the hypothalamus. We hypothesized that increased GABA‐mediated inhibition within PF‐LHA contributes to the suppression of neuronal activity during non‐REM sleep. EEG and EMG activity of rats were monitored for 2 h during microdialytic delivery of artificial cerebrospinal fluid (aCSF) or bicuculline, a GABA_A receptor antagonist, into the PF‐LHA in spontaneously sleeping rats during the lights‐on period. At the end of aCSF or bicuculline perfusion, rats were killed and c‐Fos immunoreactivity (Fos‐IR) in HCRT, MCH and other PF‐LHA neurones was quantified. In response to bicuculline perfusion into the PF‐LHA, rats exhibited a dose‐dependent decrease in non‐REM and REM sleep time and an increase in time awake. The number of HCRT, MCH and non‐HCRT/non‐MCH neurones exhibiting Fos‐IR adjacent to the microdialysis probe also increased dose‐dependently in response to bicuculline. However, significantly fewer MCH neurones exhibited Fos‐IR in response to bicuculline as compared to HCRT and other PF‐LHA neurones. These results support the hypothesis that PF‐LHA neurones, including HCRT neurones, are subject to increased endogenous GABAergic inhibition during sleep. In contrast, MCH neurones appear to be subject to weaker GABAergic control during sleep.

Growing evidence supports a role for the medullary parafacial zone in non-rapid eye movement (non-REM) sleep regulation. Cell-body specific lesions of the parafacial zone or disruption of its GABAergic/glycinergic transmission causes suppression of non-REM sleep, whereas, targeted activation of parafacial GABAergic/glycinergic neurons reduce sleep latency and increase non-REM sleep amount, bout duration, and cortical electroencephalogram (EEG) slow-wave activity. Parafacial GABAergic/glycinergic neurons also express sleep-associated c-fos immunoreactivity. Currently, it is not clear if parafacial neurons are non-REM sleep-active and/or REM sleep-active or play a role in the initiation or maintenance of non-REM sleep. We recorded extracellular discharge activity of parafacial neurons across the spontaneous sleep-waking cycle using microwire technique in freely behaving rats. Waking-, non-REM sleep-, and REM sleep-active neuronal groups were segregated by the ratios of their discharge rate changes during non-REM and REM sleep versus waking and non-REM sleep versus REM sleep. Parafacial neurons exhibited heterogeneity in sleep-waking discharge patterns, but 34 of 86 (40%) recorded neurons exhibited increased discharge rate during non-REM sleep compared to waking. These neurons also exhibited increased discharge prior to non-REM sleep onset, similar to median preoptic nucleus (MnPO) and ventrolateral preoptic area (VLPO) sleep-active neurons. However, unlike MnPO and VLPO sleep-active neurons, parafacial neurons were weakly-moderately sleep-active and exhibited a stable rather than decreasing discharge across sustained non-REM sleep episode. We show for the first time that the medullary parafacial zone contains non-REM sleep-active neurons. These neurons are likely functionally important brainstem compliments to the preoptic-hypothalamic sleep-promoting neuronal networks that underlie sleep onset and maintenance.

In the mammalian brain, adult neurogenesis has been extensively studied in the hippocampal sub-granular zone and the sub-ventricular zone of the anterolateral ventricles. However, growing evidence suggests that new cells are not only “born” constitutively in the adult hypothalamus, but many of these cells also differentiate into neurons and glia and serve specific functions. The preoptic-hypothalamic area plays a central role in the regulation of many critical functions, including sleep–wakefulness and circadian rhythms. While a role for adult hippocampal neurogenesis in regulating hippocampus-dependent functions, including cognition, has been extensively studied, adult hypothalamic neurogenic process and its contributions to various hypothalamic functions, including sleep–wake regulation are just beginning to unravel. This review is aimed at providing the current understanding of the hypothalamic adult neurogenic processes and the extent to which it affects hypothalamic functions, including sleep–wake regulation. We propose that hypothalamic neurogenic processes are vital for maintaining the proper functioning of the hypothalamic sleep–wake and circadian systems in the face of regulatory challenges. Sleep–wake disturbance is a frequent and challenging problem of aging and age-related neurodegenerative diseases. Aging is also associated with a decline in the neurogenic process. We discuss a hypothesis that a decrease in the hypothalamic neurogenic process underlies the aging of its sleep–wake and circadian systems and associated sleep–wake disturbance. We further discuss whether neuro-regenerative approaches, including pharmacological and non-pharmacological stimulation of endogenous neural stem and progenitor cells in hypothalamic neurogenic niches, can be used for mitigating sleep–wake and other hypothalamic dysfunctions in aging.