GABA‐mediated control of hypocretin‐ but not melanin‐concentrating hormone‐immunoreactive neurones during sleep in rats

Abstract

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.

MCH-containing neurons in the hypothalamus of the cat: Searching for a role in the control of sleep and wakefulness

“…These data are comparable with those obtained by Alam et al (Alam, et al, 2005), which demonstrated that the majority of neurons expressing Fos during active waking induced by bicuculline application into the lateral hypothalamus of the rat were non-hypocretinergic nonMCHergic neurons (ibid.). The postero-lateral and adjacent hypothalamic areas are known to be involved in the control of motor activity.…”

Selective loss of GABA B receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture

“…During sleep, orexin neurons would be inhibited by GABAergic influences from neurons in the preoptic area (1), which are likely important for stably silencing orexin neurons (33,34). In oxGKO mice, both GABA A -and GABA B -mediated inhibition of orexin neurons was severely impaired (Figs.…”

Effect of microdialysis perfusion of 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol in the perifornical hypothalamus on sleep–wakefulness: Role of δ-subunit containing extrasynaptic GABAA receptors

“…Single unit recording studies suggest that the orexin neurons exhibited the Wake-On/REM -Off discharge pattern (W>nonREM<REM) (Alam et al, 2002;Lee et al, 2005;Mileykovskiy et al, 2005). The δ-subunit-containing GABA A receptors are present in the PFH (Pirker et al, 2000) and the role of PFH GABA A receptors in sleep induction has been previously shown (Alam et al, 2004). However, it is yet unclear whether extrasynaptic GABA A receptors in the PFH have any role in control of sleep-wakefulness.…”

“…Although the PFH contains several cell types, including the orexin/hypocretin and the melanin concentrating hormone containing neurons, there is compelling and consistent evidence implicating the orexins neurons in the control of wakefulness (McCarley, 2007). For example, local administration of orexin in various brain regions produced wakefulness (Bourgin et (Pirker et al, 2000) and the role of PFH GABA A receptors in sleep induction has been previously shown (Alam et al, 2004). However, it is yet unclear whether extrasynaptic GABA A receptors in the PFH have any role in control of sleep-wakefulness.…”