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

• Published in: The Journal of physiology Vol. 563; no. 2; pp. 569 - 582
• Main Authors: Alam, Md. Noor, Kumar, Sunil, Bashir, Tariq, Suntsova, Natalia, Methippara, Melvi M., Szymusiak, Ronald, McGinty, Dennis
• Format: Journal Article
• Language: English
• Published: 9600 Garsington Road , Oxford , OX4 2DQ , UK The Physiological Society 01.03.2005; Blackwell Science Ltd; Blackwell Science Inc
• Subjects: Animals; Bicuculline - pharmacology; Circadian Rhythm; Dose-Response Relationship, Drug; gamma-Aminobutyric Acid - physiology; Genes, fos - physiology; Hypothalamic Area, Lateral - physiology; Hypothalamic Area, Lateral - ultrastructure; Hypothalamic Hormones - physiology; Integrative Physiology; Intracellular Signaling Peptides and Proteins - physiology; Male; Melanins - physiology; Neurons - drug effects; Neurons - physiology; Neurons - ultrastructure; Neuropeptides - physiology; Orexins; Pituitary Hormones - physiology; Rats; Rats, Sprague-Dawley; Sleep Stages - physiology
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2004.076927

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.