The role of cholinergic basal forebrain neurons in adenosine-mediated homeostatic control of sleep: Lessons from 192 IgG–saporin lesions

• Published in: Neuroscience Vol. 157; no. 1; pp. 238 - 253
• Main Authors: Kalinchuk, A.V, McCarley, R.W, Stenberg, D, Porkka-Heiskanen, T, Basheer, R
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 11-11-2008; Elsevier
• Subjects: Acetylcholinesterase - metabolism; Adenosine - metabolism; Adenosine - physiology; Animals; Antibodies, Monoclonal - pharmacology; Basal Ganglia - cytology; Basal Ganglia - metabolism; Basal Ganglia - physiology; Biological and medical sciences; Choline O-Acetyltransferase - metabolism; Cholinergic Agents - pharmacology; cholinergic lesion; Chromatography, High Pressure Liquid; delta activity; Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes; Electroencephalography - drug effects; Electromyography - drug effects; Fundamental and applied biological sciences. Psychology; Glutamate Decarboxylase - metabolism; Homeostasis - physiology; immunotoxin; Injections, Intraventricular; Male; Medical sciences; Nerve Fibers - metabolism; Nerve Fibers - physiology; Nervous system (semeiology, syndromes); Neurology; Neurons - physiology; Parasympathetic Nervous System - cytology; Parasympathetic Nervous System - metabolism; Parasympathetic Nervous System - physiology; Prosencephalon - cytology; Prosencephalon - metabolism; Prosencephalon - physiology; rat; Rats; Rats, Wistar; Ribosome Inactivating Proteins, Type 1 - pharmacology; Saporins; Sleep - physiology; sleep deprivation; Sleep Stages - drug effects; Sleep Stages - physiology; Sleep. Vigilance; stereology; Vertebrates: nervous system and sense organs; nucleus basalis magnocellularis; phosphate buffer; medial septum; NBTI; choline acetyltransferase immunoreactivity; electromyogram; horizontal diagonal band; NF-κB; NBM; EMG; PBS; rat; EEG; MS; basal forebrain; stereology; GAD; electroencephalogram; glutamic acid decarboxylase; nuclear factor-κB; MCPO; sleep deprivation; magnocellular preoptic nucleus; rapid-eye movement; RM-ANOVA; BF; HDB; IgG; NREM; SD; analysis of variance; ANOVA; VDB; SI; immunotoxin; ChAT; S-(p-nitrobenzyl)-6-thioinosine; AChE; immunoglobulin G; delta activity; vertical diagonal band; acetylcholinesterase; ChAT-ir; ACSF; substantia innominata; artificial cerebrospinal fluid; choline acetyltransferase; non-rapid-eye movement; cholinergic lesion; repeated measures analysis of variance; REM; Cholinergic neuron; Nervous system diseases; Adenosine; Rat; Rodentia; Central nervous system; Sleep disorder; Prosencephalon; Vertebrata; Mammalia; Sleep; Insomnia; Animal; Stereology; Lesion; Neurological disorder
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2008.08.040

Abstract A topic of high current interest and controversy is the basis of the homeostatic sleep response, the increase in non-rapid-eye-movement (NREM) sleep and NREM-delta activity following sleep deprivation (SD). Adenosine, which accumulates in the cholinergic basal forebrain (BF) during SD, has been proposed as one of the important homeostatic sleep factors. It is suggested that sleep-inducing effects of adenosine are mediated by inhibiting the wake-active neurons of the BF, including cholinergic neurons. Here we examined the association between SD-induced adenosine release, the homeostatic sleep response and the survival of cholinergic neurons in the BF after injections of the immunotoxin 192 immunoglobulin G (IgG)–saporin (saporin) in rats. We correlated SD-induced adenosine level in the BF and the homeostatic sleep response with the cholinergic cell loss 2 weeks after local saporin injections into the BF, as well as 2 and 3 weeks after i.c.v. saporin injections. Two weeks after local saporin injection there was an 88% cholinergic cell loss, coupled with nearly complete abolition of the SD-induced adenosine increase in the BF, the homeostatic sleep response, and the sleep-inducing effects of BF adenosine infusion. Two weeks after i.c.v. saporin injection there was a 59% cholinergic cell loss, correlated with significant increase in SD-induced adenosine level in the BF and an intact sleep response. Three weeks after i.c.v. saporin injection there was an 87% cholinergic cell loss, nearly complete abolition of the SD-induced adenosine increase in the BF and the homeostatic response, implying that the time course of i.c.v. saporin lesions is a key variable in interpreting experimental results. Taken together, these results strongly suggest that cholinergic neurons in the BF are important for the SD-induced increase in adenosine as well as for its sleep-inducing effects and play a major, although not exclusive, role in sleep homeostasis.