Cholinergic neurons of the basal forebrain mediate biochemical and electrophysiological mechanisms underlying sleep homeostasis

• Published in: The European journal of neuroscience Vol. 41; no. 2; pp. 182 - 195
• Main Authors: Kalinchuk, Anna V., Porkka-Heiskanen, Tarja, McCarley, Robert W., Basheer, Radhika
• Format: Journal Article
• Language: English
• Published: France Blackwell Publishing Ltd 01-01-2015
• Subjects: adenosine; Adenosine - metabolism; Animals; Antibodies, Monoclonal; Basal Forebrain - drug effects; Basal Forebrain - physiology; Basal Forebrain - physiopathology; Cholinergic Neurons - drug effects; Cholinergic Neurons - physiology; Delta Rhythm - drug effects; Delta Rhythm - physiology; Homeostasis - drug effects; Homeostasis - physiology; inducible nitric oxide synthase; Lactic Acid - metabolism; Male; Nitrates - metabolism; nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Donors - pharmacology; Nitrites - metabolism; Nitroso Compounds - pharmacology; Pyruvic Acid - metabolism; rat; Rats, Wistar; Ribosome Inactivating Proteins, Type 1; Saporins; Sleep - drug effects; Sleep - physiology; Sleep Deprivation - physiopathology; Theta Rhythm - drug effects; Theta Rhythm - physiology; adenosine; nitric oxide; rat; inducible nitric oxide synthase
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.12766

The tight coordination of biochemical and electrophysiological mechanisms underlies the homeostatic sleep pressure (HSP) produced by sleep deprivation (SD). We have reported that during SD the levels of inducible nitric oxide synthase (iNOS), extracellular nitric oxide (NO), adenosine [AD]ex, lactate [Lac]ex and pyruvate [Pyr]ex increase in the basal forebrain (BF). However, it is not clear whether all of them contribute to HSP leading to increased electroencephalogram (EEG) delta activity during non‐rapid eye movement (NREM) recovery sleep (RS) following SD. Previously, we showed that NREM delta increase evident during RS depends on the presence of BF cholinergic (ChBF) neurons. Here, we investigated the role of ChBF cells in coordination of biochemical and EEG changes seen during SD and RS in the rat. Increases in low‐theta power (5–7 Hz), but not high‐theta (7–9 Hz), during SD correlated with the increase in NREM delta power during RS, and with the changes in nitrate/nitrite [NOx]ex and [AD]ex. Lesions of ChBF cells using IgG 192‐saporin prevented increases in [NOx]ex, [AD]ex and low‐theta activity, during SD, but did not prevent increases in [Lac]ex and [Pyr]ex. Infusion of NO donor DETA NONOate into the saporin‐treated BF failed to increase NREM RS and delta power, suggesting ChBF cells are important for mediating NO homeostatic effects. Finally, SD‐induced iNOS was mostly expressed in ChBF cells, and the intensity of iNOS induction correlated with the increase in low‐theta activity. Together, our data indicate ChBF cells are important in regulating the biochemical and EEG mechanisms that contribute to HSP.
During sleep deprivation we observed a tight correlation between increases in low frequency theta power, an electroencephalogram (EEG) marker of homeostatic sleep pressure, and biochemical sleep markers, such as adenosine and nitric oxide. Saporin lesioning of basal forebrain cholinergic cells prevented these increased measures and related correlation. Cholinergic basal forebrain neurons are therefore important for homeostatic sleep control and link the biochemical and EEG mechanisms of homeostatic sleep pressure.