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Cholinergic neurons of the basal forebrain and nitric oxide-mediated regulation of sleep homeostasis.

Kalinchuk AV, Porkka-Heiskanen T, Mccarley RW, Basheer R (2011) Cholinergic neurons of the basal forebrain and nitric oxide-mediated regulation of sleep homeostasis. Neuroscience 2011 Abstracts 397.15. Society for Neuroscience, Washington, DC.

Summary: The levels of adenosine (AD) and inducible nitric oxide (NO) synthase (iNOS)-mediated NO increase during sleep deprivation (SD) in the basal forebrain (BF), and, with prolongation of SD, in the frontal cortex (FC). NO donor (DETA NONOate) infusion increases AD and sleep, while iNOS/NO inhibition prevents SD-induced AD increase, suggesting that iNOS/NO stimulates AD increase (Kalinchuk et al., 2006). iNOS induction during SD occurs in wake-active neurons in the BF and FC (Kalinchuk et al., 2010, 2011), however, neurotransmitter specificity of these cells has not described. The lesion of BF cholinergic cells attenuates both SD-induced AD increase and recovery sleep response (Kalinchuk et al., 2008). Hence in this study, we tested the role of cholinergic versus non-cholinergic neurons in iNOS/NO release in BF and FC and homeostatic sleep response. Methods. We performed two types of experiments. Experiment #1. Immunohistochemical detection of neurotransmitter specificity of cells inducing iNOS during SD. The brains of SD animals and their non-SD time-of-day matched controls were subjected to double-labeling with specific markers for iNOS, acetylcholinetransferase (ChAT), vesicular glutamate transporters (VGlut) and glutamate decarboxylase (GAD67). Experiment #2. The effects of SD on iNOS/NO production and the effect of NO-donor, DETA NONOate infusion on sleep were investigated before and after destruction of BF cholinergic neurons using 192 IgG-saporin. In both experiments male rats were implanted for electrographic recording and Experiment # 2 used guide cannula for microdialysis probes targeting BF and FC. In Experiment #2, recording of sleep-waking cycle, SD for 3h and infusion of DETA NONOate for 3h were performed on the same animals before and 2 weeks after targeted saporin injections. Results. Experiment #1. SD led to significant increases in number of iNOS+ cells in the BF and FC. Preliminary data showed that in the BF, in SD group, 96% of ChAT+ cells were also iNOS+, while in the non-SD group only 4% of ChAT+ neurons had weak iNOS+ staining. Numbers of iNOS+/ChAT+ cells positively correlated with SD-induced increase in theta power. Experiment #2. Before saporin injection, both SD and infusion of DETA NONOate induced significant increases in subsequent NREM sleep/NREM delta power (by 35/47% and 39/41%, respectively). After saporin injection, both recovery NREM sleep and DETA NONOate-induced sleep were significantly attenuated (8 and 4% increase as compared with baseline) and increases in delta power were totally blocked. Conclusions. We conclude that cholinergic neurons of the BF are important for iNOS/NO-mediated homeostatic sleep control.

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