Original Article

Neuropsychopharmacology (2016) 41, 2133–2146; doi:10.1038/npp.2016.13; published online 17 February 2016

Basal Forebrain Cholinergic Neurons Primarily Contribute to Inhibition of Electroencephalogram Delta Activity, Rather Than Inducing Behavioral Wakefulness in Mice

Li Chen1, Dou Yin1, Tian-Xiao Wang1,2, Wei Guo1, Hui Dong1,2, Qi Xu1, Yan-Jia Luo1,2, Yoan Cherasse3, Michael Lazarus3, Zi-long Qiu4, Jun Lu5, Wei-Min Qu1,2 and Zhi-Li Huang1,2

  1. 1State Key Laboratory of Medical Neurobiology, Department of Pharmacology and Shanghai Key Laboratory of Bioactive Small Molecules, School of Basic Medical Sciences, Fudan University, Shanghai, China
  2. 2The Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China
  3. 3International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, Japan
  4. 4Institute of Neuroscience, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China
  5. 5Department of Neurology, Division of Sleep Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA

Correspondence: Professor W-M Qu or Professor Z-L Huang, Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P. R. China, Tel: +86 21 54237043, Fax: +86 21 54237103, E-mail: quweimin@fudan.edu.cn or huangzl@fudan.edu.cn

Received 5 September 2015; Revised 24 November 2015; Accepted 22 December 2015
Accepted article preview online 22 January 2016; Advance online publication 17 February 2016

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Abstract

The basal forebrain (BF) cholinergic neurons have long been thought to be involved in behavioral wakefulness and cortical activation. However, owing to the heterogeneity of BF neurons and poor selectivity of traditional methods, the precise role of BF cholinergic neurons in regulating the sleep–wake cycle remains unclear. We investigated the effects of cell-selective manipulation of BF cholinergic neurons on the sleep–wake behavior and electroencephalogram (EEG) power spectrum using the pharmacogenetic technique, the ‘designer receptors exclusively activated by designer drugs (DREADD)’ approach, and ChAT-IRES-Cre mice. Our results showed that activation of BF cholinergic neurons expressing hM3Dq receptors significantly and lastingly decreased the EEG delta power spectrum, produced low-delta non-rapid eye movement sleep, and slightly increased wakefulness in both light and dark phases, whereas inhibition of BF cholinergic neurons expressing hM4Di receptors significantly increased EEG delta power spectrum and slightly decreased wakefulness. Next, the projections of BF cholinergic neurons were traced by humanized Renilla green fluorescent protein (hrGFP). Abundant and highly dense hrGFP-positive fibers were observed in the secondary motor cortex and cingulate cortex, and sparse hrGFP-positive fibers were observed in the ventrolateral preoptic nucleus, a known sleep-related structure. Finally, we found that activation of BF cholinergic neurons significantly increased c-Fos expression in the secondary motor cortex and cingulate cortex, but decreased c-Fos expression in the ventrolateral preoptic nucleus. Taken together, these findings reveal that the primary function of BF cholinergic neurons is to inhibit EEG delta activity through the activation of cerebral cortex, rather than to induce behavioral wakefulness.

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