Chronic Suppression of Hypothalamic Cell Proliferation and Neurogenesis Induces Aging-Like Changes in Sleep–Wake Organization in Young Mice. (15th April 2019)

• Record Type: Journal Article
• Authors: Kostin, Andrey; Alam, Md. Aftab; McGinty, Dennis; Szymusiak, Ronald; Alam, Md. Noor
• Is Part Of: Neuroscience. Volume 404(2019)
• Page Start: 541
• Page End: 556
• Publication Date: 2019-04-15
• Subjects: aCSF Artificial cerebrospinal fluid -- AraC Cytosine-β-D-arabinofuranoside -- AW Active-waking -- BrdU 5-bromo-2'-deoxyuridine -- EEG Electroencephalogram -- EMG Electromyogram -- ICV Intra-cerebroventricular -- IP Intraperitoneal -- LV Lateral ventricle -- MPO Medial preoptic area -- MnPO Median preoptic nucleus -- nonREM Non-rapid eye movement -- QW Quiet-waking -- SCN Suprachiasmatic nucleus -- SGZ Subgranular zone -- SVZ Subventricular zone; sleep–wake regulatory systems -- aging -- cell proliferation -- neurogenesis -- hypothalamus -- cytosine-β-D-arabinofuranoside; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2019.01.053
• Languages: English
• ISSNs: 0306-4522

Abstract

Abstract: Aging is associated with sleep–wake disruption, dampening of circadian amplitudes, and a reduced homeostatic sleep response. Aging is also associated with a decline in hypothalamic cell proliferation. We hypothesized that the aging-related decline in cell-proliferation contributes to the dysfunction of preoptic–hypothalamic sleep–wake and circadian systems and consequent sleep–wake disruption. We determined if cytosine-β-D-arabinofuranoside (AraC), an antimitotic agent known to suppress hypothalamic cell proliferation and neurogenesis, causes sleep–wake instability in young mice. The sleep–wake profiles were compared during baseline, during 4 weeks of artificial cerebrospinal fluid (aCSF) + 5-bromo-2′-deoxyuridine (BrdU) or AraC + BrdU infusion into the lateral ventricle, and 8 weeks after treatments. The sleep–wake architecture after AraC treatment was further compared with sleep–wake profiles in aged mice. Compared to aCSF + BrdU, 4 weeks of AraC + BrdU infusion significantly decreased (− 96%) the number of BrdU + cells around the third ventricular wall and adjacent preoptic–hypothalamic area and produced a) sleep disruption during the light phase with decreases in non-rapid eye movement (nonREM) (− 9%) and REM sleep (− 21%) amounts, and increased numbers of shorter (< 2 min; 142 versus 98 episodes/12 h) and decreased numbers of longer (> 5 min; 19 versus 26 episodes/12 h) nonREM sleep episodes; and b) wake disruption during the dark phase, with increased numbers of shorter (138 versus 91 episodes/12 h) and decreased numbers of longer active waking (17 versus 24 episodes/12 h) episodes. AraC-treated mice also exhibited lower delta activity within nonREM recovery sleep. The sleep–wake architecture of AraC-treated mice was similar to that observed in aged mice. These findings are consistent with a hypothesis that a decrease in hypothalamic cell proliferation/neurogenesis is detrimental to sleep–wake and circadian systems and may underlie sleep–wake disturbance in aging. Highlights: Sleep–wake disruption is one of the most frequent and challenging problems of advancing age. We hypothesized that a chronic suppression of hypothalamic cell proliferation causes aging-associated sleep–wake disruption. Chronic central infusion of AraC, an antimitotic agent, produced sleep–wake features of aging in young mice. The results support that A CHRONIC DECLINE IN CELL PROLIFERATION AND NEUROGENESIS UNDERLIES SLEEP–WAKE DISTURBANCE IN AGING.