Chronic Suppression of Hypothalamic Cell Proliferation and Neurogenesis Induces Aging-like Changes in Sleep-Wake Organization in Young Mice.

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 four weeks of artificial cerebrospinal fluid (aCSF) + 5-bromo-2'-deoxyuridine (BrdU) or AraC+BrdU infusion into the lateral-ventricle, and eight 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 nonREM (-9%) and REM-sleep (-21%) amounts, 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 were 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.