Research Service (151A3), Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, California, USA.
Research Service (151A3), Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, California, USA; Department of Psychiatry, University of California, Los Angeles, California, USA.
Neuroscience. 2019 Apr 15;404:541-556. doi: 10.1016/j.neuroscience.2019.01.053. Epub 2019 Feb 8.
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.
衰老是与睡眠-觉醒中断、昼夜节律幅度降低以及稳态睡眠反应减弱有关。衰老是与下丘脑细胞增殖减少有关。我们假设，与衰老相关的细胞增殖下降导致了前脑-下丘脑睡眠-觉醒和昼夜节律系统的功能障碍，并导致了睡眠-觉醒中断。我们确定了细胞分裂抑制剂胞嘧啶-β-D-阿拉伯呋喃糖苷（AraC）是否会导致年轻小鼠的睡眠-觉醒不稳定，AraC 是一种已知可以抑制下丘脑细胞增殖和神经发生的抗有丝分裂剂。在基线期间、在侧脑室中进行 4 周的人工脑脊液（aCSF）+5-溴-2'-脱氧尿苷（BrdU）或 AraC+BrdU 输注期间以及治疗 8 周后，比较了睡眠-觉醒谱。AraC 治疗后的睡眠-觉醒结构与老年小鼠的睡眠-觉醒谱进一步进行了比较。与 aCSF+BrdU 相比，4 周的 AraC+BrdU 输注显著减少（-96%）了第三脑室壁周围和相邻的前脑-下丘脑区域中 BrdU+细胞的数量，并产生了 a）在光照期的睡眠中断，非快速眼动（非 REM）睡眠减少（-9%）和 REM 睡眠减少（-21%），较短（<2 分钟；142 次/12 小时与 98 次/12 小时）的非 REM 睡眠发作次数增加，较长（>5 分钟；19 次/12 小时与 26 次/12 小时）的非 REM 睡眠发作次数减少；b）在暗期的觉醒中断，较短（138 次/12 小时与 91 次/12 小时）的觉醒发作次数增加，较长的活动觉醒（17 次/12 小时与 24 次/12 小时）的觉醒发作次数减少。AraC 处理的小鼠在非 REM 恢复睡眠中也表现出较低的 delta 活动。AraC 处理的小鼠的睡眠-觉醒结构与老年小鼠观察到的相似。这些发现与一个假设一致，即下丘脑细胞增殖/神经发生的减少对睡眠-觉醒和昼夜节律系统有害，可能是衰老中睡眠-觉醒障碍的基础。
