Department of Psychology, UCLA, 405 Hilgard, Los Angeles, CA 90095, USA.
Neuroscience. 2010 Sep 29;170(1):247-58. doi: 10.1016/j.neuroscience.2010.06.038. Epub 2010 Jul 2.
Sleep fragmentation (SF) is prevalent in human sleep-related disorders. In rats, sustained SF has a potent suppressive effect on adult hippocampal dentate gyrus (DG) neurogenesis. Adult-generated DG neurons progressively mature over several weeks, and participate in certain hippocampal-dependent cognitive functions. We predicted that suppression of neurogenesis by sustained SF would affect hippocampal-dependent cognitive functions in the time window when new neurons would reach functional maturity. Sprague-Dawley rats were surgically-prepared with electroencephalogram (EEG) and electromyogram (EMG) electrodes for sleep state detection. We induced sleep-dependent SF for 12 days, and compared SF animals to yoked sleep fragmentation controls (SFC), treadmill controls (TC) and cage controls (CC). Rats were injected with bromodeoxyuridine on treatment days 4 and 5. Rats were returned to home cages for 14 days. Cognitive performance was assessed in a Barnes maze with 5 days at a constant escape position followed by 2 days at a rotated position. After Barnes maze testing rats were perfused and DG sections were immunolabeled for BrdU and neuronal nuclear antigen (NeuN), a marker of mature neurons.SF reduced BrdU-labeled cell counts by 32% compared to SFC and TC groups. SF reduced sleep epoch duration, but amounts of rapid eye movement (REM) sleep did not differ between SF and SFC rats, and non-rapid eye movement (NREM) was reduced only transiently. In the Barnes maze, SF rats exhibited a progressive decrease in escape time, but were slower than controls. SF animals used different search strategies. The use of a random, non-spatial search strategy was significantly elevated in SF compared to the SFC, TC and CC groups. The use of random search strategies was negatively correlated with NREM sleep bout length during SF. Sustained sleep fragmentation reduced DG neurogenesis and induced use of a non-spatial search strategy, which could be seen 2 weeks after terminating the SF treatment. The reduction in neurogenesis induced by sleep fragmentation is likely to underlie the delayed changes in cognitive function.
睡眠片段化（SF）在人类睡眠相关障碍中普遍存在。在大鼠中，持续的 SF 对成年海马齿状回（DG）神经发生具有强烈的抑制作用。成年产生的 DG 神经元在数周内逐渐成熟，并参与某些海马依赖的认知功能。我们预测，持续的 SF 抑制神经发生会影响新神经元达到功能成熟的时间窗口内的海马依赖认知功能。Sprague-Dawley 大鼠接受脑电图（EEG）和肌电图（EMG）电极手术准备，用于睡眠状态检测。我们诱导睡眠依赖 SF 持续 12 天，并将 SF 动物与配对睡眠片段化对照（SFC）、跑步机对照（TC）和笼对照（CC）进行比较。在治疗第 4 和第 5 天，大鼠注射溴脱氧尿苷。大鼠返回笼中 14 天。在 Barnes 迷宫中进行认知性能评估，固定逃避位置 5 天，然后旋转位置 2 天。在 Barnes 迷宫测试后，大鼠进行灌注，DG 切片进行 BrdU 和神经元核抗原（NeuN）免疫标记，NeuN 是成熟神经元的标志物。与 SFC 和 TC 组相比，SF 减少了 32%的 BrdU 标记细胞计数。SF 减少了睡眠时相持续时间，但 SF 大鼠和 SFC 大鼠的快速眼动（REM）睡眠时间没有差异，非快速眼动（NREM）仅短暂减少。在 Barnes 迷宫中，SF 大鼠的逃避时间逐渐增加，但比对照组慢。SF 动物使用不同的搜索策略。与 SFC、TC 和 CC 组相比，SF 组中随机、非空间搜索策略的使用显著增加。SF 期间，随机搜索策略的使用与 NREM 睡眠回合长度呈负相关。持续的睡眠片段化减少了 DG 神经发生，并诱导使用非空间搜索策略，这种策略在停止 SF 治疗 2 周后即可观察到。睡眠片段化引起的神经发生减少可能是认知功能延迟变化的基础。
