Institute for Integrative Physiology, Section of Emergency Medicine, The University of Chicago, Chicago, Illinois 60637.
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98109.
J Neurosci. 2019 Feb 13;39(7):1320-1331. doi: 10.1523/JNEUROSCI.1359-18.2018. Epub 2018 Dec 26.
Individuals with sleep apnea often exhibit changes in cognitive behaviors consistent with alterations in the hippocampus. It is hypothesized that adult neurogenesis in the dentate gyrus is an ongoing process that maintains normal hippocampal function in many mammalian species, including humans. However, the impact of chronic intermittent hypoxia (IH), a principal consequence of sleep apnea, on hippocampal adult neurogenesis remains unclear. Using a murine model, we examined the impact of 30 d of IH (IH) on adult neurogenesis and synaptic plasticity in the dentate gyrus. Although IH did not affect paired-pulse facilitation, IH suppressed long-term potentiation (LTP). Immunohistochemical experiments also indicate that IH perturbs multiple aspects of adult neurogenesis. IH increased the number of proliferating Sox2 neural progenitor cells in the subgranular zone yet reduced the number of doublecortin-positive neurons. Consistent with these findings, cell lineage tracing revealed that IH increased the proportion of radial glial cells in the subgranular zone, yet decreased the proportion of adult-born neurons in the dentate gyrus. While administration of a superoxide anion scavenger during IH did not prevent neural progenitor cell proliferation, it mitigated the IH-dependent suppression of LTP and prevented adult-born neuron loss. These data demonstrate that IH causes both reactive oxygen species-dependent and reactive oxygen species-independent effects on adult neurogenesis and synaptic plasticity in the dentate gyrus. Our findings identify cellular and neurophysiological changes in the hippocampus that may contribute to cognitive and behavioral deficits occurring in sleep apnea. Individuals with sleep apnea experience periods of intermittent hypoxia (IH) that can negatively impact many aspects of brain function. Neurons are continually generated throughout adulthood to support hippocampal physiology and behavior. This study demonstrates that IH exposure attenuates hippocampal long-term potentiation and reduces adult neurogenesis. Antioxidant treatment mitigates these effects indicating that oxidative signaling caused by IH is a significant factor that impairs synaptic plasticity and reduces adult neurogenesis in the hippocampus.
患有睡眠呼吸暂停的个体通常表现出与海马体改变一致的认知行为变化。有假说认为，成年海马体神经发生是一个持续的过程，它维持着许多哺乳动物物种（包括人类）的正常海马体功能。然而，慢性间歇性低氧（IH）对海马体成年神经发生的影响仍不清楚。通过使用一种啮齿动物模型，我们研究了 30 天 IH（IH）对齿状回成年神经发生和突触可塑性的影响。虽然 IH 不影响成对脉冲易化，但 IH 抑制了长时程增强（LTP）。免疫组织化学实验还表明，IH 扰乱了成年神经发生的多个方面。IH 增加了颗粒下区增殖的 Sox2 神经祖细胞数量，但减少了双皮质素阳性神经元的数量。与这些发现一致的是，细胞谱系追踪显示 IH 增加了颗粒下区放射状胶质细胞的比例，但减少了齿状回中成年神经元的比例。虽然在 IH 期间给予超氧化物阴离子清除剂不能防止神经祖细胞增殖，但它减轻了 IH 对 LTP 的抑制作用，并防止了成年神经元的丢失。这些数据表明，IH 对齿状回的成年神经发生和突触可塑性产生了依赖于活性氧和不依赖于活性氧的影响。我们的研究结果确定了海马体中的细胞和神经生理学变化，这些变化可能导致睡眠呼吸暂停中发生的认知和行为缺陷。患有睡眠呼吸暂停的个体经历间歇性低氧（IH）期，这可能对大脑功能的许多方面产生负面影响。神经元在整个成年期持续产生，以支持海马体的生理和行为。这项研究表明，IH 暴露会减弱海马体的长时程增强作用并减少成年神经发生。抗氧化剂治疗减轻了这些影响，表明 IH 引起的氧化信号是一个重要因素，它损害了海马体的突触可塑性并减少了成年神经发生。
