Center for Neuroscience Research, Children's National Medical Center, Washington, DC, USA.
Dev Neurosci. 2011;33(5):428-41. doi: 10.1159/000329423. Epub 2011 Aug 25.
Down syndrome (DS), the most frequent genetic cause of intellectual disability and developmental delay, results from impaired neural stem cell proliferation and differentiation. Impaired neurogenesis in the neocortex, hippocampus and cerebellum is believed to be the underlying cause of learning and behavioral deficits in the Ts65Dn mouse model of DS. Aggressive sensorimotor and cognitive therapies have shown promise in mitigating the cognitive disabilities in DS but these behavioral therapies have not yet been investigated at the cellular level. Here, using the Ts65Dn mouse model of DS, we demonstrate that a combination of environmental enrichment and physical exercise starting in juvenile mice (postnatal day 18) markedly increases cell proliferation, neurogenesis and gliogenesis in the hippocampal dentate gyrus (DG) and the forebrain subventricular zone (SVZ) of both male and female mice. Enrichment and exercise increased the rate of Ts65Dn DG neurogenesis to be comparable to that of the nonenriched euploid group, while the effect on SVZ neurogenesis was reduced and seen only after prolonged exposure. These results clearly indicate that in a comprehensive stimulatory environment, the postnatal DS brain has the intrinsic capability of improving neurogenesis and gliogenesis to the levels of normal matched controls and that this cellular response underlies the cognitive improvement seen following behavioral therapies.
唐氏综合征（Down syndrome，DS）是智力障碍和发育迟缓最常见的遗传原因，其源于神经干细胞增殖和分化受损。人们认为，新皮层、海马体和小脑中的神经发生受损是 Ts65Dn 唐氏综合征小鼠模型学习和行为缺陷的潜在原因。积极的感觉运动和认知疗法已显示出减轻 DS 认知障碍的希望，但这些行为疗法尚未在细胞水平上进行研究。在这里，我们使用 Ts65Dn 唐氏综合征小鼠模型证明，从幼年（出生后第 18 天）开始，将环境丰富化和体育锻炼相结合，可显著增加雄性和雌性小鼠海马齿状回（DG）和前脑室下区（SVZ）中的细胞增殖、神经发生和神经胶质发生。丰富化和锻炼使 Ts65Dn 小鼠 DG 神经发生的速度提高到与非丰富化正常二倍体组相当的水平，而对 SVZ 神经发生的影响则降低，仅在长期暴露后才可见。这些结果清楚地表明，在全面刺激的环境中，出生后 DS 大脑具有提高神经发生和神经胶质发生的内在能力，达到正常匹配对照的水平，而这种细胞反应是行为疗法后认知改善的基础。
