Chronic restraint stress impairs neurogenesis and hippocampus-dependent fear memory in mice: possible involvement of a brain-specific transcription factor Npas4
Chronic restraint stress impairs neurogenesis and hippocampus-dependent fear memory in mice: possible involvement of a brain-specific transcription factor Npas4
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DOI：
10.1111/j.1471-4159.2010.06893.x
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发表时间：
2010-09-01
影响因子：
4.7
通讯作者：
Yamada, Kiyofumi
中科院分区：
文献类型：
--
作者：
Yun, Jaesuk;Koike, Hiroyuki;Yamada, Kiyofumi
海马区的神经发生存在于多种物种的整个生命过程中，可能与海马区依赖的学习和记忆有关。应激被公认为会严重扰乱生理/心理的动态平衡，影响海马区的功能。为探讨早期慢性束缚应激对海马神经发生和海马区依赖记忆的影响，对3周龄小鼠每周6天给予束缚应激，共4周。慢性束缚应激使大鼠海马区体积减少6.3%，海马齿状回Ki67，5-溴-2‘-脱氧尿苷和双皮质醇阳性细胞数量减少，损伤了海马神经发生。慢性束缚应激严重损害了海马区依赖的情景恐惧记忆，而不影响海马区非依赖性的恐惧记忆。束缚应激或急性皮质酮处理可下调脑特异性转录因子神经元PAS结构域蛋白4(NPAS4)在海马区的表达水平。在对照组和应激组小鼠齿状回的前体细胞、未成熟神经元和成熟神经元中检测到Npas4免疫反应。我们的发现表明，慢性束缚应激减少了海马神经发生，导致小鼠海马区依赖的恐惧记忆受损。皮质酮诱导的Npas4表达下调可能在应激所致的海马区功能损害中起一定作用。
Neurogenesis in the hippocampus occurs throughout life in a wide range of species and could be associated with hippocampus-dependent learning and memory. Stress is well established to seriously perturb physiological/psychological homeostasis and affect hippocampal function. In the present study, to investigate the effect of chronic restraint stress in early life on hippocampal neurogenesis and hippocampus-dependent memory, 3-week-old mice were subjected to restraint stress 6 days a week for 4 weeks. The chronic restraint stress significantly decreased the hippocampal volume by 6.3% and impaired hippocampal neurogenesis as indicated by the reduced number of Ki67-, 5-bromo-2'-deoxyuridine- and doublecortin-positive cells in the dentate gyrus. The chronic restraint stress severely impaired hippocampus-dependent contextual fear memory without affecting hippocampus-independent fear memory. The expression level of brain-specific transcription factor neuronal PAS domain protein 4 (Npas4) mRNA in the hippocampus was down-regulated by the restraint stress or by acute corticosterone treatment. Npas4 immunoreactivity was detected in progenitors, immature and mature neurons of the dentate gyrus in control and stressed mice. Our findings suggest that the chronic restraint stress decreases hippocampal neurogenesis, leading to an impairment of hippocampus-dependent fear memory in mice. Corticosterone-induced down-regulation of Npas4 expression may play a role in stress-induced impairment of hippocampal function.