Musaelyan Ksenia, Yildizoglu Selin, Bozeman James, Du Preez Andrea, Egeland Martin, Zunszain Patricia A, Pariante Carmine M, Fernandes Cathy, Thuret Sandrine
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 9NU, UK.
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
Brain Commun. 2020 Sep 26;2(2):fcaa153. doi: 10.1093/braincomms/fcaa153. eCollection 2020.
Adult hippocampal neurogenesis is involved in stress-related disorders such as depression, posttraumatic stress disorders, as well as in the mechanism of antidepressant effects. However, the molecular mechanisms involved in these associations remain to be fully explored. In this study, unpredictable chronic mild stress in mice resulted in a deficit in neuronal dendritic tree development and neuroblast migration in the hippocampal neurogenic niche. To investigate molecular pathways underlying neurogenesis alteration, genome-wide gene expression changes were assessed in the prefrontal cortex, hippocampus and the hypothalamus alongside neurogenesis changes. Cluster analysis showed that the transcriptomic signature of chronic stress is much more prominent in the prefrontal cortex compared to the hippocampus and the hypothalamus. Pathway analyses suggested huntingtin, leptin, myelin regulatory factor, methyl-CpG binding protein and brain-derived neurotrophic factor as the top predicted upstream regulators of transcriptomic changes in the prefrontal cortex. Involvement of the satiety regulating pathways (leptin) was corroborated by behavioural data showing increased food reward motivation in stressed mice. Behavioural and gene expression data also suggested circadian rhythm disruption and activation of circadian clock genes such as Period 2. Interestingly, most of these pathways have been previously shown to be involved in the regulation of adult hippocampal neurogenesis. It is possible that activation of these pathways in the prefrontal cortex by chronic stress indirectly affects neuronal differentiation and migration in the hippocampal neurogenic niche via reciprocal connections between the two brain areas.
成年海马体神经发生与应激相关疾病有关，如抑郁症、创伤后应激障碍，也与抗抑郁作用机制有关。然而，这些关联背后的分子机制仍有待充分探索。在本研究中，小鼠不可预测的慢性轻度应激导致海马神经生发微环境中神经元树突发育和神经母细胞迁移出现缺陷。为了研究神经发生改变背后的分子途径，在评估神经发生变化的同时，还对前额叶皮质、海马体和下丘脑的全基因组基因表达变化进行了评估。聚类分析表明，与海马体和下丘脑相比，慢性应激的转录组特征在前额叶皮质中更为突出。通路分析表明，亨廷顿蛋白、瘦素、髓磷脂调节因子、甲基化CpG结合蛋白和脑源性神经营养因子是前额叶皮质转录组变化的顶级预测上游调节因子。行为数据显示应激小鼠的食物奖励动机增加，这证实了饱腹感调节通路（瘦素）的参与。行为和基因表达数据还表明昼夜节律紊乱以及昼夜节律时钟基因（如周期蛋白2）的激活。有趣的是，这些通路中的大多数先前已被证明参与成年海马体神经发生的调节。慢性应激在前额叶皮质中激活这些通路，可能通过两个脑区之间的相互连接间接影响海马神经生发微环境中的神经元分化和迁移。
