Mychasiuk R, Muhammad A, Kolb B
Alberta Children's Hospital Research Institute, University of Calgary, Canada.
Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Canada.
Neuroscience. 2016 May 13;322:489-99. doi: 10.1016/j.neuroscience.2016.02.053. Epub 2016 Mar 3.
Chronic stress is associated with a plethora of cognitive symptoms such as emotional dysregulation and impaired executive function that have been attributed to modifications in neuroanatomy in the orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and hippocampus (HPC). While many studies have examined stress-induced changes in neuronal morphology, synaptic plasticity, and cellular function, there has been little investigation into persistent changes in gene expression that may be responsible for the maintenance of these changes. This study exposed adult rats to a chronic stressor and then examined changes in mRNA gene expression in the OFC, mPFC and HPC following a two-week withdrawal period. mRNA bio-sequencing results revealed sex- and region-dependent changes. Surprisingly the greatest changes in gene expression were found in the OFC, and similar to anatomical studies, analysis of gene changes with Ingenuity Pathway Analysis software demonstrated that the mPFC and OFC exhibited contrasting activation of canonical pathways and functional networks. The HPC demonstrated the largest degree of sex-dependent change in gene expression. In general, chronic stress induced persistent changes in gene expression in the three brain regions we examined and these changes could be associated with the commonly reported cognitive symptoms. The current study highlights the region- and sex-dependent nature of the brain's response to chronic stress and the difficulty we face when attempting to develop treatment options.
慢性应激与大量认知症状相关，如情绪调节障碍和执行功能受损，这些症状被认为与眶额皮质（OFC）、内侧前额叶皮质（mPFC）和海马体（HPC）的神经解剖结构改变有关。虽然许多研究已经考察了应激诱导的神经元形态、突触可塑性和细胞功能变化，但对于可能导致这些变化持续存在的基因表达的持续性变化却鲜有研究。本研究将成年大鼠暴露于慢性应激源下，然后在为期两周的撤药期后检查OFC、mPFC和HPC中mRNA基因表达的变化。mRNA生物测序结果显示了性别和区域依赖性变化。令人惊讶的是，基因表达的最大变化出现在OFC中，并且与解剖学研究类似，使用 Ingenuity Pathway Analysis软件对基因变化进行分析表明，mPFC和OFC在经典通路和功能网络的激活方面表现出相反的情况。HPC在基因表达方面表现出最大程度的性别依赖性变化。总体而言，慢性应激在我们所检查的三个脑区中诱导了基因表达的持续性变化，这些变化可能与常见的认知症状有关。当前研究突出了大脑对慢性应激反应的区域和性别依赖性本质，以及我们在尝试开发治疗方案时所面临的困难。
