Duan Toni Q, Hagenauer Megan H, Flandreau Elizabeth I, Bader Anne, Nguyen Duy Manh, Maras Pamela M, De Lima Randriely Merscher S, Gyles Trevonn, Mclain Christabel, Meaney Michael J, Nestler Eric J, Watson Stanley J, Akil Huda
Grinnell College, Grinnell, IA USA.
Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI USA.
bioRxiv. 2024 Nov 24:2024.11.22.624315. doi: 10.1101/2024.11.22.624315.
Early life stress (ELS) refers to exposure to negative childhood experiences, such as neglect, disaster, and physical, mental, or emotional abuse. ELS can permanently alter the brain, leading to cognitive impairment, increased sensitivity to future stressors, and mental health risks. The prefrontal cortex (PFC) is a key brain region implicated in the effects of ELS.
To better understand the effects of ELS on the PFC, we ran a meta-analysis of publicly available transcriptional profiling datasets. We identified five datasets (GSE89692, GSE116416, GSE14720, GSE153043, GSE124387) that characterized the long-term effects of multi-day postnatal ELS paradigms (maternal separation, limited nesting/bedding) in male and female laboratory rodents (rats, mice). The outcome variable was gene expression in the PFC later in adulthood as measured by microarray or RNA-Seq. To conduct the meta-analysis, preprocessed gene expression data were extracted from the Gemma database. Following quality control, the final sample size was n=89: n=42 controls & n=47 ELS: GSE116416 n=23 (no outliers); GSE116416 n=44 (2 outliers); GSE14720 n=7 (no outliers); GSE153043 n=9 (1 outlier), and GSE124387 n=6 (no outliers). Differential expression was calculated using the pipeline followed by an empirical Bayes correction. For each gene, a random effects meta-analysis model was then fit to the ELS vs. Control effect sizes (Log2 Fold Changes) from each study.
Our meta-analysis yielded stable estimates for 11,885 genes, identifying five genes with differential expression following ELS (false discovery rate< 0.05): (, (, (, ( and (, all of which were downregulated. Broadly, gene sets associated with oligodendrocyte differentiation, myelination, and brain development were downregulated following ELS. In contrast, genes previously shown to be upregulated in Major Depressive Disorder patients were upregulated following ELS.
These findings suggest that ELS during critical periods of development may produce long-term effects on the efficiency of transmission in the PFC and drive changes in gene expression similar to those underlying depression.
早年生活应激（ELS）是指童年时期经历的负面事件，如被忽视、遭遇灾难以及受到身体、精神或情感虐待。ELS可永久性改变大脑，导致认知障碍、对未来应激源的敏感性增加以及心理健康风险。前额叶皮质（PFC）是涉及ELS影响的关键脑区。
为了更好地理解ELS对PFC的影响，我们对公开可用的转录谱数据集进行了荟萃分析。我们确定了五个数据集（GSE89692、GSE116416、GSE14720、GSE153043、GSE124387），这些数据集描述了多日产后ELS范式（母婴分离、有限筑巢/垫料）对雄性和雌性实验啮齿动物（大鼠、小鼠）的长期影响。结局变量是成年后期通过微阵列或RNA测序测量的PFC中的基因表达。为了进行荟萃分析，从Gemma数据库中提取预处理的基因表达数据。经过质量控制后，最终样本量为n = 89：n = 42为对照组，n = 47为ELS组：GSE116416组n = 23（无异常值）；GSE116416组n = 44（2个异常值）；GSE14720组n = 7（无异常值）；GSE153043组n = 9（1个异常值），GSE124387组n = 6（无异常值）。使用该流程计算差异表达，随后进行经验贝叶斯校正。然后针对每个基因，将随机效应荟萃分析模型应用于每项研究中ELS与对照效应大小（Log2倍变化）。
我们的荟萃分析对11,885个基因得出了稳定的估计值，确定了ELS后差异表达的五个基因（错误发现率<0.05）：（基因名称1）、（基因名称2）、（基因名称3）、（基因名称4）和（基因名称5），所有这些基因均下调。总体而言，与少突胶质细胞分化、髓鞘形成和脑发育相关的基因集在ELS后下调。相比之下，先前在重度抑郁症患者中显示上调的基因在ELS后上调。
这些发现表明，发育关键期的ELS可能对PFC中的神经传递效率产生长期影响，并驱动与抑郁症潜在机制类似的基因表达变化。
