Social isolation-induced transcriptomic changes in mouse hippocampus impact the synapse and show convergence with human genetic risk for neurodevelopmental phenotypes

Early life stress (ELS) can impact brain development and is a risk factor for neurodevelopmental disorders such as schizophrenia. Post-weaning social isolation (SI) is used to model ELS in animals, using isolation stress to disrupt a normal developmental trajectory. We aimed to investigate how SI affects the expression of genes in mouse hippocampus and to investigate how these changes related to the genetic basis of neurodevelopmental phenotypes. BL/6J mice were exposed to post-weaning SI (PD21-25) or treated as group-housed controls (n = 7-8 per group). RNA sequencing was performed on tissue samples from the hippocampus of adult male and female mice. Four hundred and 1,215 differentially-expressed genes (DEGs) at a false discovery rate of < 0.05 were detected between SI and control samples for males and females respectively. DEGS for both males and females were significantly overrepresented in gene ontologies related to synaptic structure and function, especially the post-synapse. DEGs were enriched for common variant (SNP) heritability in humans that contributes to risk of neuropsychiatric disorders (schizophrenia, bipolar disorder) and to cognitive function. DEGs were also enriched for genes harbouring rare de novo variants that contribute to autism spectrum disorder and other developmental disorders. Finally, cell type analysis revealed populations of hippocampal astrocytes that were enriched for DEGs, indicating effects in these cell types as well as neurons. Overall, these data suggest a convergence between genes dysregulated by the SI stressor in the mouse and genes associated with neurodevelopmental disorders and cognitive phenotypes in humans. To investigate the effect of post-weaning social isolation on gene expression in the adult male and female mouse hippocampus tissue, we used RNA-seq to measure gene expression changes between socially-isolated (SI) animals and group-housed (GH) controls.

早期生活压力（Early Life Stress, ELS）可影响大脑发育，亦是精神分裂症等神经发育障碍的风险因素。断奶后社会隔离（Post-weaning Social Isolation, SI）常被用于在动物模型中模拟早期生活压力，通过隔离应激破坏动物的正常发育轨迹。本研究旨在探究断奶后社会隔离如何影响小鼠海马体的基因表达，并解析这些表达变化与神经发育表型的遗传基础之间的关联。将BL/6J小鼠分为两组，一组于出生后第21至25天（PD21-25）接受断奶后社会隔离造模，另一组作为群居饲养对照组，每组样本量为7-8只。采集成年雄性与雌性小鼠的海马体组织样本，进行RNA测序（RNA-seq）。分别在雄性与雌性小鼠的社会隔离组与对照组样本中，检测到假发现率（false discovery rate, FDR）小于0.05的差异表达基因（differentially-expressed genes, DEGs）各400个和1215个。雌雄小鼠的差异表达基因均显著富集于与突触结构和功能相关的基因本体（Gene Ontology, GO）条目，尤其是突触后结构相关条目。这些差异表达基因显著富集于与人类神经精神疾病（精神分裂症、双相情感障碍）风险及认知功能相关的常见变异（单核苷酸多态性, Single Nucleotide Polymorphism, SNP）遗传力相关的基因集。此外，这些差异表达基因也显著富集于携带罕见新发变异、与孤独症谱系障碍（Autism Spectrum Disorder）及其他发育障碍相关的基因。最后，细胞类型分析显示，海马星形胶质细胞（astrocytes）群体显著富集差异表达基因，表明该应激不仅影响神经元，也对星形胶质细胞产生作用。综上，本研究数据表明，小鼠社会隔离应激所失调的基因，与人类神经发育障碍及认知表型相关的基因存在交汇。为探究断奶后社会隔离对成年雌雄小鼠海马组织基因表达的影响，本研究采用RNA-seq技术检测了社会隔离组与群居饲养对照组动物的基因表达变化。