Kuznetsova Maria, Wilson Carey, Cheng Lesley, Pang Terence, Li Shanshan, Roberts Blaine R, Lago Larissa C, Tran Harvey, Hill Andrew F, Hannan Anthony J, Renoir Thibault
Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Australia.
La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia.
Neuropharmacology. 2025 Mar 1;265:110240. doi: 10.1016/j.neuropharm.2024.110240. Epub 2024 Nov 27.
Environmental changes may alter gene expression in depression and anxiety disorders through epigenetic regulation, including via small non-coding RNAs (sncRNAs) and their major subclass, microRNAs (miRNAs). However, underlying mechanisms mediating miRNA regulation in response to changing environmental stimuli are unclear. Using the serotonin transporter (5-HTT) knockout (KO) mouse model of depression/anxiety, this study aimed to compare the effects of voluntary exercise (EX) versus chronic treatment with the stress hormone corticosterone (CT), on hippocampal miRNA transcriptome and proteome in five comparison groups: WT-SH vs. KO-SH; WT-SH vs. WT-EX; KO-SH vs. KO-EX; WT-SH vs. WT-CT; KO-SH vs. KO-CT. We hypothesized that treatment with stress hormone will result in miRNA and proteomics changes observed in genetic model of depression, while exercise will have beneficial effects similar to antidepressant treatment. Using high-throughput sequencing of miRNAs and mass spectrometry (MS)-based approaches for protein expression, we revealed 337 differentially expressed (DE) miRNAs and 67 proteins in 5-HTT KO mice compared to wild-type (WT) control mice in standard-housing conditions. After exercise, there were 200 DE miRNAs and 3 DE proteins in WT mice, and 20 DE miRNAs and 95 DE proteins in 5-HTT KO mice, while corticosterone treatment led to 168 DE miRNAs and 1 DE protein in WT, and 21 DE miRNAs and 21 DE proteins in 5-HTT KO mice. Serotonergic dysfunction (due to the 5-HTT KO gene mutation) induced altered expression of miRNAs and proteins involved in regulation of neurodevelopment, neurogenesis and neuroinflammatory responses. Treatment with the stress hormone corticosterone in WT mice activated pathways which were also found altered in 5-HTT KO mice, while exercise caused antidepressant-like effects. These findings suggest that functional 5-HTT might be required for the beneficial effects of exercise on miRNA expression. Our study is the first to explore how gene-environment interactions affect miRNA/proteomic composition in a mouse model of depression/anxiety, and extends our understanding of gene-environmental interactions underlying these affective disorders.
环境变化可能通过表观遗传调控改变抑郁症和焦虑症中的基因表达，包括通过小非编码RNA（sncRNAs）及其主要亚类微小RNA（miRNAs）。然而，介导miRNA调控以响应不断变化的环境刺激的潜在机制尚不清楚。本研究使用抑郁症/焦虑症的血清素转运体（5-HTT）基因敲除（KO）小鼠模型，旨在比较自愿运动（EX）与应激激素皮质酮慢性治疗（CT）对五个比较组海马miRNA转录组和蛋白质组的影响：野生型标准饲养组（WT-SH）与基因敲除标准饲养组（KO-SH）；WT-SH与野生型运动组（WT-EX）；KO-SH与基因敲除运动组（KO-EX）；WT-SH与野生型皮质酮治疗组（WT-CT）；KO-SH与基因敲除皮质酮治疗组（KO-CT）。我们假设，应激激素治疗将导致在抑郁症遗传模型中观察到的miRNA和蛋白质组学变化，而运动将产生与抗抑郁治疗类似的有益效果。通过对miRNA的高通量测序和基于质谱（MS）的蛋白质表达方法，我们发现与标准饲养条件下的野生型（WT）对照小鼠相比，5-HTT基因敲除小鼠中有337个差异表达（DE）miRNA和67种蛋白质。运动后，野生型小鼠中有200个DE miRNA和3种DE蛋白质，5-HTT基因敲除小鼠中有20个DE miRNA和95种DE蛋白质，而皮质酮治疗导致野生型小鼠中有168个DE miRNA和1种DE蛋白质，5-HTT基因敲除小鼠中有21个DE miRNA和21种DE蛋白质。血清素功能障碍（由于5-HTT基因敲除基因突变）导致参与神经发育、神经发生和神经炎症反应调节的miRNA和蛋白质表达改变。野生型小鼠中应激激素皮质酮治疗激活的通路在5-HTT基因敲除小鼠中也有改变，而运动则产生抗抑郁样效果。这些发现表明，功能性5-HTT可能是运动对miRNA表达产生有益影响所必需的。我们的研究首次探讨了基因-环境相互作用如何影响抑郁症/焦虑症小鼠模型中的miRNA/蛋白质组组成，并扩展了我们对这些情感障碍潜在基因-环境相互作用的理解。
