Maternal Separation Followed by Chronic Mild Stress in Adulthood Is Associated with Concerted Epigenetic Regulation of AP-1 Complex Genes

Abstract

Depression is one of the most prevalent mental diseases worldwide. Patients with psychiatric diseases often have a history of childhood neglect, indicating that early-life experiences predispose to psychiatric diseases in adulthood. Two strong models were used in the present study: the maternal separation/early deprivation model (MS) and the chronic mild stress model (CMS). In both models, we found changes in the expression of a number of genes such as Creb and Npy. Strikingly, there was a clear regulation of expression of four genes involved in the AP-1 complex: c-Fos, c-Jun, FosB, and Jun-B. Interestingly, different expression levels were observed depending on the model, whereas the combination of the models resulted in a normal level of gene expression. The effects of MS and CMS on gene expression were associated with distinct histone methylation/acetylation patterns of all four genes. The epigenetic changes, like gene expression, were also dependent on the specific stressor or their combination. The obtained results suggest that single life events leave a mark on gene expression and the epigenetic signature of gene promoters, but a combination of different stressors at different life stages can further change gene expression through epigenetic factors, possibly causing the long-lasting adverse effects of stress.

Prolonged Maternal Separation Reduces Anxiety State and Increases Compulsive Burying Activity in the Offspring of BALB/c Mice

“…Over the past few decades, there has been mounting evidence that adverse childhood experiences can affect how individuals respond to both disease and treatment [65]. Many studies showed that childhood adversity can cause epigenetic changes [66] and increase an individual's susceptibility to various illnesses, such as cancer, heart disease, endocrine disorders and mental illnesses [67,68]. Likewise, the findings of the current study provide supporting evidence that mice exposed to early life stress by being separated from their mothers (from day 1 to 30 postnatal) were more likely to exhibit aberrant behaviors than their non-separated peers.…”

Antidepressant effect of electroacupuncture on modulating the expression of c‐Fos/AP‐1 through the JNK signaling pathway

“…However, the expression of c-Jun in the hypothalamus and serum AP-1 in the SP600125 group decreased significantly in the model group after the inhibition of JNK signaling pathway by SP600125, indicating that c-Jun and AP-1 are key regulators in the pathogenesis of depression. Similarly, previous studies have reported that the stressinduced upregulation of the molecules in JNK signaling pathway, including c-Fos, c-Fun, and p-JNK, might be involved in the pathogenesis of depression (Huguet, Kadar, Temel, & Lim, 2017;Lundgaard Donovan et al, 2021;Meng, Wang, & Luo, 2019). Moreover, clinical studies have also shown that c-Fos gene expression is upregulated in depressed patients, and may lead to the deterioration of patients' survival (Yi, Liu, Wu, Wu, & Zhang, 2019).…”

Maternal Substance Use and Early-Life Adversity: Inducing Drug Dependence in Offspring, Interactions, Mechanisms, and Treatments

“… 74 Expression of the transcription factor cAMP response element-binding protein and neuropeptide Y and a reduction of Jun-B mRNA have been reported after MS. Jun-B is one of four genes in the activator protein-1 complex that could be epigenetically regulated. 75 ELS triggers epigenetic modifications in genes outside the HPA axis, including BDNF, the serotonin transporter (5-HTT or Slc6a4) gene, the estrogen receptor-α gene, glutamate decarboxylase-1, and Reelin genes. 71 …”