Although early life stress (ELS) can increase susceptibility to adulthood psychiatric disorders and produce a greater inflammatory response in a stressful event, targeted preventive and therapeutic drugs still remain scarce. Ganoderma lucidum triterpenoids (GLTs) can exert anti-inflammatory effects in the periphery and central nervous systems. This study employed a combined model of “childhood maternal separation + adulthood sub-stress” to explore whether GLTs may alleviate anxiety- and depression-like behaviors in male and female mice by mitigating inflammation. Male and female pups were separated from their mothers for four hours per day from postnatal day 1 (PND 1) to PND 21; starting from PND 56, GLTs were administered intraperitoneally once daily for three weeks and followed by three days of sub-stress. Results showed that maternal separation increased the anxiety- and depression-like behaviors in both male and female mice, which disappeared after the preemptive GLTs treatment (40 mg/kg) before adulthood sub-stress. Maternal separation up-regulated the pro-inflammatory markers in the periphery and brain, and activated microglia in the prefrontal cortex and hippocampus. All the abnormalities were reversed by GLTs administration, with no adverse effects on immune organ indices, liver, and renal function. Our findings suggest that GLTs can be a promising candidate in treating ELS-induced psychiatric disorders.

Introduction: Gonadotropin-releasing hormone (GnRH) is a hypothalamic neuropeptide that plays important roles in the female fertility. Accumulating evidence suggests that ERα present in the astrocytes of the hypothalamus region is essential for production of GnRH. The astrocytes display age-related senescence associated to oxidative stress induced by the estrogen metabolites. However, it is still unclear whether and how ERα expression changes during astrocyte aging. Methods: Immunofluorescence was performed to analyze the ERα gene levels in hypothalamic astrocytes of naturally aging C57BL/6J female mice. We employed an oxidative stress cell model receiving 2-hydroxyestradiol (2OH-E2) intervention to confirm the downregulation of ERα expression in primary astrocytes. Western blot analysis was used to explore which oxidative stress signaling pathways induced loss of the ERα gene. Finally, ChIP-qPCR was employed to evaluate whether the c-Jun protein is able to regulate ERα gene expression. Results: Compared to young mice, we found that the ERα expression of mid-aged mice was significantly decreased. In hypothalamic astrocytes, 2OH-E2 treatment significantly reduced the expression of the ERα gene. Moreover, we observed that transcription factor c-Jun could directly inhibit transcriptional ERα gene expression and might also reduce it by decreasing H3K27 acetylation at promoter regions. Administration of the antioxidants Rg1 and astaxanthin significantly attenuated the decrease in ERα gene expression induced by oxidative stress. Conclusions: The current data demonstrate that oxidative stress leads to loss of ERα involving the activation of the p38 and ERK1/2 pathways and the induction of the c-Jun protein in hypothalamic astrocytes. C-Jun protein regulates ERα gene expression via direct transcriptional repression or involving histone acetylation modifications at ERα gene promoter sites.

Objectives: This study attempted to investigate whether early life stress (ELS) induces lipid peroxidation in the prefrontal cortex (PFC) of mice and its correlation with depression-like behavioral changes. Methods: A mouse ELS model was established via maternal separation. Depressive and anxiety-like behaviors were assessed using the forced swim test, sucrose preference test, tail suspension test, and open field test. The expression levels of GPX4, SLC3A2, SLC7A11, TFR1, and lipid peroxidation markers in the PFC of mice were measured and correlated with depression-like behavioral changes. Results: ELS induced depressive and anxiety-like behaviors in mice. The mRNA and protein expressions of GPX4, SLC3A2, and SLC7A11 were downregulated in the PFC of ELS mice; the mRNA level of TFR1 was upregulated but its protein level remained unchanged. In the PFC of ELS mice, the product of lipid peroxidation, malondialdehyde, was significantly increased, while the antioxidants, glutathione and superoxide dismutase, were significantly decreased. These markers were significantly correlated with sucrose preference or immobility time of the ELS mice. Conclusions: The study evidences that early life stress can induce lipid peroxidation in the PFC of mice and that the latter is closely associated with depression-like behaviors, hinting that ELS may induce depression via lipid peroxidation in the PFC. These findings may suggest a potential strategy for the treatment of early-stage stress-related depression.