Enduring sex-dependent effects of lipopolysaccharide treatment on the hypothalamic-pituitary-gonadal axis in mice.

Pubertal stress causes enduring sexual behavior dysfunction in males and females, but the underlying mechanism remains unknown. These changes may arise from pubertal programming of the hypothalamic-pituitary-gonadal axis. Previous findings show that stress exposure downregulates the hypothalamic-pituitary-gonadal axis, particularly through the reduction of the neuropeptide kisspeptin (Kiss1) and its receptor (Kiss1R). Although acute changes in kiss1 and Kiss1r genes have been observed following pubertal immune stress, it is unclear whether immune stress-induced downregulation of kiss1 and kiss1r persists beyond puberty. The current study investigated the enduring sex-specific consequences of lipopolysaccharide on the expression of Kiss1 and Kiss1r in 160 pubertal or adult mice at multiple time points. Six-week and 10-week-old male and female mice were treated with either saline or with lipopolysaccharide. Mice were euthanized either 8 h or 4 weeks following treatment. Although we did not identify any sex differences, our results revealed that lipopolysaccharide treatment decreases hypothalamic Kiss1 and Kiss1r in both pubertal and adult mice within 8 h of treatment. The decreased hypothalamic Kiss1 expression persists 4 weeks later only in mice treated with lipopolysaccharide during puberty. Our findings highlight the age-dependent vulnerability of the hypothalamic-pituitary-gonadal axis to immune stress, providing a better understanding of the mechanisms implicated in allostatic shift during immune stress. Finally, our findings also show the effects of immune stress on various components of the hypothalamic-pituitary-gonadal axis, which could have implications for sexual and fertility-related dysfunctions.

Environmental enrichment alters LPS-induced changes in BDNF and PSD-95 expressions during puberty.

Puberty is a critical period of cortical reorganization and increased synaptogenesis. Healthy cortical reorganization and synaptic growth require sufficient environmental stimuli and minimalized stress exposure during pubertal development. Exposure to impoverished environments or immune challenges impact cortical reorganization and reduce the expression of proteins associated with neuronal plasticity (BDNF) and synaptogenesis (PSD-95). Environmentally enriched (EE) housing includes improved social-, physical-, and cognitive stimulation. We hypothesized that enriched housing environment would mitigate pubertal stress-induced decreases in BDNF and PSD-95 expressions. Three-week-old male and female CD-1 mice (n = 10 per group) were housed for three weeks in either EE, social or deprived housing conditions. At 6 weeks of age, mice were treated with either lipopolysaccharide (LPS) or saline eight hours prior to tissue collection. Male and female EE mice displayed greater BDNF and PSD-95 expressions in the medial prefrontal cortex and hippocampus compared to socially housed and deprived housed mice. LPS treatment decreased BDNF expression in all the brain regions examined in EE mice, except for the CA3 region of the hippocampus, where EE housing successfully mitigated the pubertal LPS-induced decrease in BDNF expression. Interestingly, LPS-treated mice housed in deprived conditions displayed unexpected increases in BDNF and PSD-95 expressions throughout the medial prefrontal cortex and hippocampus. Both enriched and deprived housing conditions moderate how an immune challenge influences BDNF and PSD-95 expressions in a region-specific manner. These findings also emphasize the vulnerability of brain plasticity during puberty to various environmental factors.