Sex-Specific Mechanisms of Pubertal Stress-Induced Inhibition of the HPG Axis

Abstract

Puberty is a critical period of development that is characterized by significant remodeling and reorganization of neuronal connections. Additionally, this period is marked by the transition to a fertile state and the development of secondary sex characteristics driven by a surge in gonadal steroid hormones. Puberty is also vulnerable to stress exposure, as pubertal stress during this period results in negative enduring changes to the brain and behavior. Treatment with the bacterial endotoxin lipopolysaccharide (LPS) results in enduring dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis in male and female mice. However, the mechanism underlying this dysfunction was unclear. Thus, this thesis was designed to investigate possible mechanisms through which pubertal stress could alter HPG axis functioning. This work first examined the acute effects of LPS treatment on various components of the HPG axis, such as kisspeptin (Kiss1) and kisspeptin receptor (Kiss1R) expressions in the brain, and luteinizing (LH) and follicle stimulating hormone (FSH) concentrations in the blood (Study 1). The next study examined the enduring effects of LPS treatment on inflammation as well as on Kiss1 and Kiss1R expressions in the brain, and LH and FSH concentrations in the blood (Study 2). The findings showed that Kiss1 and Kiss1R were downregulated in an acute and enduring manner following LPS treatment and are likely responsible for HPG axis downregulation. The final study amalgamates the novel discoveries of the previous findings and hypothesizes that pharmaceutical Kiss1 treatment will prevent adult sexual behavior dysfunction after pubertal LPS treatment. Findings from this study will inform us whether the enduring HPG axis downregulation following pubertal LPS treatment is reversible in adulthood and could provide a viable prospective intervention for fertility complications across species.