Sex- and age-specific differences in relaxin family peptide receptor expression within the hippocampus and amygdala in rats

Relaxin is an essential pregnancy-related hormone with broad peripheral effects mediated by activation of relaxin-like family peptide 1 receptors (RXFP1). More recent studies suggest an additional role for relaxin as a neuropeptide, with RXFP1 receptors expressed in numerous brain regions. Neurons in an area of the brainstem known as the nucleus incertus (NI) produce relaxin 3 (RLN3), the most recently identified neuropeptide in the relaxin family. RLN3 has been shown to activate both RXFP1 and relaxin-like family peptide receptor 3 (RXFP3) receptor subtypes. Studies suggest wide-ranging neuromodulatory effects of both RXFP1 and RXFP3 activation, although to date the majority of studies have been conducted in young males. In the current study, we examined potential sex- and age-related changes in RLN3 gene expression in the NI as well as RXFP1 and RXFP3 gene expression in the dorsal hippocampus (HI), ventral hippocampus (vHI) and amygdala (AMYG) using young adult (9–12 weeks) and middle-aged (9–12 months) male and female rats. In addition, regional changes in RXFP1 and RXFP3 protein expression were examined in the CA1, CA2/CA3 and dentate gyrus (DG) as well as within basolateral (BLA), central (CeA), and medial (MeA) amygdaloid nuclei. In the NI, RLN3 showed an age-related decrease in males. In the HI, only the RXFP3 receptor showed an age-related change in gene expression, however, both receptor subtypes showed age-related changes in protein expression that were region specific. Additionally, while gene and protein expression of both receptors increased with age in AMYG, these effects were both region- and sex-specific. Finally, overall males displayed a greater number of cells that express the RXFP3 protein in all of the amygdaloid nuclei examined. Cognitive and emotional processes regulated by activity within the HI and AMYG are modulated by both sex and age. The vast majority of studies exploring the influence of sex on age-related changes in the HI and AMYG have focused on sex hormones, with few studies examining the role of neuropeptides. The current findings suggest that changes in relaxin family peptides may contribute to the significant sex differences observed in these brain regions as a function of aging.