Abstract
Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH) neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinizing hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic–GnIH neuronal system using enhanced green fluorescent protein (EGFP)-tagged GnIH transgenic rats. Socially isolated rats were observed for anxious and depressive behaviors. Using immunohistochemistry, we examined c-Fos protein expression in EGFP–GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group housing. We also inspected serotonergic fiber juxtapositions in EGFP–GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviors. The total number of EGFP–GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fiber juxtapositions on EGFP–GnIH neurons were also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early-life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure.
Highlights
Gonadotropin-releasing hormone (GnRH) and the newly identified neuropeptide gonadotropin-inhibitory hormone (GnIH) are regulators of reproductive activity in vertebrates [1]
We showed that post-weaning social isolation impairs GnIH neuronal activity and the serotonergic system in the dorsomedial hypothalamic nucleus (DMN), which may contribute to the deregulation of GnRH neuronal activity in the pre-optic area (POA) and sexual dysfunction
Our results show that post-weaning social isolation decreases the expression of GnRH mRNA in male rats, which could lead to sexual dysfunction
Summary
Gonadotropin-releasing hormone (GnRH) and the newly identified neuropeptide gonadotropin-inhibitory hormone (GnIH) are regulators of reproductive activity in vertebrates [1]. GnIH neuropeptides contain an Arg–Phe–NH2 motif [LPXRFamide (X = L or Q) sequence] at their C termini in most vertebrate species. Our recent study [8] showed that exposure to the glucocorticoid receptor agonist dexamethasone during early life increases GnIH expression, GnIH receptor expression, and the number of fiber projections to the POA in adult female mice. These findings suggest that the GnIH system is sensitive to glucocorticoids, which can influence GnRH neuronal activity and reproduction
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