Absence of Female-Typical Pheromone-Induced Hypothalamic Neural Responses and Kisspeptin Neuronal Activity in α-Fetoprotein Knockout Female Mice

Abstract

Pheromones induce sexually dimorphic neuroendocrine responses, such as LH secretion. However, the neuronal network by which pheromones are converted into signals that will initiate and modulate endocrine changes remains unclear. We asked whether 2 sexually dimorphic populations in the anteroventral periventricular and periventricular nuclei that express kisspeptin and tyrosine hydroxylase (TH) are potential candidates that will transduce the olfactory signal to the neuroendocrine system. Furthermore, we assessed whether this transduction is sensitive to perinatal actions of estradiol by using female mice deficient in α-fetoprotein (AfpKO), which lack the protective actions of Afp against maternal estradiol. Wild-type (WT) and AfpKO male and female mice were exposed to same- versus opposite-sex odors and the expression of Fos (the protein product of the immediate early gene c-Fos) was analyzed along the olfactory projection pathways as well as whether kisspeptin, TH, and GnRH neurons are responsive to opposite-sex odors. Male odors induced a female-typical Fos expression in target forebrain sites of olfactory inputs involved in reproduction in WT, but not in AfpKO females, whereas female odors induced a male-typical Fos expression in males of both genotypes. In WT females, opposite-sex odors induced Fos in kisspeptin and TH neurons, whereas in AfpKO females and WT males, only a lower, but still significant, Fos expression was observed in TH but not in kisspeptin neurons. Finally, opposite-sex odors did not induce any significant Fos expression in GnRH neurons of both sexes or genotypes. Our results strongly suggest a role for fetal estrogen in the sexual differentiation of neural responses to sex-related olfactory cues.

Medial Amygdala <b><i>Kiss1</i></b> Neurons Mediate Female Pheromone Stimulation of Luteinizing Hormone in Male Mice

“…Using double transgenic Kiss1 CreEGFP/wt /Rosa26 lox-stop-lox-tdTomato/wt male mice, we observed a significant elevation of c-Fos in both the MeApv and MeApd, but not in the MeAa after female urine exposure. These data are in line with other studies in male mice which found elevated c-Fos throughout the MeA after female pheromone exposure, but c-Fos-ir was most prominent in the MeApd [8, 32]. We then quantified c-Fos-ir specifically within MeA tdTomato + (MeA Kiss ) neurons in response to urine exposure and observed raised c-Fos levels in MeA Kiss neurons throughout the MeA, but this was most significant in the MeApd.…”

“…Although activation of the MeA in response to opposite-sex chemosensory cues has been reported previously [8, 32], the specific neural circuit underlying the reproductive endocrine response remains poorly defined. Due to the recently revealed connectivity of MeA Kiss neurons with the AOB and GnRH neurons [14], we hypothesized that MeA Kiss neurons process sexually relevant olfactory stimuli to regulate reproductive neuroendocrine function.…”

“…Surprisingly, the large CNO-mediated induction of LH release was not accompanied by increased c-Fos-ir in GnRH neurons despite ∼40% of the MeA Kiss neurons being activated. Previous studies in male mice have also failed to detect pheromone-induced c-Fos-ir in GnRH neurons accompanying LH rises [3] or after increased neuronal activation in the amygdala [8]. Previous research has shown that GnRH neurons in mice extend long dendritic projections to the median eminence and receive synaptic input along their length.…”

“…MeA lesions advance puberty onset in rodents [5] and monkeys [6], but also disrupt sexual behaviours including the investigation and preference towards opposite-sex pheromones [7]. Exposure to opposite-sex pheromones leads to neuronal activation throughout the MeA [3, 8] and raised serum luteinizing hormone (LH) in male rodents [9, 10]. …”

Enhancement of the luteinising hormone surge by male olfactory signals is associated with anteroventral periventricular Kiss1 cell activation in female rats

“…proposed that kisspeptin could be a specific target of primer pheromones, allowing these pheromones to modulate the gonadotroph axis and GnRH activity. Recently, Taziaux and Bakker showed that intact male mice odour activated AVPV kisspeptin neurones in OVX+E 2 female mice. We therefore hypothesised that AVPV and/or ARC kisspeptin neurones are a target of olfactory signals derived from male or female rats to regulate LH secretion in female rats.…”