Gonadal and nongonadal regulation of sex differences in hypothalamic Kiss1 neurones

Abstract

The brains of males and females differ anatomically and physiologically, including sex differences in neurone size or number, synapse morphology and specific patterns of gene expression. Brain sex differences may underlie critical sex differences in physiology or behaviour, including several aspects of reproduction, such as the timing of sexual maturation (earlier in females than males) and the ability to generate a preovulatory gonadotrophin surge (in females only). The reproductive axis is controlled by afferent pathways that converge upon forebrain gonadotrophin-releasing hormone (GnRH) neurones, but GnRH neurones are not sexually dimorphic. Although most reproductive sex differences probably reflect sex differences in the upstream circuits and factors that regulate GnRH secretion, the key sexually-dimorphic factors that influence reproductive status have remained poorly defined. The recently-identified neuropeptide kisspeptin, encoded by the Kiss1 gene, is an important regulator of GnRH secretion, and Kiss1 neurones in rodents are sexually dimorphic in specific hypothalamic populations, including the anteroventral periventricular nucleus-periventricular nucleus continuum (AVPV/PeN) and the arcuate nucleus (ARC). In the adult AVPV/PeN, Kiss1 neurones are more abundant in females than males, representing a sex difference that is regulated by oestradiol signalling during critical periods of postnatal and pubertal development. By contrast, Kiss1 neurones in the ARC are not sexually differentiated in adult rodents but, in mice, the regulation of ARC Kiss1 cells by gonadal hormone-independent factors is sexually dimorphic during prepubertal development. These various sex differences in hypothalamic Kiss1 neurones may relate to known sex differences in reproductive physiology, such as puberty onset and positive feedback.

Figure 1

Sexually dimorphic Kiss1 gene expression in the AVPV/PeN of adult male and female mice. Females have significantly more Kiss1 neurons and Kiss1 mRNA/neuron in the AVPV/PeN than do males, regardless of the adulthood sex steroid milieu. (3V = 3^rd ventricle) [For pictures of similar AVPV/PeN sex differences at the protein level, refer to articles by Clarkson and Herbison, 2006 and Adachi et al, 2007.]

Figure 2

Kiss1 expression in the ARC is not sexually dimorphic in adult rodents. Adult male and female mice exhibit similar numbers of Kiss1 neurons in the ARC in both intact and gonadectomized conditions. (3V = 3^rd ventricle; OVX = ovariectomized; cast= castrated)

Figure 3

Intact prepubertal male and female mice exhibit similar numbers of Kiss1 neurons in the ARC. However, gonadectomized prepubertal females have higher ARC Kiss1 expression than similarly-aged gonadectomized males. The absence of elevated Kiss1 expression in gonadectomized prepubertal males suggests that some non-gonadal factor(s) acts to suppress the ARC Kiss1 system in males at this developmental stage. (3V = 3^rd ventricle; OVX = ovariectomized; cast= castrated)