Kisspeptin modulates sex-like phenotypes in the neonatal period

In recent years, our understanding of the physiological role of kisspeptin (Kiss1) has evolved significantly, revealing its pivotal role in shaping sexual differentiation within the brain. Predominantly expressed in the hypothalamus, Kiss1 plays a crucial role in regulating release of the gonadotrophin-releasing hormone (GnRH). Kisspeptin 1 receptor (Kiss1R) exhibits sex-dependent expression in various brain regions, including the medial amygdala and preoptic area (POA) of the hypothalamus, regions underlying sexual development. Importantly, in the critical period for the sexual development in mammals occurs a synchronized surge of Kiss1 and testosterone, highlighting its importance in sexual dimorphism. It has been suggested that the neonatal Kiss1 surge is associated with the buildup of gender-linked social development. We investigated this hypothesis by testing the effect of neonatal blockage of Kiss1 signaling on the sex-like phenotype in rats. We postulate that Kiss1 actions are both time and region-dependent, particularly during the neonatal period, having lasting impact on social interactions. For that we injected intracerebroventricular (ICV) a Kiss1R antagonist, Kp234, in the first 24h of life. Our data showed, that neonatal Kiss1 is determinant in modulating physiological responses, such as weight and testis development in males (N: males Veh = 10; males Kp234 = 10). Also, we document, for the first time, that Kiss1 modulates the testosterone surge in males and inhibits it in females (N: males Vehicle = 3; males Kp234 = 4; females Vehicle = 3; females Kp234 = 4). Furthermore, neonatal Kiss1 blockade modulated the sexual drive in, while the sexual performance in both sexes is maintained males (N: males Vehicle = 8; males Kp234 = 9; females Vehicle = 7; females Kp234 = 8). In conclusion, this study underscores the significance of Kiss1 during the neonatal period, a critical phase for sexual differentiation and neuroplasticity. Neonatal Kiss1 emerges as a key player in the development of a sex-like phenotype in rats. Additionally, our findings show dimorphic patterns in Kiss1 influence. This work raises the intriguing possibility that the early influence of Kiss1 in brain circuitry is pivotal in the modulation of gender and plays a role in the social construction of the bimodality of gender identity.