SUN-088 Sexual Dimorphism and Social Behavioral Role of Lateral Septal Kisspeptin Neurons in Male Mice

Abstract Disclosure: S.T. Zdon: None. M.S. Silva: None. V.M. Navarro: None. Kisspeptin (Kiss1) neurons are crucial regulators of the hypothalamic-pituitary-gonadal axis (HPG), making them essential for reproductive function. While primarily located in the hypothalamus where they control gonadotropin-releasing hormone (GnRH) secretion, additional Kiss1 neurons are found in areas outside of the hypothalamus, particularly in limbic areas, such as the lateral septum (LS). The LS, comprising ventral (VLS) and intermediate (ILS) divisions, integrates social, feeding, anxiety, and fear behaviors, and Kiss1 neurons in this region are regulated by sex steroids. However, the sexual dimorphism and behavioral functions of Kiss1LS neurons remain unknown. Using Kiss1cre mice expressing tdTomato specifically in Kiss1 neurons (Kiss1-tdTomato), we characterized Kiss1LS neuron distribution in both male and female mice and explored the functional relevance of these neurons in various social behaviors in male mice. Quantitative analysis revealed a marked sexual dimorphism, with females showing significantly more Kiss1ILS compared to males (Male: 7.00 ± 2.864 vs. Female: 74.40 ± 17.68 neurons, **P = 0.0043). This sexual dimorphism was absent in Kiss1VLS neurons. Next, we investigated their functional relevance in various social behavioral tests through targeted manipulation of Kiss1VLS neurons in male mice. First, we ablated Kiss1VLS neurons using Cre-dependent Caspase-3 and observed significantly impaired social behaviors including reduced mounting attempts in sexual behavior, reduced sociability in the social preference test, and reduced anogenital sniffing time in the resident intruder test. Conversely, chemogenetic activation using hM3D increased sociability in the social preference test but reduced aggression behaviors in resident intruder test, and mounting attempts in sexual behavior. Notably, neither manipulation affected circulating luteinizing hormone concentrations, indicating independence from HPG axis regulation. These findings demonstrate a sexual dimorphic Kiss1LS population with a prominent role in male social behavior regulation, expanding our understanding of extra-hypothalamic Kiss1 neuron functions. Presentation: Sunday, July 13, 2025