Molecularly defined Kiss1RP3V neuronal subtypes as drivers of sexual and maternal behaviors

Sexually dimorphic social behaviors, such as male mating and female maternal care, are essential for reproductive success and are orchestrated by specialized hypothalamic circuits. Among these, neurons located in the rostral periventricular area of the third ventricle (RP3V), a profoundly sexually dimorphic region, play a pivotal role in coordinating neuroendocrine and behavioral responses to reproductive cues. Kisspeptin-expressing neurons within the RP3V (Kiss1RP3V) are known to regulate female reproductive physiology, yet their existence and functional relevance in males have long been underestimated. Our recent findings overturn this assumption by demonstrating that Kiss1RP3V neurons persist into adulthood in males, display distinct transcriptional signatures, and are functionally connected to the hypothalamic-pituitary-gonadal axis, where they can rapidly stimulate testosterone synthesis. These discoveries raise the possibility that Kiss1RP3V neurons contribute directly to male sexual behavior, a question that has yet to be addressed. Concurrently, dopaminergic neurons within this brain area have emerged as key regulators of sexually dimorphic behaviors. These neurons promote mating motivation in males and drive maternal care in females. Our data reveal that Kiss1RP3V neurons include multiple molecularly defined subsets, including dopaminergic populations shared by both sexes and a DAT-expressing dopaminergic subset found exclusively in females. This organization suggests that discrete Kiss1RP3V neuronal subtypes may serve as specialized substrates for sex-specific social behaviors, yet their molecular identities, functional roles, and circuit mechanisms remain unknown. The overarching goal of this project is to identify and mechanistically define the Kiss1RP3V neuronal subtypes that drive sexually dimorphic social behaviors in mice. We will combine single-cell transcriptomics, intersectional chemogenetics, and circuit-mapping approaches to uncover how these neuronal populations encode mating and maternal states, how their transcriptional programs differ across sexes and behavioral conditions, and through which downstream circuits they exert their effects. This integrated strategy will delineate the molecular and functional architecture of Kiss1RP3V neurons and reveal how dopaminergic and non-dopaminergic subtypes contribute to male mating behavior and female maternal care. Impacto científico técnico o internacional esperable: This proposal is expected to generate significant scientific and technical advances in the understanding of how hypothalamic circuits give rise to sexually dimorphic social behaviors. By defining the molecular heterogeneity of Kiss1RP3V neurons and identifying the specific subtypes that regulate male sexual and female maternal behavior, the project will provide the first comprehensive framework linking transcriptional diversity, neuronal identity, and behavioral function within a key neuroendocrine circuit. These insights will clarify long-standing questions regarding the organization and functional relevance of Kiss1RP3V neurons in both sexes, overturning previous assumptions about their limited role in males and revealing new mechanisms underlying female-specific maternal responses. Technically, the project will advance methodological capabilities in the field by integrating single-cell transcriptomics, intersectional chemogenetics, and projection-based circuit mapping to dissect small, molecularly defined neuronal populations with unprecedented resolution. This approach will establish versatile tools that can be applied broadly to other hypothalamic circuits involved in social, motivational, and reproductive behaviors. The knowledge generated will deepen our understanding of the principles by which sex-specific neuronal subtypes are selectively engaged by behavioral states, and influence downstream neuroendocrine pathways. This will have broad implications for the study of reproductive physiology and the neural basis of social behavior. The project will also provide conceptual foundations for biomedical research on sex differences in conditions in which hypothalamic and neuroendocrine circuits are disrupted, including disorders of fertility linked to impaired GnRH or kisspeptin signaling, postpartum alterations associated with dysregulated dopaminergic or oxytocin pathways, and motivational deficits arising from dysfunction in preoptic dopamine circuits. Overall, the proposal will make a substantial contribution to the scientific and technical knowledge within the thematic area of hypothalamic function, neuroendocrine regulation, and sexually dimorphic circuits, establishing a mechanistic framework that will guide future research in sex-specific social and reproductive behaviors.