Kisspeptin fiber and receptor distribution analysis suggests its potential role in central sensorial processing and behavioral state control

Background Kisspeptin (KP) signaling in the brain is defined by the anatomical distribution of KP-producing neurons, their fibers, receptors, and connectivity. Technological advances have prompted a re-evaluation of these chemoanatomical aspects, originally studied in the early years after the discovery of KP and its receptor Kiss1r. We have previously characterized(1) seven KP neuronal populations in the mouse brain at the mRNA level, including two novel populations, and examined their short-term response to gonadectomy. Methods In this study, we mapped KP fiber distribution in rats and mice using immunohistochemistry under intact and short- and long-term post-gonadectomy conditions. Kiss1r mRNA expression was examined via RNAscope, in relation to vesicular GABA transporter ( Slc32a1 ) in whole mouse brain and to KP and vesicular glutamate transporter 2 ( Kiss1 and Slc17a6 ) in hypothalamic RP3V and arcuate regions. Results We identified KP fibers in 118 brain regions, primarily in extra-hypothalamic areas associated with sensorial processing and behavioral state control. KP-immunoreactive fiber density and distribution were largely unchanged by gonadectomy. Kiss1r was expressed prominently in sensorial and state control regions such as septal nuclei, the suprachiasmatic nucleus, locus coeruleus, hippocampal layers, thalamic nuclei, and cerebellar structures. Co-expression of Kiss1r and Kiss1 was observed in hypothalamic neurons, suggesting both autocrine and paracrine KP signaling mechanisms. Conclusion These findings enhance our understanding of KP signaling beyond reproductive functions, particularly in sensorial and behavioral state regulation. This study opens new avenues for investigating KP’s role in controlling complex physiological processes, including those not related to reproduction.