Background/Aims: The medial amygdala (MeA) responds to olfactory stimuli and alters reproductive physiology. However, the neuronal circuit that relays signals from the MeA to the reproductive axis remains poorly defined. This study aimed to test whether MeA kisspeptin (MeA^Kiss) neurons in male mice are sensitive to sexually relevant olfactory stimuli and transmit signals to alter reproductive physiology. We also investigated whether MeA^Kiss neurons have the capacity to elaborate glutamate and GABA neurotransmitters and potentially contribute to reproductive axis regulation. Methods: Using female urine as a pheromone stimulus, MeA^Kiss neuronal activity was analysed and serum luteinizing hormone (LH) was measured in male mice. Next, using a chemogenetic approach, MeA^Kiss neurons were bi-directionally modulated to measure the effect on serum LH and evaluate the activation of the preoptic area. Lastly, using in situ hybridization, we identified the proportion of MeA^Kiss neurons that express markers for GABAergic (Vgat) and glutamatergic (Vglut2) neurotransmission. Results: Male mice exposed to female urine showed a two-fold increase in the number of c-Fos-positive MeA^Kiss neurons concomitant with raised LH. Chemogenetic activation of MeA^Kiss neurons significantly increased LH in the absence of urine exposure, whereas inhibition of MeA^Kiss neurons did not alter LH. In situ hybridization revealed that MeA^Kiss neurons are a mixed neuronal population in which 71% express Vgat mRNA, 29% express Vglut2 mRNA, and 6% express both. Conclusions: Our results uncover, for the first time, that MeA^Kiss neurons process sexually relevant olfactory signals to influence reproductive hormone levels in male mice, likely through a complex interplay of neuropeptide and neurotransmitter signalling.

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