BACKGROUND. Resting brain connectivity is a crucial component of human behavior demonstrated by disruptions in psychosexual and emotional disorders. Kisspeptin, a recently identified critical reproductive hormone, can alter activity in certain brain structures but its effects on resting brain connectivity and networks in humans remain elusive.

METHODS. We determined the effects of kisspeptin on resting brain connectivity (using functional neuroimaging) and behavior (using psychometric analyses) in healthy men, in a randomized double-blinded 2-way placebo-controlled study.

RESULTS. Kisspeptin’s modulation of the default mode network (DMN) correlated with increased limbic activity in response to sexual stimuli (globus pallidus r= 0.500, P= 0.005; cingulate r= 0.475, P= 0.009). Furthermore, kisspeptin’s DMN modulation was greater in men with less reward drive (r=–0.489, P= 0.008) and predicted reduced sexual aversion (r=–0.499, P= 0.006), providing key functional significance. Kisspeptin also enhanced key mood connections including between the amygdala-cingulate, hippocampus-cingulate, and hippocampus–globus pallidus (all P< 0.05). Consistent with this, kisspeptin’s enhancement of hippocampus–globus pallidus connectivity predicted increased responses to negative stimuli in limbic structures (including the thalamus and cingulate [all P< 0.01]).

CONCLUSION. Taken together, our data demonstrate a previously unknown role for kisspeptin in the modulation of functional brain connectivity and networks, integrating these with reproductive hormones and behaviors. Our findings that kisspeptin modulates resting brain connectivity to enhance sexual and emotional processing and decrease sexual aversion, provide foundation for kisspeptin-based therapies for associated disorders of body and mind.