Abstract
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.FUNDING. NIHR, MRC, and Wellcome Trust.
Highlights
Mammalian reproductive physiology encompasses crucial links between reproductive hormones, brain functions, and behavior, in order to produce and coordinate a complex collection of reproductive functions
We examined the effects of kisspeptin on resting networks defined using specific a priori limbic and paralimbic seed regions, as well as the 3 major functionally connected large-scale resting networks: the default mode network (DMN), which is associated with social and emotional internal processing, and is disrupted in psychosexual dysfunction [19, 24]; the executive control network (ECN), which activates on task performance [24]; and the salience network (SN), which selects stimuli that are deserving of our attention [19]
Kisspeptin did not have a global effect on DMN, ECN, or SN connectivity
Summary
Mammalian reproductive physiology encompasses crucial links between reproductive hormones, brain functions, and behavior, in order to produce and coordinate a complex collection of reproductive functions. The reproductive hormone kisspeptin (encoded by the KISS1 gene), has recently been identified as the master regulator of the reproductive axis, with emerging roles in sexual and emotional behavior [1,2,3,4,5,6] To this end, kisspeptin and its cognate receptor (encoded by the KISS1R gene) are expressed in key emotional structures of the limbic system in both rodents [7,8,9,10,11] and humans [12,13,14]. The effects of kisspeptin on resting brain networks and connections between these structures, and how this may influence subsequent responses to sexual and emotional stimuli is currently unknown. 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
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