Modulations of human resting brain connectivity by kisspeptin enhance sexual and emotional functions

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.

Dissociable effects of cannabis with and without cannabidiol on the human brain’s resting-state functional connectivity

“…Seed-based functional connectivity analyses were conducted using the general methodological approach previously used by Demetriou et al (2018) and (Comninos et al, 2018). Regions Of Interest (ROIs) were defined in the posterior cingulate cortex (PCC) and anterior insula (AI) as seed-regions (see supplementary figure S1).…”

Kisspeptin as a Behavioral Hormone

“…43 In a second fMRI analysis of healthy heterosexual men, peripheral administration of kisspeptin also modulated the default mode network, which correlated with enhanced limbic brain activity in response to sexual images. 44 Of functional significance, kisspeptin's modulation of this network was greater in men with less reward drive and correlated with reduced sexual aversion. 44 It is notable that kisspeptin also enhanced resting global connectivity between key limbic structures, including the amygdalacingulate and hippocampus-cingulate, 44 which are established connections governing emotions and bonding.…”

“…44 Of functional significance, kisspeptin's modulation of this network was greater in men with less reward drive and correlated with reduced sexual aversion. 44 It is notable that kisspeptin also enhanced resting global connectivity between key limbic structures, including the amygdalacingulate and hippocampus-cingulate, 44 which are established connections governing emotions and bonding. [45][46][47][48] Collectively, these data illustrate an important role for kisspeptin signaling in governing key copulatory behaviors and sexual motivation in male and female rodents (summarized in ►Fig.…”

The Roles of the Amygdala Kisspeptin System

“…In a second fMRI study of healthy heterosexual men, peripheral administration of kisspeptin enhanced resting global connectivity in the amygdala-cingulate network. 60 Crucially, this established network has important roles in controlling emotions and bonding. [61][62][63] It is salient to note that in both of these studies, kisspeptin administration had no effect on other relevant hormones (testosterone, oxytocin, and cortisol).…”