Investigating Kisspeptin Signalling in Sexual and Emotional Brain Processing

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Hypoactive Sexual Desire Disorder (HSDD) is characterised by a lack or absence of sexual fantasies and desire for sexual activity. Studies estimate that in the UK HSDD affects 17-40% of men and women, making it one of the most prevalent sexual health complaints. It can result in devastating distress and effects on a person's physical and mental wellbeing with established links to infertility and interpersonal difficulties. However, despite its significant burden, medical and psychological treatments have shown only modest benefit, indicating a need to better understand the underlying sexual and emotional brain activity in HSDD in order to help develop more effective treatments.Kisspeptin is a naturally occurring hormone which is predominantly produced by a region of the brain called the hypothalamus. However, beyond the hypothalamus, kisspeptin is also found in areas of the limbic system - the part of the brain involved in behavioural and emotional responses - including the amygdala. Research in rodents has revealed that kisspeptin plays a key role in controlling important reproductive behaviours, including sexual partner preference and sexual arousal. Furthermore, recent research from my proposed laboratory has utilised the novel imaging technique functional MRI (fMRI) to measure and map the brains activity during tasks, demonstrating that an infusion of kisspeptin into the bloodstream of healthy men results in increased brain activity in regions linked to sexual arousal whilst viewing erotic images. Furthermore, I have generated preliminary pilot data revealing that in healthy men an infusion of kisspeptin whilst observing female faces also increases activity in brain regions involved in assessing facial attractiveness, including the medial prefrontal cortex. Taken together, these findings provide the scientific basis to investigate the kisspeptin pathway in patients suffering from HSDD. Given that this has yet to be studied, it will form the basis of my proposed PhD fellowship. I will receive training and supervision from specialists in the field to complete my proposed experiments. In the first part, I have designed an fMRI study using tasks to determine how an infusion of kisspeptin into the bloodstream affects brain activation in men with HSDD. These tasks will include viewing erotic images and female faces, coupled with physiological parameters and psychometric questionnaires in to order to provide functional significance for the brain activity results. This study will allow me to establish the effects of kisspeptin on sexual and emotional brain activity in men with HSDD, encompassing sexual arousal and visual attraction.Furthermore, to understand how kisspeptin affects brain responses and provide key mechanistic insights, it is important to explore the effects of kisspeptin in specific limbic brain regions on sexual behaviour. To investigate this, my proposed second host laboratory have previously utilised specialised techniques to activate kisspeptin neurones in living male mice, demonstrating the potential to heighten sexual partner preference. Therefore, for the second part of this PhD Fellowship, I will receive specialist training and teaching to use and optimise this technology in adult male mice to activate and also deactivate specific kisspeptin neuronal populations of interest in key limbic brain regions and observe the resultant effects on sexual behaviour.To this end, the findings from these two experiments will provide a new insight into mammalian sexual function and dysfunction. The overall aim is to investigate kisspeptin neuroendocrinology in HSDD and sexual behaviours, to ultimately provide further evidence for the use of kisspeptin as a future treatment to address the significant burden related to HSDD.