Investigating how the novel hormone kisspeptin modulates sexual and emotional brain processing in response to odour cues.

Psychosexual dysfunction is caused by problems with sexual functioning due to a psychological rather than a physical problem. It involves several disorders (including impotence and reduced sexual desire) that collectively affect 1 in 3 people. There are severe consequences for individuals and their partners, impairing quality of life and interpersonal relationships as well as reducing chances for successful conception. In the UK the cost of treating psychosexual disorders with medical and psychological therapy is estimated at £32 million/year. Current medical treatments are limited by side-effects such as increased heart disease and cancer risk, and engagement with psychological therapies continues to be poor. Therefore, there is an unmet need to understand human sexual brain processing to help develop safer and more effective treatments.

The limbic system is an area of the brain known to control emotions and instincts, including those related to sexual desire and reproductive behaviours. The limbic system interacts with several other brain centres including those involved in reproduction and interestingly, it also connects with brain areas that process smells. Smell underpins many important mating behaviours through the action of pheromones. Pheromones are chemicals that are released into the air and cause specific behaviours when smelled by an individual. There is growing evidence that pheromones affect human behaviour, for example men who smell t-shirts worn by women in their fertile phase, find that smell more sexually appealing compared to the smell of t-shirts from women who are not in their fertile phase.

Kisspeptin is a hormone that reduces sexual aversion and negative mood when given to healthy men with specific brain changes seen on functional magnetic resonance imaging (fMRI). Recent work shows nerve fibres that contain kisspeptin make connections between the olfactory bulb (brain area processing smell), the limbic system and hypothalamus (a gland producing reproductive hormones). In animals, kisspeptin is closely linked with smell and mating e.g. when male mice lose their kisspeptin receptors, they also lose the ability to preferentially sniff out a female partner. Also, when female rats smell a male rat, they show increased kisspeptin activity in their brains. At present this relationship between kisspeptin, smell and sexual behaviour has not been explored in humans.

I have designed an fMRI experiment using fragrance and pheromone smells to determine how kisspeptin affects brain response when these smells are presented to healthy men. Working alongside experts in this field, I have already collected pilot data which shows that smelling sexually arousing female fragrance activates limbic brain areas in healthy men. My preliminary work is very promising and demonstrates the imaging techniques I propose to use can detect activation in the brain areas of interest when smelling a female fragrance. To understand how kisspeptin in the bloodstream is able to carry out its actions on these brain areas, it is important to establish how kisspeptin gets across the blood-brain barrier into the brain. To do this, my laboratory has generated pilot data in a small group of mice showing that kisspeptin in the bloodstream builds up in the brain over time, which suggests that kisspeptin does cross the blood-brain barrier. I will now use specialised techniques to identify how kisspeptin moves across the blood-brain barrier. This will be beneficial for the development of kisspeptin-related treatments that can reach the brain in different ways. The overall aim is to use my results to help develop safer and more effective therapies for psychosexual disorders.

Psychosexual dysfunction affects 1 in 3 individuals and costs the NHS over £32 million/year. The novel hormone kisspeptin is a crucial activator of the reproductive axis and is also expressed in the limbic system where its role is largely unknown. Recent work shows kisspeptin signalling in the amygdala modulates reproductive hormones in rodents and visual-evoked sexual brain processing in healthy men. This suggests the presence of a kisspeptin-mediated psycho-neuroendocrine framework uniting sexual and emotional brain processing with reproduction. In this way, kisspeptin may modulate psychosexual function. Olfaction underpins many mating behaviours through the actions of odours that elicit specific behaviours in animals and humans. Recent data in rodents show kisspeptin neurons interconnect the olfactory bulb, amygdala and hypothalamus. The functional relevance of these connections is demonstrated by loss of olfactory-mediated partner preference in kisspeptin receptor knock-out male mice. However kisspeptin's role as a hormonal regulator between olfactory-limbic-reproductive (OLR) brain structures has not been examined in humans. My pilot fMRI data shows limbic brain areas activated in men by female fragrance odour correspond to areas enhanced by kisspeptin. This suggests kisspeptin and olfaction modulate similar limbic pathways in humans. I propose to use advanced fMRI techniques coupled with olfactory, facial perception and psychometric tasks to determine how kisspeptin mediates OLR brain activity and associated behaviours in humans. Additionally, I will perform in vivo animal experiments to identify how kisspeptin crosses the blood-brain barrier to mediate these effects. Collectively, this project will determine how kisspeptin accesses the brain to modulate sexual and emotional brain processing in response to olfactory cues and answer key questions regarding kisspeptin BBB transport for the development of kisspeptin as a treatment for psychosexual disorders.

This research will benefit several groups both directly and indirectly. The project will determine the mechanisms by which kisspeptin mediates sexual and emotional brain processing in response to odour cues and investigate how peripheral kisspeptin crosses the blood-brain barrier to facilitate these effects.

The benefit to the general public, particularly patients and their partners, is central to the aims of this project. The results of my work have the potential to identify novel therapeutic avenues for kisspeptin in the treatment of psychosexual disorders, which currently affects 1 in 3 people. Following the completion of my project, I envisage that it will take approximately 4-7 years to benefit patients directly (allowing time for clinical trials etc.).

Psychosexual disorders have a significant economic cost including treatment and lost productivity of over £32 million/year. Determining the neuroendocrine pathways involved in psychosexual dysfunction will allow the design of safer and more effective therapies that can have a major economic impact. This work will be of direct benefit to pharmaceutical companies who are currently developing kisspeptin for therapeutic use in common reproductive disorders but as yet not for psychosexual disorders. Some of the benefit to the pharmaceutical industry will be immediate as phase 2 clinical trials using kisspeptin compounds for common reproductive disorders are already underway.

The Department of Investigative Medicine has a strong commitment to public engagement with science and has a track record of drawing public attention to its scientific findings. In addition to publication in peer reviewed journals, I intend to publicise my results via several media streams and organise presentations on my findings through the following schemes facilitated by my department:-

- The Imperial College Outreach scheme, which organises popular science education events for pre-university students, their teachers and their parents or guardians, introducing them to the science of Endocrinology and discussing the Department's latest discoveries.

- The Dana Centre is an organisation designed as a forum to promote public awareness of science. It facilitates non-scientists to take part in exciting, informative and innovative debates about contemporary science, technology and culture.

The Department of Investigative Medicine already has an excellent record for maximising the impact and benefit of its research. The first study administering kisspeptin to humans was carried out in my host laboratory in 2005 and it has since become a world-leading centre for advancing research in the field. This has included pioneering the successful use of kisspeptin as an ovulation trigger for in vitro fertilisation, which has resulted in considerable interest from patients, academia and industry.