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

性心理功能障碍是由于心理问题而不是生理问题导致的性功能问题。它涉及几种疾病(包括阳萎和性欲下降)，总共影响三分之一的人。这会给个人和他们的伴侣带来严重的后果，损害生活质量和人际关系，并减少成功受孕的机会。在英国，通过医疗和心理治疗治疗精神性障碍的费用估计为3200万英镑/年。目前的医疗治疗受到诸如增加心脏病和癌症风险等副作用的限制，而且心理治疗的参与度仍然很低。因此，了解人类性脑过程的需求尚未得到满足，以帮助开发更安全、更有效的治疗方法。边缘系统是大脑中控制情绪和本能的区域，包括与性欲和生殖行为相关的情绪和本能。边缘系统与其他几个大脑中心相互作用，包括那些参与生殖的中心，有趣的是，它还与处理气味的大脑区域联系。气味通过信息素的作用支撑着许多重要的交配行为。信息素是一种化学物质，会被释放到空气中，当个体闻到时会导致特定的行为。越来越多的证据表明，信息素影响人类行为，例如，男性闻到女性在生育期穿的t恤的气味，会发现与非生育期女性t恤的气味相比，这种气味更具性吸引力。Kispeptin是一种激素，当给健康男性服用时，它可以减少性厌恶和负面情绪，功能磁共振成像(FMRI)显示出特定的大脑变化。最近的研究表明，含有Kispeptin的神经纤维在嗅球(大脑处理气味的区域)、边缘系统和下丘脑(产生生殖激素的腺体)之间建立联系。在动物中，Kispeptin与嗅觉和交配密切相关，例如，当雄性小鼠失去Kispeptin受体时，它们也失去了优先嗅到雌性伴侣的能力。此外，当雌性大鼠闻到雄性大鼠的气味时，它们的大脑中Kispeptin活性增加。目前，Kispeptin、气味和性行为之间的这种关系还没有在人类身上得到探索。我设计了一项使用香水和信息素气味的功能磁共振实验，以确定当这些气味呈现给健康男性时，Kispeptin如何影响大脑反应。与这一领域的专家一起工作，我已经收集了试点数据，表明闻到女性气味会激活健康男性的边缘大脑区域。我的初步工作是非常有希望的，并证明了我建议使用的成像技术可以在闻到女性香水时检测到大脑感兴趣区域的激活。为了了解血流中的Kispeptin是如何在这些大脑区域发挥作用的，重要的是要确定Kispeptin是如何穿过血脑屏障进入大脑的。为了做到这一点，我的实验室在一小群小鼠身上产生了试点数据，表明随着时间的推移，血液中的Kispeptin在大脑中积聚，这表明Kispeptin确实跨越了血脑屏障。我现在将使用专门的技术来确定Kispeptin是如何跨越血脑屏障的。这将有利于开发与Kispeptin相关的治疗方法，这些治疗方法可以通过不同的方式到达大脑。总体目标是利用我的结果帮助开发更安全、更有效的性心理障碍治疗方法。

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.