Investigating Kisspeptin Signalling in Sexual and Emotional Brain Processing

研究性和情绪大脑处理中的 Kisspeptin 信号传导

• 批准号: MR/T006242/1
• 负责人: Edouard Mills
• 金额: $ 35.72万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT006242%2F1
• 关键词: Investigating; Kisspeptin; Signalling; Sexual; Emotional

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.

性欲减退症（HSDD）的特征是缺乏或不存在性幻想和对性活动的渴望。研究估计，在英国，HSDD影响17-40%的男性和女性，使其成为最普遍的性健康投诉之一。它可能导致毁灭性的痛苦和对一个人的身心健康的影响，并与不孕症和人际关系困难建立联系。然而，尽管它的显着负担，医学和心理治疗只显示出适度的好处，表明需要更好地了解潜在的性和情感的大脑活动在HSDD，以帮助开发更有效的治疗.Kisspeptin是一种天然存在的激素，主要是由大脑的一个区域称为下丘脑产生.然而，除了下丘脑，kisspeptin也存在于边缘系统的区域-大脑中参与行为和情绪反应的部分-包括杏仁核。对啮齿动物的研究表明，kisspeptin在控制重要的生殖行为中起着关键作用，包括性伴侣偏好和性唤起。此外，我提议的实验室最近的研究利用新型成像技术功能性核磁共振成像（fMRI）来测量和绘制任务期间的大脑活动，表明将kisspeptin注入健康男性的血液会导致与性相关的区域的大脑活动增加观看色情图像时的性唤起。此外，我已经生成了初步的试验数据，显示在健康男性中，在观察女性面孔的同时注入kisspeptin也会增加与评估面部吸引力有关的大脑区域的活动，包括内侧前额叶皮层。综上所述，这些发现为研究患有HSDD的患者的kisspeptin通路提供了科学依据。鉴于这还有待研究，它将构成我拟议的博士奖学金的基础。我将接受该领域专家的培训和监督，以完成我提出的实验。在第一部分中，我设计了一项功能磁共振成像研究，使用任务来确定将kisspeptin注入血液如何影响患有HSDD的男性的大脑激活。这些任务将包括观看色情图像和女性面孔，再加上生理参数和心理测量问卷，以便为大脑活动结果提供功能意义。这项研究将使我能够确定kisspeptin对患有HSDD的男性的性和情感大脑活动的影响，包括性唤起和视觉吸引力。此外，为了了解kisspeptin如何影响大脑反应并提供关键的机制见解，重要的是要探索kisspeptin在特定边缘脑区域对性行为的影响。为了研究这一点，我提议的第二个宿主实验室以前利用专门的技术激活活雄性小鼠的kisspeptin神经元，证明了提高性伴侣偏好的潜力。因此，在博士研究的第二部分，我将接受专业培训和教学，在成年雄性小鼠中使用和优化这项技术，以激活和失活关键边缘脑区域中感兴趣的特定kisspeptin神经元群体，并观察其对性行为的影响。为此，这两个实验的结果将为哺乳动物性功能和功能障碍提供新的见解。总体目标是研究kisspeptin在HSDD和性行为中的神经内分泌学，最终为kisspeptin作为未来治疗方法的使用提供进一步的证据，以解决与HSDD相关的重大负担。

项目成果

Bone Perspectives in Functional Hypothalamic Amenorrhoea: An Update and Future Avenues.

• DOI: 10.3389/fendo.2022.923791
• 发表时间: 2022
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2

Endocrine Responses to Triptorelin in Healthy Women, Women With Polycystic Ovary Syndrome, and Women With Hypothalamic Amenorrhea.

• DOI: 10.1210/clinem/dgad026
• 发表时间: 2023-06-16
• 期刊: The Journal of clinical endocrinology and metabolism
• 作者: Abbara A;Phylactou M;Eng PC;Clarke SA;Pham TD;Ho TM;Ng KY;Mills EG;Purugganan K;Hunjan T;Salim R;Comninos AN;Vuong LN;Dhillo WS
• 通讯作者: Dhillo WS

Letter to the editor of clinical endocrinology: Assessment of adrenal function in patients who survive COVID-19.

致临床内分泌学编辑的信：评估 COVID-19 存活患者的肾上腺功能。

• DOI: 10.1111/cen.14816
• 发表时间: 2023
• 期刊: Clinical endocrinology
• 影响因子: 3.2
• 作者: Clarke SA

Performance of plasma kisspeptin as a biomarker for miscarriage improves with gestational age during the first trimester.

• DOI: 10.1016/j.fertnstert.2021.04.031
• 发表时间: 2021-09
• 期刊: Fertility and sterility
• 影响因子: 6.7
• 作者: Abbara A;Al-Memar M;Phylactou M;Kyriacou C;Eng PC;Nadir R;Izzi-Engbeaya C;Clarke SA;Mills EG;Daniels E;Huo L;Pacuszka E;Yang L;Patel B;Tan T;Bech P;Comninos AN;Fourie H;Kelsey TW;Bourne T;Dhillo WS
• 通讯作者: Dhillo WS

Quantifying the variability in the assessment of reproductive hormone levels.

量化生殖激素水平评估的变异性。

• DOI: 10.1016/j.fertnstert.2023.11.010
• 发表时间: 2023
• 期刊: Fertility and sterility
• 影响因子: 6.7
• 作者: Abbara A