Effects of peripubertal pharmacological blockade of GnRH action on neuronal function and architecture.

人们早就认识到荷尔蒙对我们的思维和行为有深远的影响。现代成像研究表明，激素对大脑的结构和功能都有依赖作用，这或许可以解释激素对人类和动物行为的影响。虽然这些激素引起的差异可能在生命的早期就开始了，包括在出生前，但也有人认为，青春期生殖激素的变化可能会导致大脑结构及其细胞的改变，这可能会导致我们成年后社会行为和处理信息方式的差异。因此，青春期激素模式的任何变化（无论是自然的还是由于医疗干预或暴露于环境中的化学物质）都可能影响正常的大脑发育。在这方面，值得注意的是，人类和动物在经历青春期的转变时，行为会发生一些已知的变化，比如冒险的增加，以及与大脑功能改变相关的各种临床状况，比如精神分裂症、饮食失调和强迫症，这些通常在青春期变得明显。该项目将以绵羊为动物模型，梳理生殖激素变化对男性大脑发育的影响，以及青春期周围是否代表正常大脑发育的关键时期。这将通过使用一种药物来阻止雄性绵羊的青春期过渡来实现，这种药物目前用于阻止患有各种疾病的人类患者的青春期，包括生长迟缓和早发性性别认同障碍。我们将通过推迟青春期或区分GnRH（一种在大脑中产生的驱动生殖系统活动的激素）和性腺类固醇的作用来实现这一目标，通过替代动物体内的睾丸激素，这些动物的生殖轴活动因阻止GnRH的作用而停止。这项工作具有重要意义，因为青春期的医学封锁被广泛用于治疗人类医学上的各种疾病，包括生长缺陷和性别焦虑症。如果生殖激素在青春期的变化确实在青少年大脑的成熟中起着至关重要的作用，那么接受这种治疗的患者的认知和/或生殖功能可能会受到永久性的影响。这项工作也有可能告诉我们，随着年龄的增长，认知功能会发生变化，这可能会增加患阿尔茨海默病等疾病的风险，因为随着生殖功能的下降，体内的生殖激素水平也会发生变化。该项目将有助于对内分泌因子和生殖系统内与激活和衰老相关的神经变化之间相互作用的基本机制的理解。实现这些目标可以指导可用于治疗神经认知疾病的干预策略，这些疾病的发病率/风险在青春期增加，如强迫症和精神分裂症，以及随着年龄的增长，如阿尔茨海默病。

It has long been recognised that hormones have a profound effect on how we think and behave. Modern imaging studies have shown that there are hormone dependent effects on both the structure and functioning of the brain, which might explain these effects of hormones on behaviour in both humans and animals. While some of these hormone induced differences may start very early in life, including prior to birth, it has also been suggested that the changes in reproductive hormones at puberty may lead to alterations in the structure of the brain and its cells that could be responsible for differences in social behaviour and the way we process information as adults. Consequently, any changes in the pattern of hormones experienced at puberty (either naturally or as a result of medical interventions or exposure to chemicals in our environment) may affect normal brain development. In this regard, it is worthy of note that there are known changes in behaviour as humans and animals go through the pubertal transition, such as increased risk taking and there are a variety of clinical conditions associated with altered brain function such as schizophrenia, eating- and obsessive compulsive-disorders, which often become apparent at puberty. Using the sheep as an animal model, this project will tease apart the effects of changes in reproductive hormones on male brain development and whether the peripubertal period represents a critical period of normal brain development. This will be done by blocking the pubertal transition in male sheep using a drug treatment currently used to block puberty in human patients for a variety of medical conditions including growth retardation and early onset gender identity disorder. We will do this by either delaying puberty or differentiating the effects of GnRH (a hormone produced in the brain that drives activity within the reproductive system) and gonadal steroids, by replacing testosterone in animals in which activity within the reproductive axis was stopped by blocking the effects of GnRH. This work is of significance as the medical blockade of puberty is widely used in the treatment of a variety of conditions in human medicine, including growth deficiency and gender dysphoria. If the pubertal changes in reproductive hormones indeed play a crucial role in the maturation of the adolescent brain, the cognitive and/or reproductive functions of patients receiving this treatment may be permanently affected. This work also has the potential to inform us about changes in cognitive function that occur as we age and may contribute to the risk of developing conditions such as Alzheimer's disease, as these changes also occur when the levels of reproductive hormones in the body change as reproductive function declines. This project will contribute to a fundamental understanding of the mechanisms that underlie the interaction between endocrine factors and the neural changes that occur in association with activation and senescence within the reproductive system. Achieving these objectives may direct intervention strategies that can be used in the treatment of neurocognitive conditions, the incidence/risk of which increases at puberty, such as obsessive compulsive disorder and schizophrenia and with ageing e.g. Alzheimer's disease.