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方式和行为方式有着深远的影响。现代成像研究表明，荷尔蒙对大脑的结构和功能都有依赖作用，这可能解释了荷尔蒙对人类和动物行为的影响。虽然其中一些荷尔蒙引起的差异可能在生命早期就开始了，包括在出生之前，但也有研究表明，青春期生殖荷尔蒙的变化可能会导致大脑及其细胞结构的变化，这可能是导致社会行为和成年后我们处理信息的方式差异的原因。因此，青春期经历的荷尔蒙模式的任何变化(无论是自然的还是由于药物干预或暴露在我们环境中的化学物质的结果)都可能影响正常的大脑发育。在这方面，值得注意的是，随着人类和动物经历青春期转变，行为发生了已知的变化，例如冒险增加，以及与大脑功能改变相关的各种临床情况，如精神分裂症、进食和强迫症，这些通常在青春期表现出来。以绵羊为动物模型，该项目将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。这将通过阻断雄性绵羊的青春期过渡来实现，目前一种药物疗法用于阻止人类患者的青春期，这些患者患有各种医疗疾病，包括生长迟缓和早发性性别认同障碍。我们将通过延缓青春期或区分GnRH(一种在大脑中产生的推动生殖系统活动的激素)和性腺类固醇的影响，通过在生殖轴内的活动被阻断GnRH的影响而停止的动物中替换睾丸素来做到这一点。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中的各种疾病，包括生长缺陷和性别焦虑症。如果青春期生殖激素的变化确实对青春期大脑的成熟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。这项工作还有可能让我们了解随着年龄的增长而发生的认知功能的变化，并可能导致阿尔茨海默病等疾病的风险，因为当生殖功能下降时，体内生殖激素水平也会发生变化。该项目将有助于从根本上理解内分泌因素与与生殖系统内的激活和衰老相关的神经变化之间相互作用的机制。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，这种疾病的发病率/风险在青春期增加，如强迫症和精神分裂症，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.