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

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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.