Hormonal Programming
Our goal is to understand the nature and origins of brain sex dimorphisms, which pervade many aspects of brain function, including those that are not directly associated with reproductive success.
This knowledge will shed light on sex differences that are manifest in major psychiatric and neurodegenerative conditions. It will also highlight important new opportunities for developing urgently needed improvements to sex-specific treatments for debilitating conditions that affect men and women in different ways.
We are investigating urgently needed improvements to sex-specific treatments for debilitating conditions"
Emeritus Professor Glenda Gillies
Our research centres on the ability of sex and stress hormones to sculpt brain structure and function, and to modify disease susceptibility. In all mammalian species studied, including humans, gonadal sex steroid hormones are largely responsible for ‘hard-wiring’ brain sex differences during mid-late gestation and the neonatal period, and for differentially activating this dimorphic circuitry after puberty.
The brain is also higly sensitive to glucocorticoids (GCs), the adrenal steroids released in response to stress and infection: raised levels can interfere with sexual differentiation of the brain, and may oppose the actions of sex hormones in the adult brain.
Current research
Sex differences and influences of systemic vs centrally generated hormones in the nigrostriatal dopaminergic pathway (NSDA) in health and disease (PD)
We have recently identified sex differences in the structural organization of the dopaminergic neurones of the substantia nigra pars compacta (SNc), in the susceptibility of the NSDA pathway to experimental PD (thereby mimicking sex differences in clinical PD which afflicts twice as many men than women), and in the key role played by gonadal steroids, which are neuroprotective in females but detrimental in males (thereby contributing to the sex bias).
These findings support our hypothesis that fundamental differences in the organization of specific neuronal pathways will dictate sex differences in vulnerability to and/or mechanisms of CNS pathology.
Contrary to our findings with systemic estrogens, those generated in the brain after NSDA injury are protective in both males and females. An important goal for future studies is to understand the relative contributions and inter-relationships of systemic and centrally generated steroids on the NSDA system, where the latter may prove more attractive therapeutic targets than the former.
In collaboration with Professor David Dexter and our PhD student Dr Felwah Al-Zaid, we are now extending our studies to a role for glial cells, specifically astrocytes, in contributing to sex bias in Parkinson’s disease.
Disruption of normal neural developmental trajectories in midbrain dopaminergic systems (midDAs)
Inappropriate exposure to stress and stress hormones (glucocorticoids, GCs) during development is a recognised risk factor for developing neurological and psychiatric disorders in later life. This is thought to be due, largely, to perturbations of the normal developmental trajectories of neuronal populations at critical stages, but the precise mechanisms are unclear.
We have demonstrated that perinatal exposure to GCs permanently disrupted the 3-dimensional cytoarchitecture in the adult SNc and VTA in a sex-specific manner, involving both the principal dopaminergic neurones and the astrocyte populations in these midbrain nuclei. Despite co-incident profound, sexually dimorphic changes in markers of dopaminergic transmission, we showed, in collaboration with Jeff Dalley and Trevor Robbins at Cambridge University, that in utero GC over-exposure has a surprisingly modest or no effect on a range of conditioned and unconditioned behaviours known to depend on midbrain dopaminergic circuitry, and these behavioural outcomes varied with the sex of the animal and the specific behavioural test. This demonstrates that inappropriate GC exposure during development induces powerful adaptations in adult midbrain circuitry, which are different, often opponent, in males and females, leading to sexually dimorphic behavioural resilience. Such findings have translational implications for sex biases commonly found in midbrain dopamine-associated disorders, including schizophrenia, ADHD, autism, depression and anxiety.