Current research
1. 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 the underlying, key role played by gonadal steroids which are neuroprotective in females, but detrimental in males.
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.
2. Disruption of normal neural developmental trajectories in midDAs
We have characterised sex differences in the total numbers and distribution of midDAs within the rodent ventral tegmental area (VTA) and SNc, and demonstrated that perinatal GC treatment permanently disrupted this 3-dimensional cytoarchitecture in the adult midDAs. Current work is testing our hypothesis that this results in altered connectivity and functionality, with potential pathophysiological consequences.
3. Homeostasis and neuroprotection by endogenous anti-inflammatory molecules in midDAs
Current research (with Drs E. Solito and S. McArthur) explores the role of the natural, anti-inflammatory molecule, annexin 1 (Anxa1), in controlling innate inflammatory responses in experimental PD, using in vivo and in vitro models. This work raises interesting possibilities for neurone-glial interactions in health and disease.
