The central hypothesis of AND-PD is that PD is associated with DRN microcircuit dysfunction caused by the functional decline of dopaminergic neurons in the DRN, leading to PD-related anxiety/depression.
To test the hypothesis, several different PD models were validated in the project. The Aphakia and Glong mouse models were found to be useful for studying depression and anxiety in PD, whereas the MPTP mice model was ineffective. However, administering MPTP to nonhuman primates was found to help researchers study the anxiety/depression phenotype.
Stereological and morphological evidence in these pre-clinical models suggested that dopaminergic neurone degradation in the DRN is responsible for comorbid anxiety in PD. The results also suggested the presence of a complex connectivity pattern, with the basolateral amygdala as a synaptic hub between DRN and the DS, involving different neuromodulatory systems to modulate anxiety and depression-like responses.
Our results also revealed that single target SINEUPs can increase endogenous expressions of the neuroprotective factor Gdnf and its receptor, providing a new tool for increasing the neuroprotection of DA neurons and a new path for PD drug development.
Our research also showed that three DA cell subtypes can be identified using single cell RNA expression data. In mice models, we were able to provoke a change in the expression of genes involved in neuronal differentiation, immune system response, and inflammation. Inflammation, in particular, was linked to depression in PD individuals, providing a scientific foundation for further research into the role of inflammation in the pathogenesis of depression in PD models.
In human brain samples of patients with PD, our research identified that a history of comorbidity of anxiety and depression was consistently associated with a higher rate of dopaminergic cell loss in the DRN, providing important support for the role of dopaminergic neuron degeneration in these PD comorbidities. We discovered that patients diagnosed with anxiety in later life are more likely to be diagnosed with PD, and there are specific clinical features that identify those with anxiety at increased risk of PD. We also found that the development of anxiety in patients with PD is caused by both dopaminergic deficit in the basal ganglia and non-dopaminergic or extrastriatal pathology, which is consistent with the pre-clinical studies.
Finally, in the imaging study in human participants, AND-PD created normative maps of the dopaminergic and serotonergic systems for PET image analysis, which will be invaluable in the study of anxiety and depression, as well as other research of these systems across disease areas.
