Mapping and treating circuit dysfunctions in Parkinson´s disease

We aim to unravel the role of specific neuronal circuits, dopamine receptors (DAR), and large-scale brain networks in the motor and neuropsychiatric dysfunctions of Parkinson´s disease (PD) using rodent models.

Specific aim 1 investigates corticostriatal systems and cortical interneurons in the sensorimotor abnormalities linked with hypokinesia and L-DOPA-induced dyskinesia.

Specific aim 2 pursues mechanisms of D2/3 agonist-induced impulse control disorders with a focus on different DAR types and limbic circuits. Specific aim 3 addresses the cellular underpinnings of brain-wide network dysfunctions.

Large-scale connectivity networks are identified in fMRI scans using analytical tools derived from human studies, and network metrics are finally correlated with cellular pathologies.

Methods: Rodents with mild or severe neurotoxin-induced DA denervation or seeded alpha-synuclein pathology are phenotyped using ad hoc behavioural test batteries. Animals are treated with L-DOPA and/or selective DAR ligands. Neuronal activity or connectivity maps are created using immunohistochemical markers or fMRI.

Optogenetic manipulations are applied to cells or pathways of interest. Specific circuits are studied using electrophysiological or fiber-photometry recordings. Specific DAR are deleted from regions and cells of interest using Cre-lox technology.

Significance/Outcome: We will deliver major scientific and translational progress in the study of PD-related brain circuit dysfunctions.