Neural and vascular contributions to sensory impairments in a human alpha-synuclein transgenic mouse model of Parkinson’s disease

Abstract

Parkinson's disease (PD) is a complex progressive neurodegenerative disorder involving hallmarks such as α[jls-end-space/]-Synuclein ( α[jls-end-space/]Syn) aggregation and dopaminergic dysfunction that affect brain-wide neural activity. Although movement disorders are prominent in PD, sensory impairments also occur relatively early on, mainly in olfactory and, to a lesser extent visual systems. While these deficits have been described mainly at the behavioral and molecular levels, the underlying network-level activity remains poorly understood. Here, we harnessed a human α[jls-end-space/]Syn transgenic mouse model of PD with in vivo functional MRI (fMRI) to map evoked activity in the visual and olfactory pathways, along with pseudo-Continuous Arterial Spin Labeling (pCASL) and c-FOS measurements to disentangle vascular from neuronal effects. Upon stimulation with either odors or flickering lights, we found significant decreases in fMRI responses along both olfactory and visual pathways, in multiple cortical and subcortical sensory areas. Average Cerebral Blood Flow rates were decreased by ∼10% in the α[jls-end-space/]Syn group, while c-FOS levels were reduced by over 50%, suggesting a strong neural driver for the dysfunction, along with more modest vascular contributions. Our study provides insight into brain-level activity in an α[jls-end-space/]Syn-based model, and suggests a novel target for biomarking via quantification of simple sensory evoked responses.