Neuromodulation modifies α-synuclein spreading dynamics in vivo and the pattern is predicted by changes in...

Area of Science:

• Neuroscience
• Neuromodulation
• Neurodegenerative disease research

Background:

• Current treatments for neurodegenerative diseases like Parkinson's Disease (PD) primarily manage symptoms by addressing circuit dysfunction.
• The impact of these treatments on the underlying disease progression, particularly the spread of pathological hallmarks like alpha-synuclein, is not well understood.

Purpose of the Study:

• To investigate whether neuromodulation can influence the in vivo spreading dynamics of alpha-synuclein pathology.
• To explore the relationship between neuromodulation-induced changes in brain activity and pathology distribution.

Main Methods:

• Induction of widespread alpha-synuclein pathology in a mouse model via striatal injection of pre-formed fibrils.
• Application of daily optogenetic stimulation to the Secondary Motor Area (Layer V) for two weeks post-pathology induction.
• Whole-brain imaging using light-sheet fluorescent microscopy after immunolabeling and clearing.

Main Results:

• Optogenetic stimulation resulted in reduced alpha-synuclein pathology at the stimulation site and surrounding areas.
• A notable increase in pathology was observed in the contralateral cortex.
• Changes in pathology spatially correlated with, but were opposite in polarity to, optogenetic-fMRI measured brain activity.

Conclusions:

• Neuromodulation can effectively modulate and predict the distribution of alpha-synuclein pathology across the brain.
• These findings open new avenues for developing optimized neuromodulation therapies for Parkinson's Disease and related disorders.