Abstract
The degeneration of midbrain dopamine (DA) neurons disrupts the neural control of natural behavior, such as walking, posture, and gait in Parkinson’s disease. While some aspects of motor symptoms can be managed by dopamine replacement therapies, others respond poorly. Recent advancements in machine learning-based technologies offer opportunities to better understand the organizing principles of behavior modules at fine time scales and its dependence on dopaminergic modulation. In the present study, we applied the motion sequencing (MoSeq) platform to study the spontaneous locomotor activities of neurotoxin and genetic mouse models of Parkinsonism as the midbrain DA neurons progressively degenerate. We also evaluated the treatment efficacy of levodopa (L-DOPA) on behavioral modules at fine time scales. We revealed robust changes in the kinematics and usage of the behavioral modules that encode spontaneous locomotor activity. Further analysis demonstrates that fast behavioral modules with higher velocities were more vulnerable to loss of DA and preferentially affected at early stages of Parkinsonism. Last, L-DOPA effectively improved the velocity, but not the usage and transition probability, of behavioral modules in Parkinsonian animals. In conclusion, the hypokinetic phenotypes in Parkinsonism involve the decreased velocities of behavioral modules and their disrupted temporal organization during movement. Moreover, we showed that the therapeutic effect of L-DOPA is mainly mediated by its effect on the velocities of behavior modules at fine time scales. This work documents robust changes in the velocity, usage, and temporal organization of behavioral modules and their responsiveness to dopaminergic treatment under the Parkinsonian state.
Significance Statement Parkinson’s disease is the second largest neurodegenerative disease without a cure. Detection of subtle Parkinsonian signs is critical for disease-modification by applying early interventions. The present work explores the possibility of using machine learning-based approaches for early detection of subtle behavioral changes in Parkinsonian animals and evaluating the therapeutic efficacy of dopaminergic medications.
Footnotes
Behavior recordings were conducted at the Van Andel Research Institute. Data analysis and manuscript preparation were performed and completed at Georgetown University Medical Center. This work was partially supported by research grants from the National Institutes of Health (R01NS121371, R21NS135545, H.Y.C; and R01NS133338, S.M.D. and H.Y.C.), Department of Defense Congressionally Directed Medical Research Programs (W81XWH-21-1-0943, H.Y.C.), and Parkinson’s Foundation (PF-IMP-1045313, H.Y.C.). This work was also funded in whole or in part by Aligning Science Across Parkinson’s (ASAP-020572) through the Michael J. Fox Foundation for Parkinson’s Research (MJFF). For the purpose of open access, the authors have applied a CC BY public copyright license to all Author Accepted Manuscripts arising from this submission.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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