Author(s): Alcacer, Cristina ; Klaus, Andreas ; Mendonça, Marcelo ; Abalde, Sara F. ; Cenci, Maria Angela ; Costa, Rui M.
Date: 2025
Persistent ID: http://hdl.handle.net/10362/185537
Origin: Repositório Institucional da UNL
Subject(s): behavioral clustering; calcium imaging; CP: Neuroscience; freely moving mice; IMUs; inertial measurement units; L-DOPA-induced dyskinesia; motor behavior; parkinson's disease; striatal spiny projection neurons; Biochemistry, Genetics and Molecular Biology(all)
Funding Information: We thank Vitor Paix\u00E3o for designing and customizing the unsupervised behavioral clustering (Klaus et al. 2017) by incorporating the change-point calculations; Joaquim Alves da Silva for technical support with IMUs; Catarina Carvalho and Ana Vaz for animal care; and all members of the Costa laboratory for discussions. We also thank the Histopathology and Scientific Software Platforms at the Champalimaud Foundation and the Hardware Platform\u2014particularly Paulo Carri\u00E7o for developing a rotating platform for calcium imaging experiments to overcome the rotations of dyskinetic mice and Artur Silva for support with the IMUs/WEAR system. Additional thanks to Laurent Lachaux and Ivo Marcelo for help with building setups and motion-correction analysis. Graphical abstract illustration support: Gil Costa. This study was supported by the Swedish Research Council , a grant co-funded by the Marie Sk\u0142odowska Curie Actions FP7 ( GS-2015-0006X ) granted to C.A.; Ayudas Mar\u00EDa Zambrano - Alcal\u00E1 University , Spanish Ministry of Universities , Next Generation UE funds to C.A.; Momentum Programme - CSIC ( Spanish National Research Council ), MRR-Next Generation EU funds to C.A.; the Swedish Research Council ( 2020-02696 ) to M.A.C.; the Swedish Brain Foundation ( FO2022-0293 ) to M.A.C.; and the National Institutes of Health funding ( 5U19NS104649 ) and the Aligning Science Across Parkinson's ( ASAP-020551 ) through the Michael J. Fox Foundation for Parkinson's Research (MJFF) to R.M.C. Publisher Copyright: © 2025
L-DOPA-induced dyskinesia (LID) is a debilitating complication of dopamine replacement therapy in Parkinson's disease and the most common hyperkinetic disorder of basal ganglia origin. Abnormal activity of striatal D1 and D2 spiny projection neurons (SPNs) is critical for LID, yet the link between SPN activity patterns and specific dyskinetic movements remains unknown. To explore this, we implemented a data-driven method for clustering movements based on high-resolution motion sensors and video recordings. In a mouse model of LID, this method identified two main dyskinesia types and pathological rotations, all absent during normal behavior. Using single-cell-resolution imaging, we found that specific sets of both D1- and D2-SPNs were abnormally active during these pathological movements. Under baseline conditions, these SPN sets were active during behaviors sharing physical features with LID movements. These findings indicate that ensembles of behavior-encoding D1- and D2-SPNs form new combinations of hyperactive neurons mediating specific dyskinetic features.
