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Abnormal hyperactivity of specific striatal ensembles encodes distinct dyskinetic behaviors revealed by high-resolution clustering

Alcacer, Cristina LU ; Klaus, Andreas ; Mendonça, Marcelo ; Abalde, Sara F ; Cenci, Maria Angela LU orcid and Costa, Rui M (2025) In Cell Reports 44(7).
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, Mice, Corpus Striatum/physiopathology, Receptors, Dopamine D1/metabolism, Levodopa/adverse effects, Receptors, Dopamine D2/metabolism, Dyskinesia, Drug-Induced/physiopathology, Neurons/metabolism, Male, Disease Models, Animal, Mice, Inbred C57BL, Parkinson Disease, Behavior, Animal
in
Cell Reports
volume
44
issue
7
article number
115988
publisher
Cell Press
external identifiers
  • scopus:105009909109
  • pmid:40638389
ISSN
2211-1247
DOI
10.1016/j.celrep.2025.115988
language
English
LU publication?
yes
additional info
Published by Elsevier Inc.
id
06452e0f-1134-4e3c-904e-f01b88cff401
date added to LUP
2025-12-01 14:59:44
date last changed
2025-12-16 05:34:53
@article{06452e0f-1134-4e3c-904e-f01b88cff401,
  abstract     = {{<p>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.</p>}},
  author       = {{Alcacer, Cristina and Klaus, Andreas and Mendonça, Marcelo and Abalde, Sara F and Cenci, Maria Angela and Costa, Rui M}},
  issn         = {{2211-1247}},
  keywords     = {{Animals; Mice; Corpus Striatum/physiopathology; Receptors, Dopamine D1/metabolism; Levodopa/adverse effects; Receptors, Dopamine D2/metabolism; Dyskinesia, Drug-Induced/physiopathology; Neurons/metabolism; Male; Disease Models, Animal; Mice, Inbred C57BL; Parkinson Disease; Behavior, Animal}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{7}},
  publisher    = {{Cell Press}},
  series       = {{Cell Reports}},
  title        = {{Abnormal hyperactivity of specific striatal ensembles encodes distinct dyskinetic behaviors revealed by high-resolution clustering}},
  url          = {{http://dx.doi.org/10.1016/j.celrep.2025.115988}},
  doi          = {{10.1016/j.celrep.2025.115988}},
  volume       = {{44}},
  year         = {{2025}},
}