Functional analysis of distinct populations of subthalamic nucleus neurons on Parkinson’s disease and OCD-like behaviors in mice
- 7 June 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Molecular Psychiatry
- Vol. 26 (11), 7029-7046
- https://doi.org/10.1038/s41380-021-01162-6
Abstract
The subthalamic nucleus (STN) is a component of the basal ganglia and plays a key role to control movement and limbic-associative functions. STN modulation with deep brain stimulation (DBS) improves the symptoms of Parkinson’s disease (PD) and obsessive–compulsive disorder (OCD) patients. However, DBS does not allow for cell-type-specific modulation of the STN. While extensive work has focused on elucidating STN functionality, the understanding of the role of specific cell types is limited. Here, we first performed an anatomical characterization of molecular markers for specific STN neurons. These studies revealed that most STN neurons express Pitx2, and that different overlapping subsets express Gabrr3, Ndnf, or Nos1. Next, we used optogenetics to define their roles in regulating locomotor and limbic functions in mice. Specifically, we showed that optogenetic photoactivation of STN neurons in Pitx2-Cre mice or of the Gabrr3-expressing subpopulation induces locomotor changes, and improves locomotion in a PD mouse model. In addition, photoactivation of Pitx2 and Gabrr3 cells induced repetitive grooming, a phenotype associated with OCD. Repeated stimulation prompted a persistent increase in grooming that could be reversed by fluoxetine treatment, a first-line drug therapy for OCD. Conversely, repeated inhibition of STNGabrr3 neurons suppressed grooming in Sapap3 KO mice, a model for OCD. Finally, circuit and functional mapping of STNGabrr3 neurons showed that these effects are mediated via projections to the globus pallidus/entopeduncular nucleus and substantia nigra reticulata. Altogether, these data identify Gabrr3 neurons as a key population in mediating the beneficial effects of STN modulation thus providing potential cellular targets for PD and OCD drug discovery.Funding Information
- Boehringer Ingelheim Fonds
- Kavli Foundation
- Howard Hughes Medical Institute
This publication has 56 references indexed in Scilit:
- Mechanisms of deep brain stimulation for obsessive compulsive disorder: effects upon cells and circuitsFrontiers in Integrative Neuroscience, 2012
- Subthalamic deep brain stimulation and impulse control in Parkinson’s diseaseEuropean Journal of Neurology, 2009
- High frequency stimulation and pharmacological inactivation of the subthalamic nucleus reduces ‘compulsive’ lever-pressing in ratsExperimental Neurology, 2009
- The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey ReplicationMolecular Psychiatry, 2008
- Analyzing grooming microstructure in neurobehavioral experimentsNature Protocols, 2007
- Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant miceNature, 2007
- Stimulation of subterritories of the subthalamic nucleus reveals its role in the integration of the emotional and motor aspects of behaviorProceedings of the National Academy of Sciences of the United States of America, 2007
- Genome-wide atlas of gene expression in the adult mouse brainNature, 2006
- The subthalamic nucleus exerts opposite control on cocaine and 'natural' rewardsNature Neuroscience, 2005
- Transient Acute Depression Induced by High-Frequency Deep-Brain StimulationThe New England Journal of Medicine, 1999