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Functional analysis of distinct populations of subthalamic nucleus neurons on Parkinson’s disease and OCD-like behaviors in mice

Molecular Psychiatry volume 26, pages 7029–7046 (2021)Cite this article

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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.

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Fig. 1: Identification of subthalamic nucleus (STN) neuronal subpopulations.
Fig. 2: Optogenetic activation of STN neurons (STNPitx2) inhibits locomotion and induces OCD-like repetitive behavior in mice.
Fig. 3: Optogenetic activation of Gabrr3-expressing STN neuronal subpopulation (STNGabrr3) inhibits locomotion and induces OCD-like repetitive behavior in mice.
Fig. 4: Optogenetic modulation of STNGabrr3 neurons improves the pathologic phenotypes of PD and OCD mouse models.
Fig. 5: Anatomic and functional study of STNGabrr3 neuronal inputs and outputs.

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Acknowledgements

We thank Dr Timothy Cox of the University of Washington for contributing the Pitx2-Cre mice, Dr Marc Flajolet and the Greengard Laboratory at The Rockefeller University for allowing the use of the Home Cage Environment (Clever Sys Inc.), Drs Claire Henchcliffe, Andrea Lee, and the PD & Movement Disorders Institute at Weill Cornell Medicine for consulting on the behavioral phenotype, Drs Alejandro Lopez and Jessica Jimenez for helpful discussions and manuscript revision, James Knox and Kyle Pellegrino for technical assistance, Anoj Ilanges and Dr Virginia A. Pedicord for the helpful discussions, and The Rockefeller University Comparative Bioscience Center and Bio-Imaging Resource Center. LP acknowledges support from the The David Rockefeller Fellowship and Boehringer Ingelheim Fonds PhD Fellowship. JMF acknowledges support from JPB foundation. MS acknowledges support from the Kavli NSI Fellowship, the Robertson Therapeutic Fund and NIDDK grant K99 (DK120869).

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  1. Laboratory of Molecular Genetics, Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA

    Luca Parolari, Marc Schneeberger & Jeffrey M. Friedman

  2. Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA

    Nathaniel Heintz

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Parolari, L., Schneeberger, M., Heintz, N. et al. Functional analysis of distinct populations of subthalamic nucleus neurons on Parkinson’s disease and OCD-like behaviors in mice. Mol Psychiatry 26, 7029–7046 (2021). https://doi.org/10.1038/s41380-021-01162-6

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