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Npas1+-Nkx2.1+ Neurons Are an Integral Part of the Cortico-pallido-cortical Loop.

  • Abecassis, Zachary A1
  • Berceau, Brianna L1
  • Win, Phyo H1
  • Garcia, Daniela1
  • Xenias, Harry S1
  • Cui, Qiaoling1
  • Pamukcu, Arin1
  • Cherian, Suraj1
  • Hernández, Vivian M1
  • Chon, Uree2
  • Kook Lim, Byung3
  • Kim, Yongsoo2
  • Justice, Nicholas J4, 5
  • Awatramani, Raj6
  • Hooks, Bryan M7
  • Gerfen, Charles R8
  • Boca, Simina M9
  • Chan, C Savio10
  • 1 Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 2 Department of Neural and Behavioral Sciences, College of Medicine, Penn State University, Hershey, PA, USA.
  • 3 Neurobiology Section, Biological Sciences Division, University of California San Diego, La Jolla, CA, USA.
  • 4 Center for Metabolic and degenerative disease, Institute of Molecular Medicine, University of Texas, Houston, TX USA.
  • 5 Department of Integrative Pharmacology, University of Texas, Houston, TX USA.
  • 6 Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 7 Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 8 Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, MD, USA.
  • 9 Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington D.C., USA.
  • 10 Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA [email protected]
Published Article
Journal of Neuroscience
Society for Neuroscience
Publication Date
Dec 06, 2019
DOI: 10.1523/JNEUROSCI.1199-19.2019
PMID: 31811030


Within the basal ganglia circuit, the external globus pallidus (GPe) is critically involved in motor control. Aside from Foxp2+ neurons and ChAT+ neurons that have been established as unique neuron types, there is little consensus on the classification of GPe neurons. Properties of the remaining neuron types are poorly-defined. In this study, we leverage new mouse lines, viral tools, and molecular markers to better define GPe neuron subtypes. We found that Sox6 represents a novel, defining marker for GPe neuron subtypes. Lhx6+ neurons that lack the expression of Sox6 were devoid of both parvalbumin and Npas1. This result confirms previous assertions of the existence of a unique Lhx6+ population. Neurons that arise from the Dbx1+ lineage were similarly abundant in the GPe and displayed a heterogeneous makeup. Importantly, tracing experiments revealed that Npas1+-Nkx2.1+ neurons represent the principal non-cholinergic, cortically-projecting neurons. In other words, they form the pallido-cortical arm of the cortico-pallido-cortical loop. Our data further described that pyramidal-tract neurons in the cortex collateralized within the GPe, forming a closed-loop system between the two brain structures. Overall, our findings reconcile some of the discrepancies that arose from differences in techniques or the reliance on pre-existing tools. While spatial distribution and electrophysiological properties of GPe neurons reaffirm the diversification of GPe subtypes, statistical analyses strongly support the notion that these neuron subtypes can be categorized under the two principal neuron classes-i.e., PV+ neurons and Npas1+ neurons.SIGNIFICANCE STATEMENTThe poor understanding of the neuronal composition in the GPe undermines our ability to interrogate its precise behavioral and disease involvements. In this study, twelve different genetic crosses were used, hundreds of neurons were electrophysiologically-characterized, and over 100,000 neurons were histologically- and/or anatomically-profiled. Our current study further establishes the segregation of GPe neuron classes and illustrates the complexity of GPe neurons in adult mice. Our results support the idea that Npas1+-Nkx2.1+ neurons are a distinct GPe neuron subclass. By providing a detailed analysis of the organization of the cortico-pallidal-cortical projection, our findings establish the cellular and circuit substrates that can be important for motor function and dysfunction. Copyright © 2019 the authors.

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