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

Zachary A. Abecassis, Brianna L. Berceau, Phyo H. Win, Daniela Garcia, View ORCID ProfileHarry S. Xenias, View ORCID ProfileQiaoling Cui, Arin Pamucku, Suraj Cherian, Vivian M. Hernández, Uree Chon, View ORCID ProfileByung Kook Lim, View ORCID ProfileNicholas J. Justice, View ORCID ProfileRaj Awatramani, View ORCID ProfileYongsoo Kim, View ORCID ProfileBryan M. Hooks, Charles R. Gerfen, View ORCID ProfileSimina M. Boca, View ORCID ProfileC. Savio Chan
doi: https://doi.org/10.1101/644674
Zachary A. Abecassis
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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Brianna L. Berceau
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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Phyo H. Win
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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Daniela Garcia
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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Harry S. Xenias
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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Qiaoling Cui
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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Arin Pamucku
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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Suraj Cherian
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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Vivian M. Hernández
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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Uree Chon
2Department of Neural and Behavioral Sciences, College of Medicine, Penn State University, Hershey, PA, USA
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Byung Kook Lim
3Neurobiology Section, Biological Sciences Division, University of California San Diego, La Jolla, CA, USA
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Nicholas J. Justice
4Center for Metabolic and degenerative disease, Institute of Molecular Medicine, University of Texas, Houston, TX USA
5Department of Integrative Pharmacology, University of Texas, Houston, TX USA
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Raj Awatramani
6Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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Yongsoo Kim
2Department of Neural and Behavioral Sciences, College of Medicine, Penn State University, Hershey, PA, USA
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Bryan M. Hooks
7Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Charles R. Gerfen
8Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, MD, USA
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Simina M. Boca
9Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington D.C., USA
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  • ORCID record for Simina M. Boca
C. Savio Chan
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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  • ORCID record for C. Savio Chan
  • For correspondence: saviochan@gmail.com
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Abstract

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 statement The 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.

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Posted August 22, 2019.
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Npas1+-Nkx2.1+ Neurons Are an Integral Part of the Cortico-pallido-cortical Loop
Zachary A. Abecassis, Brianna L. Berceau, Phyo H. Win, Daniela Garcia, Harry S. Xenias, Qiaoling Cui, Arin Pamucku, Suraj Cherian, Vivian M. Hernández, Uree Chon, Byung Kook Lim, Nicholas J. Justice, Raj Awatramani, Yongsoo Kim, Bryan M. Hooks, Charles R. Gerfen, Simina M. Boca, C. Savio Chan
bioRxiv 644674; doi: https://doi.org/10.1101/644674
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Npas1+-Nkx2.1+ Neurons Are an Integral Part of the Cortico-pallido-cortical Loop
Zachary A. Abecassis, Brianna L. Berceau, Phyo H. Win, Daniela Garcia, Harry S. Xenias, Qiaoling Cui, Arin Pamucku, Suraj Cherian, Vivian M. Hernández, Uree Chon, Byung Kook Lim, Nicholas J. Justice, Raj Awatramani, Yongsoo Kim, Bryan M. Hooks, Charles R. Gerfen, Simina M. Boca, C. Savio Chan
bioRxiv 644674; doi: https://doi.org/10.1101/644674

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