Stage-dependent remodeling of projections to motor cortex in ALS mouse model revealed by a new variant retrograde-AAV9

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Abstract

Amyotrophic Lateral Sclerosis (ALS) is characterized by the progressive degeneration of motoneurons in the primary motor cortex (pMO) and in spinal cord. However, the pathogenic process involves multiple subnetworks in the brain and functional MRI studies demonstrate an increase in functional connectivity in areas connected to pMO despite the ongoing neurodegeneration. The extent and the structural basis of the motor subnetwork remodelling in experimentally-tractable models remain unclear. We have developed a new retrograde AAV9 to quantitatively map the projections to pMO in the SOD1(G93A) ALS mouse model. We show an increase in the number of neurons projecting from somatosensory cortex to pMO at presymptomatic stages, followed by an increase in projections from thalamus, auditory cortex and contralateral MO (inputs from 20 other structures remains unchanged) as disease advances. The stage- and structure-dependent remodeling of projection to pMO in ALS may provide insights into the hyperconnectivity observed in ALS patients.

Data availability

All the murine data generated or analysed during this study are included in the manuscript and supporting files. The raw images are deposited on the Dataverse database (https://doi.org/10.7910/DVN/5VNSXE)

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Barbara Commisso

Department of Neurology, University of Ulm, Ulm, Germany

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The authors declare that no competing interests exist.
Lingjun Ding

Department of Neurology, University of Ulm, Ulm, Germany

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The authors declare that no competing interests exist.
Karl Varadi

Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany

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The authors declare that no competing interests exist.
Martin Gorges

Department of Neurology, University of Ulm, Ulm, Germany

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The authors declare that no competing interests exist.
David Bayer

Department of Neurology, University of Ulm, Ulm, Germany

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The authors declare that no competing interests exist.
Tobias M Boeckers

Department of Anatomy and Cell Biology, University of Ulm, Ulm, Germany

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The authors declare that no competing interests exist.
Albert C Ludolph

Department of Neurology, University of Ulm, Ulm, Germany

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The authors declare that no competing interests exist.
Jan Kassubek

Department of Neurology, University of Ulm, Ulm, Germany

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The authors declare that no competing interests exist.
Oliver Mueller

Dept. of Internal Medicine III, University of Kiel, Kiel, Germany

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The authors declare that no competing interests exist.
Francesco Roselli

Department of Neurology, University of Ulm, Ulm, Germany

For correspondence
francesco.roselli@uni-ulm.de

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9935-6899

Funding

Baustein program-Ulm University Medical Faculty

Francesco Roselli

Deutsche Forschungsgemeinschaft (GRK1789)

David Bayer

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments have been approved by the Regierungpraesidium Tubingen under the licence no. 1312. All animals were handled according to the federal regulations on animal experimentations and under the supervision of the local veterinary office. Every effort was made to adhere to the 3R guidelines and to minimize suffering.

Human subjects: All subjects included in the human study provided written informed consent according to institutional guidelines; the consent includes the declaration of the understanding of the study design, the agreement to the participation to the study, to the publication of the results, and to the data protection and anonymization procedures (under the chaptes Einwilligungserklaerung"", ""Probandeninformation"", ""Darstellung der Experimente"", ""Datenschutzerklärung""). The study was approved by the Ethics Committee of Ulm University, Ulm, Germany (reference #19/12) and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.