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.
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)
- Francesco Roselli
- David Bayer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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.
- Moritz Helmstaedter, Max Planck Institute for Brain Research, Germany
© 2018, Commisso et al.
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