Stage-dependent remodeling of projections to motor cortex in ALS mouse model revealed by a new variant retrograde-AAV9
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)
Article and author information
Author details
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
© 2018, Commisso et al.
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.
Metrics
-
- 2,709
- views
-
- 450
- downloads
-
- 22
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Neuroscience
What determines where to move the eyes? We recently showed that pupil size, a well-established marker of effort, also reflects the effort associated with making a saccade (‘saccade costs’). Here, we demonstrate saccade costs to critically drive saccade selection: when choosing between any two saccade directions, the least costly direction was consistently preferred. Strikingly, this principle even held during search in natural scenes in two additional experiments. When increasing cognitive demand experimentally through an auditory counting task, participants made fewer saccades and especially cut costly directions. This suggests that the eye-movement system and other cognitive operations consume similar resources that are flexibly allocated among each other as cognitive demand changes. Together, we argue that eye-movement behavior is tuned to adaptively minimize saccade-inherent effort.
-
- Neuroscience
The increasing use of tissue clearing techniques underscores the urgent need for cost-effective and simplified deep imaging methods. While traditional inverted confocal microscopes excel in high-resolution imaging of tissue sections and cultured cells, they face limitations in deep imaging of cleared tissues due to refractive index mismatches between the immersion media of objectives and sample container. To overcome these challenges, the RIM-Deep was developed to significantly improve deep imaging capabilities without compromising the normal function of the confocal microscope. This system facilitates deep immunofluorescence imaging of the prefrontal cortex in cleared macaque tissue, extending imaging depth from 2 mm to 5 mm. Applied to an intact and cleared Thy1-EGFP mouse brain, the system allowed for clear axonal visualization at high imaging depth. Moreover, this advancement enables large-scale, deep 3D imaging of intact tissues. In principle, this concept can be extended to any imaging modality, including existing inverted wide-field, confocal, and two-photon microscopy. This would significantly upgrade traditional laboratory configurations and facilitate the study of connectomes in the brain and other tissues.