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Improving hindlimb locomotor function by Non-invasive AAV-mediated manipulations of propriospinal neurons in mice with complete spinal cord injury.
- Source :
-
Nature communications [Nat Commun] 2021 Feb 03; Vol. 12 (1), pp. 781. Date of Electronic Publication: 2021 Feb 03. - Publication Year :
- 2021
-
Abstract
- After complete spinal cord injuries (SCI), spinal segments below the lesion maintain inter-segmental communication via the intraspinal propriospinal network. However, it is unknown whether selective manipulation of these circuits can restore locomotor function in the absence of brain-derived inputs. By taking advantage of the compromised blood-spinal cord barrier following SCI, we optimized a set of procedures in which AAV9 vectors administered via the tail vein efficiently transduce neurons in lesion-adjacent spinal segments after a thoracic crush injury in adult mice. With this method, we used chemogenetic actuators to alter the excitability of propriospinal neurons in the thoracic cord of the adult mice with a complete thoracic crush injury. We showed that activating these thoracic neurons enables consistent and significant hindlimb stepping improvement, whereas direct manipulations of the neurons in the lumbar spinal cord led to muscle spasms without meaningful locomotion. Strikingly, manipulating either excitatory or inhibitory propriospinal neurons in the thoracic levels leads to distinct behavioural outcomes, with preferential effects on standing or stepping, two key elements of the locomotor function. These results demonstrate a strategy of engaging thoracic propriospinal neurons to improve hindlimb function and provide insights into optimizing neuromodulation-based strategies for treating SCI.
- Subjects :
- Animals
Antipsychotic Agents administration & dosage
Clozapine administration & dosage
Clozapine analogs & derivatives
Genetic Vectors genetics
Hindlimb innervation
Locomotion drug effects
Mice, Inbred C57BL
Mice, Transgenic
Spinal Cord drug effects
Spinal Cord metabolism
Spinal Cord physiopathology
Spinal Cord Injuries therapy
Mice
Dependovirus genetics
Hindlimb physiopathology
Locomotion physiology
Neurons metabolism
Spinal Cord Injuries physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 12
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 33536416
- Full Text :
- https://doi.org/10.1038/s41467-021-20980-4