Improving hindlimb locomotor function by Non-invasive AAV-mediated manipulations of propriospinal neurons in mice with complete spinal cord injury
Autor: | Jessica C. Page, Yu Zhang, Emilia Gouy, Philip R. Williams, Qi Wang, Wei Dai, Miao He, Zicong Zhang, Zhiyun Yang, Bo Chen, Benedikt Brommer, Junfeng Su, Jing Tang, Zhigang He, Ryan Solinsky, Junjie Zhu |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Cord Physiology Science Genetic Vectors General Physics and Astronomy Mice Transgenic Hindlimb Inhibitory postsynaptic potential General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences 0302 clinical medicine Neuromodulation Medicine Animals Spinal cord injury Clozapine Spinal Cord Injuries Neurons Multidisciplinary business.industry General Chemistry Dependovirus Spinal cord medicine.disease Mice Inbred C57BL Lumbar Spinal Cord 030104 developmental biology medicine.anatomical_structure Spinal Cord Crush injury business Neuroscience 030217 neurology & neurosurgery Locomotion Antipsychotic Agents |
Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021) Nature Communications |
ISSN: | 2041-1723 |
Popis: | 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. After complete spinal cord injury, spinal segments below the lesion maintain inter-segmental communication via the intraspinal propriospinal network. Here, the authors show that neurons in these circuits can be chemogenetically modulated to improve locomotor function in mice after spinal cord injury. |
Databáze: | OpenAIRE |
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