Chemogenetic stimulation of proprioceptors remodels lumbar in

AAV2/PHP.S-Syn-GFP, AAV2/8-ChR2-eYFP, AAV2/retro-CAG-GFP, and AAV2/9-Syn-Synaptophysin-mCherry were used for neural tracing. AAV2/PHP.S-Syn-FLEX-PLAP, AAV2/PHP.S-Syn-FLEX-hM3Dq-mCherry, and AAV2/PHP.S-Syn-FLEX-HA-hM3Dq were used for the manipulation of proprioceptors. (From BrainVTA)

The viruses used in this article from BrainVTA are in the table below

Chemogenetics	AAV2/PHP.S-Syn-FLEX-HA-hM3Dq AAV2/PHP.S-Syn-FLEX-hM3Dq-mCherry
Optogenetic	AAV2/8-ChR2-eYFP
Control	AAV2/PHP.S-Syn-GFP AAV2/retro-CAG-GFP AAV2/9-Syn-Synaptophysin-mCherry AAV2/PHP.S-Syn-FLEX-PLAP

Zhongyang Gao, Yang Yang, Zhiyun Feng, Xigong Li, Cuiting Min, Zhonghai Zhu, Hui Song, Yihe Hu, Yue Wang, Xijing He
Pub Date: 2021-04-23, DOI: 10.1016/j.ymthe.2021.04.023, Email: sales@brainvta.com

Motor recovery after severe spinal cord injury (SCI) is limited due to the disruption of direct descending commands. Despite the absence of brain-derived descending inputs, sensory afferents below injury sites remain intact. Among them, proprioception acts as an important sensory source to modulate local spinal circuits and determine motor outputs. Yet, it remains unclear whether enhancing proprioceptive inputs promotes motor recovery after severe SCI. Here, we first established a viral system to selectively target lumbar proprioceptive neurons and then introduced the excitatory Gq-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADD) virus into proprioceptors to achieve specific activation of lumbar proprioceptive neurons upon CNO administration. We demonstrated that chronic activation of lumbar proprioceptive neurons promoted the recovery of hindlimb stepping ability in a bilateral hemisection SCI mouse model. We further revealed that chemogenetic proprioceptive stimulation led to coordinated activation of proprioception-receptive spinal interneurons and facilitated transmission of supraspinal commands to lumbar motor neurons, without affecting the regrowth of proprioceptive afferents or brain-derived descending axons. Moreover, application of 4-aminopyridine-3-methanol (4-AP-MeOH) that enhances nerve conductance further improved the transmission of supraspinal inputs and motor recovery in proprioception-stimulated mice. Our study demonstrates that proprioception-based combinatorial modality may be a promising strategy to restore the motor function after severe SCI.

In this study, the authors ﬁrst established a viral system to selectively target lumbar proprioceptive neurons and then introduced the excitatory Gq-coupled Designer Receptors Exclusively Activated byDesignerDrugs (DREADD) virus into proprioceptors to achieve speciﬁc activation of lumbar proprioceptive neurons upon CNO administration. The ﬁndings suggest that treatments aimed at enhancing proprioceptive inputs are a promising therapeutic approach to improve functional recovery after severe SCI.

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