Improved Locomotor Recovery in a Rat Model of Spinal Cord Injury by BioLuminescent-OptoGenetic (BL-OG) Stimulation with an Enhanced Luminopsin

International Journal of Molecular Sciences, 2022 · DOI: 10.3390/ijms232112994 · Published: October 27, 2022

Simple Explanation

This study explores a method to improve motor function after spinal cord injury (SCI) by re-engaging specific neuronal populations. This targeted activation aims to maintain or strengthen existing connections or develop new ones. The method involves BioLuminescent-OptoGenetics (BL-OG), which stimulates neurons non-invasively. Genetically targeted neurons express luminopsins (LMOs) that are activated by a substrate called coelenterazine (CTZ). The study tests a new generation of LMOs (LMO3.2) with higher light sensitivity, allowing CTZ to be delivered peripherally (via intraperitoneal injection) rather than directly into the brain. This less invasive approach was shown to improve locomotor function in rats with SCI.

Study Duration

5 weeks

Participants

16 adult female Sprague Dawley rats

Evidence Level

Not specified

Key Findings

1
LMO3.2 induces higher photocurrents compared to LMO3, indicating a greater response to both blue light and CTZ-induced activation.
2
Intraperitoneal injection of CTZ leads to measurable bioluminescence emission over the lumbar region of the spinal cord, peaking between 60 and 120 minutes after treatment.
3
Rats that received stimulation via LMO3.2 and CTZ showed improved locomotor function after SCI, as evidenced by higher BBB scores and subscores compared to vehicle-treated rats.

Research Summary

The study demonstrates that non-invasive modulation of neuronal activity in the spinal cord, using bioluminescent optogenetics with a new, more light-sensitive luminopsin (LMO3.2), significantly improved locomotor function in rats after spinal cord injury (SCI). Peripheral delivery of the activating substrate, coelenterazine (CTZ), via intraperitoneal injection, was effective in stimulating the LMO3.2-expressing neurons, achieving comparable results to previous methods that required more invasive delivery. Gait analysis using CatWalk XT system revealed a significant decrease in stand time for the treatment group, suggesting that stimulated rats applied less pressure on their hindlimbs while undertaking weight-supported plantar steps.

Practical Implications

Less Invasive Treatment

Peripheral delivery of CTZ makes the treatment less invasive than direct injection into the brain.

Potential Therapeutic Option

The study provides further evidence that stimulating LMO-expressing neurons through intraperitoneal delivery of CTZ enhances motor function recovery and has potential as a therapeutic option for SCI patients.

Advancement in BL-OG Technology

The development of more light-sensitive luminopsins and efficient luciferins represents a significant advancement in BL-OG technology.

Study Limitations

1
The study targeted all neurons below the injury site using the synapsin promoter instead of a specific promoter to target a subset of neurons.
2
Further experiments are needed to test stimulation in the chronic phase of SCI, as this treatment timeline will be more translatable to SCI patients.
3
The severity of injury in the SCI model limited the full utilization of the CatWalk analysis complexity due to the inability of many vehicle group animals to walk using their hindlimbs.

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