Genetic control of neuronal activity enhances axonal growth only on permissive substrates

Molecular Medicine, 2022 · DOI: https://doi.org/10.1186/s10020-022-00524-2 · Published: August 3, 2022

Neurology Regenerative Medicine & Stem Cells

Simple Explanation

The study explores methods to modulate neuronal activity using opto- and chemogenetics, assessing the impact of specific neuronal stimulation on axonal regeneration following injury. Opto- and chemogenetic stimulation increased neurite outgrowth in sensory and cortical neurons in vitro and regeneration in vivo in the sciatic nerve, but not after spinal cord injury. The research indicates that while neuronal activity modulation can enhance axonal growth capacity, this is limited to permissive environments, as inhibitory substrates like chondroitin sulfate proteoglycans can block this growth.

Study Duration

Not specified

Participants

Mice

Evidence Level

Not specified

Key Findings

1
Optogenetic stimulation of DRG neurons increases axonal growth in vitro.
2
Chemogenetic stimulation of DRG neurons improves regenerative capacity after in vitro axotomy and sciatic nerve crush.
3
Optogenetic stimulation of cortical motor neurons does not improve sensorimotor performance after SCI.

Research Summary

The study investigates the therapeutic potential of modulating neuronal activity in sensory and motor neurons, using opto- and chemogenetic stimulation, to regulate axonal growth after injury. Results show that specific neuronal stimulation can increase axonal growth in vitro and in vivo, but this is contingent on the presence of permissive environments. The research suggests that while neuronal activity modulation can stimulate axonal growth, the inhibitory environment present after CNS injury can negate these effects.

Practical Implications

Therapeutic Potential

Modulating neuronal activity could be a viable therapeutic approach for promoting axonal regeneration, particularly in scenarios where the environment is permissive to growth.

Combination Therapies

Combining neuronal stimulation with strategies to overcome inhibitory signals in the CNS, such as CSPG degradation, may lead to more effective outcomes in treating spinal cord injuries.

Specificity

Cellular-specific stimulation might be less effective than more general stimulation approaches that target a broader range of neurons and circuits, suggesting the importance of neuronal plasticity in recovery.

Study Limitations

1
The lack of functional recovery after SCI with optogenetic stimulation of cortical neurons contrasts with studies using electrical stimulation, potentially due to differences in the injury model and the extent of tissue spared.
2
The study acknowledges the challenge of delivering light stimulation to DRGs for extended periods in awake animals, leading to the use of chemogenetics, which may have different effects compared to optogenetics.
3
The findings suggest that the intrinsic regenerative capacity of corticospinal neurons may be low, and the study could not exclude this as a contributing factor to the lack of regeneration across the injury.

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