Corticospinal circuit remodeling after central nervous system injury is dependent on neuronal activity

J. Exp. Med., 2019 · DOI: https://doi.org/10.1084/jem.20181406 · Published: November 4, 2019

Spinal Cord Injury Neurology Neuroplasticity

Simple Explanation

Following a spinal cord injury, the brain can sometimes rewire itself to regain some function. This rewiring involves the formation of new connections between brain cells and spinal cord cells. The study found that the selection of appropriate synaptic connections between cortical projection and spinal relay neurons depends on neuronal activity. By using genetic and chemogenetic tools, the researchers demonstrated that neuronal activity, specifically NMDAR signaling and CREB-mediated transcription, plays a critical role in maintaining these new connections during a specific period of circuit remodeling.

Study Duration

Not specified

Participants

Adult female C57/Bl6 mice (6–12 wk old), GlyT2-GFP mice, VGlut2-Cre mice, floxed NR1 mice

Evidence Level

Not specified

Key Findings

1
NMDAR signaling and CREB-mediated transcription are essential for maintaining nascent corticospinal tract (CST)–relay neuron contacts during circuit remodeling after spinal cord injury.
2
The regrowing CST axons select their postsynaptic partners in a competitive manner, with neuronal activity influencing this selection process.
3
Preventing activity-dependent shaping of corticospinal circuits limits motor recovery after spinal cord injury.

Research Summary

This study investigates how neuronal circuits remodel after spinal cord injury, focusing on the role of neuronal activity in target selection during corticospinal tract (CST) rewiring. The researchers used genetic and chemogenetic tools to modulate neuronal activity and signaling in spinal interneurons, finding that NMDAR signaling and CREB-mediated transcription are crucial for maintaining new CST-relay neuron connections. The study also demonstrates that regrowing CST axons compete for postsynaptic partners based on neuronal activity and that disrupting this activity-dependent competition impairs motor recovery.

Practical Implications

Therapeutic Timing

The existence of a defined window of endogenous post-injury remodeling has implications for the timing of therapies aimed at modulating neuronal activity, suggesting they would be most beneficial if initiated during this time.

Targeted Therapies

Strategies that enhance physiological activity patterns of relay neurons based on optogenetic or chemogenetic approaches, electrical stimulation, or rehabilitative measures might be harnessed to strengthen corticospinal connectivity and improve functional recovery.

Understanding Circuit Selection

Understanding the principles of contact selection helps ensure that functionally advantageous connections are formed and maintained while disadvantageous ones are removed, improving post-injury circuit remodeling.

Study Limitations

1
The study focuses on female mice, potentially limiting the generalizability of the findings to males.
2
The study examines a specific type of spinal cord injury (dorsal hemisection), and the results might not apply to other types of injuries.
3
The study uses specific genetic and chemogenetic tools, and the observed effects might be specific to these interventions.

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