Simone Di Giovanni, Imperial College London, London, UK

Enriched conditioning to enhance axonal regeneration

Funded in: 2020, 2021, 2022


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Problem: Degree of regrowth and of functional recovery remains very limited even after conditioning lesion of the sciatic nerve preceding a spinal injury
Target: Injury-free paradigm of conditioning relies on housing mice in an enriched environment
Goal: Lead to the genetic and pharmacological targeting of “enriched conditioning”-dependent pathways to enhance axonal regeneration and functional recovery

Long-term disability and lack of functional recovery following spinal cord injury (SCI) are due to failed reconnectivity of lesioned and spared circuitry caused by unsuccessful axonal regeneration and limited plasticity. A conditioning lesion of the sciatic nerve preceding a spinal injury is to date the best-established and most widely accepted approach to partially overcome regenerative failure and to enhance regeneration of sensory axons across a spinal lesion. However, the degree of regrowth and of functional recovery remains very limited. In a recent study from the researcher`s lab, they discovered an injury-free paradigm of conditioning that relies on housing mice in an enriched environment (EE) for about 10 days prior to a spinal cord injury. EE consists of housing a larger number of mice (about 8 mice) than usual in a larger cage with toys, wheel, enriched embedding and tunnels to favour their exploratory motor behaviour as previously described. The scientists found that EE results in a lasting increase in regenerative potential to an extent similar to what is observed in the conditioning lesion paradigm.
More importantly, when they combined a conditioning sciatic nerve axotomy (SNA) with exposure of mice to an EE for 10 days prior to SNA (EE+SNA) that we call “enriched conditioning”, they observed a significant additive regenerative effect compared to EE or SNA alone. This led to further enhancement of sensory axon regeneration and functional recovery, thus suggesting that EE and SNA act synergistically via complementary molecular mechanisms.
Here, the researchers hypothesize that molecular analysis of the mechanisms underpinning this “enriched conditioning” offers an opportunity to identify key regenerative pathways that could be targeted pharmacologically or via gene therapy.
The aims of this proposal are twofold: investigate the “enriched conditioning”-dependent mechanisms and study the regenerative phenotype and recovery after SCI in both the sensory and motor system.
Ultimately, these studies may lead to the genetic and pharmacological targeting of “enriched conditioning”-dependent pathways as a novel strategy to enhance axonal regeneration and functional recovery after SCI.