Using Zebrafish to Investigate the Onset and Recovery from Common Complications of Hyperglycemia

Abstract

Zebrafish (Danio rerio) have emerged as an excellent model system to investigate disorders associated with diabetes as they have similar glucose metabolic pathways as mammals and exhibit characteristics of diabetic comorbidities. The Clark lab has characterized a model of hyperglycemia-induced motor nerve degeneration that includes motor axon defasciculation, decreased myelination, and loss of perineurial ensheathment. While these characteristics of neurodegeneration are observed in human DPN, differences in the perineurial tight junctions were absent in this model but is widely observed in human and mice DPN. Here, we optimized the hyperglycemic-induction protocol to recapitulate mammalian models of DPN more closely, and then introduced a recovery period to determine the capacity for peripheral nerve regeneration and return of normal escape response following a return to a euglycemic state. In agreement with our previous work, glucose-immersion initiated motor nerve degeneration and behavioral deficits. However, the optimized protocol led to disruption of tight junctions between the perineurial glia within the blood-nerve barrier, a phenotype consistent with mammalian models of DPN. Following a ten-day recovery period, peripheral motor axon length and ensheathment regenerate, but axonal defasciculation and behavioral deficits persist. Given that hyperglycemia has the potential to impact multiple systems, we explored other areas whose alterations may impact behavior. We hypothesized impaired skeletal development may be impacting behavior due to the necessary coordinated actions of the skeleton for the undulating movement of swimming. Here we describe a model of peripheral motor nerve regeneration following hyperglycemic insult, which future work will exploit to elucidate molecular mechanisms involved in regeneration. The robust impairment to skeletal development was unanticipated but expands our understanding of the global impact hyperglycemia has across systems.