Mechanisms of sensory dysfunction in diabetic neuropathy

Sensory loss is a major symptom of diabetic neuropathy and a characteristic feature of ageing. Sensory changes in ageing and diabetes start distally in the longest sensory afferents, progress proximally over time and are likely to have common aetiologies in metabolic factors such as reactive oxygen species, glycating agents and neuroinflammation. During this studentship, we will elucidate the mechanisms responsible for diabetic sensory neuropathy and the maintenance of normal sensory function. Streptozotocin (STZ) induced diabetes is the most commonly used animal model of diabetes and diabetic complications. We recently showed that STZ produces TRPA1 mediated sensory changes BEFORE the onset of diabetes, which cannot be distinguished from those associated with diabetic neuropathy. We will avoid STZ by using the Ins2/Akita strain of diabetic mice, a more refined model with improved translational validity (3Rs). We have C57BL/6J Akita (suitable for crossing with transgenic strains) and have characterized the time course of sensory changes in several modalities. The most striking abnormalities are reduced mechanical and cold sensitivities. The student will also determine whether the Ins2/Akita strain develops apparent cognitive deficits in learning and memory tasks and whether brains and DRGs from diabetic Ins2/Akita mice exhibit signs of neuroinflammation.