Impact of insulin and insulin resistance on brain dopamine signalling and reward processing-An underexplored mechanism in the pathophysiology of depression?

Type 2 diabetes and major depressive disorder (MDD) are the leading causes of disability worldwide and have a high comorbidity rate with fatal outcomes. Despite the long-established association between these conditions, the underlying molecular mechanisms remain unknown.Since the discovery of insulin receptors in the brain and the brain's reward system, evidence has accumulated indicating that insulin modulates dopaminergic (DA) signalling and reward behaviour. Here, we review the evidence from rodent and human studies, that insulin resistance directly alters central DA pathways, which may result in motivational deficits and depressive symptoms. Specifically, we first elaborate on the differential effects of insulin on DA signalling in the ventral tegmental area (VTA) -the primary DA source region in the midbrain -and the striatum as well as its effects on behaviour. We then focus on the alterations induced by insulin defi-ciency and resistance. Finally, we review the impact of insulin resistance in DA pathways in promoting depressive symptoms and anhedonia on a molecular and epidemiological level and discuss its relevance for stratified treatment strategies.