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 deficiency 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.

The impact of subthalamic deep brain stimulation on belief revision and social validation.

We investigated whether Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) influences social validation as measured by a Judge-Advisor task. In contrast to healthy controls and patients with their DBS OFF, patients with their stimulation switched on do not experience a gain of confidence after receiving competent advice.

Food Intake Recruits Orosensory and Post-ingestive Dopaminergic Circuits to Affect Eating Desire in Humans.

Pleasant taste and nutritional value guide food selection behavior. Here, orosensory features of food may be secondary to its nutritional value in underlying reinforcement, but it is unclear how the brain encodes the reward value of food. Orosensory and peripheral physiological signals may act together on dopaminergic circuits to drive food intake. We combined fMRI and a novel [11C]raclopride PET method to assess systems-level activation and dopamine release in response to palatable food intake in humans. We identified immediate orosensory and delayed post-ingestive dopamine release. Both responses recruit segregated brain regions: specialized integrative pathways and higher cognitive centers. Furthermore, we identified brain areas where dopamine release reflected the subjective desire to eat. Immediate dopamine release in these wanting-related regions was inversely correlated with, and presumably inhibited, post-ingestive release in the dorsal striatum. Our results highlight the role of brain and periphery in interacting to reinforce food intake in humans.