Modulation of the dopamine system by insulin in growth restricted rats

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Dopaminergic neuronal activity encodes errors in reward prediction and therefore provides a learning signal that guides future behavior. Dopamine (DA) is a key neurotransmitter modulating the behavioral response to natural and drug rewards, mainly through projections from the ventral tegmental area (VTA) into the nucleus accumbens (NAcc). The nutritional state seems to deeply influence the relationship between a) insulin, that signals energy and glucose homeostasis and modulates DA release, b) dopamine function and c) related behaviors. Our preliminary chronoamperometry data shows exuberant differences in the way by which insulin modulates the release of dopamine in the nucleus accumbens of fetal growth restricted rats when the animals are exposed to palatable foods. However, the molecular mechanisms and the developmental trajectory of these alterations are not known. We will use a comprehensive multidisciplinary approach which includes molecular (gene expression and protein levels), neurochemical (DA release by chronoamperometry), pharmacological (injection of insulin and antagonists in specific brain areas), neuroimaging (structural and resting state connectivity), and behavioral experiments at different ages (birth, adolescence and adulthood). We will characterize the insulin cascade and compare brain insulin sensitivity between the groups by evaluating the activation of the insulin signaling cascade (activation of PI3 kinase pathway) in tyrosine hydroxylase (TH)-positive neurons in the ventral tegmentar area (VTA), as well as the DA release facing palatable foods after injection of intracerebroventricular or VTA insulin or the blockade of the insulin receptor. We will also investigate how the unbalanced insulin action in the mesocorticolimbic system of growth restricted animals modifies the development of the DA pathway and the connectivity between different brain areas involved in impulse control such as the striatum and the PFC. Finally, we will explore the hypothesis that chronic high fat/high sugar diet in adulthood exacerbate the differences between the groups. This work will contribute to a better understanding of the interface between prenatal growth, metabolism, neurochemistry and behavior.