Modulation of the dopamine system by insulin in growth restricted rats

多巴胺能神经元活动编码奖赏预测中的错误，因此提供了指导未来行为的学习信号。多巴胺(DA)是一种关键的神经递质，主要通过从腹侧被盖区(VTA)投射到伏核(NAcc)来调节对自然和药物奖励的行为反应。营养状态似乎深刻地影响了a)胰岛素、b)多巴胺功能和c)相关行为之间的关系。胰岛素是能量和葡萄糖稳态的信号并调节DA的释放。我们的初步计时电流测量数据显示，当胎儿生长受限的大鼠接触美味的食物时，胰岛素调节伏隔核多巴胺释放的方式存在显著差异。然而，这些改变的分子机制和发展轨迹尚不清楚。我们将使用一种综合的多学科方法，包括分子(基因表达和蛋白质水平)、神经化学(通过计时电流法释放DA)、药理学(在特定大脑区域注射胰岛素和拮抗剂)、神经成像(结构和静息状态连接)以及不同年龄(出生、青春期和成年期)的行为实验。我们将通过评估腹侧被盖区(VTA)酪氨酸羟基酶(TH)阳性神经元中胰岛素信号级联的激活(PI3激酶途径的激活)，以及在侧脑室或VTA注射胰岛素或阻断胰岛素受体后，面对美味食物的DA释放，来表征胰岛素级联反应，并比较两组之间的脑胰岛素敏感性。我们还将研究生长受限动物中皮质边缘系统中不平衡的胰岛素作用如何改变DA通路的发展，以及参与冲动控制的不同大脑区域之间的连接，如纹状体和前额叶。最后，我们将探索一种假设，即成年后长期的高脂肪/高糖饮食会加剧这两组人之间的差异。这项工作将有助于更好地理解产前生长、新陈代谢、神经化学和行为之间的界面。

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.