Modulation of the dopamine system by insulin in growth restricted rats

胰岛素对生长受限大鼠多巴胺系统的调节

• 批准号: RGPIN-2018-05063
• 负责人: Silveira, Patrícia
• 金额: $ 2.4万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684848
• 关键词: Modulation; dopamine; system; insulin; growth

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.

多巴胺能神经元活动编码奖励预测中的错误，因此提供了指导未来行为的学习信号。多巴胺（DA）是调节自然奖赏和药物奖赏行为反应的重要神经递质，主要通过腹侧被盖区（VTA）向丘脑腹侧核（NAcc）的投射。营养状态似乎深刻地影响a）胰岛素，其信号能量和葡萄糖稳态并调节DA释放，B）多巴胺功能和c）相关行为之间的关系。我们初步的计时电流法数据显示，当动物暴露于可口的食物时，胰岛素调节胎儿生长受限大鼠中脑核多巴胺释放的方式存在丰富的差异。然而，这些改变的分子机制和发展轨迹尚不清楚。我们将使用全面的多学科方法，包括分子（基因表达和蛋白质水平），神经化学（计时电流法DA释放），药理学（在特定脑区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）的行为实验。我们将通过评价腹侧被盖区（VTA）酪氨酸羟化酶（TH）阳性神经元中胰岛素信号级联的激活（PI 3激酶通路的激活），以及脑室内或VTA胰岛素注射或胰岛素受体阻断后DA释放面对可口食物，来表征胰岛素级联并比较各组之间的脑胰岛素敏感性。我们还将探讨如何在生长受限动物的中皮质边缘系统的胰岛素作用的不平衡修改DA通路的发展和不同的大脑区域之间的连接参与冲动控制，如纹状体和PFC。最后，我们将探讨的假设，慢性高脂肪/高糖饮食在成年期加剧组之间的差异。这项工作将有助于更好地了解产前生长，代谢，神经化学和行为之间的接口。