Target dependent effects of peptide signaling in the VTA

VTA 中肽信号传导的靶标依赖性效应

• 批准号: RGPIN-2016-04060
• 负责人: Borgland, Stephanie
• 金额: $ 3.72万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=630722
• 关键词: Target; dependent; effects; peptide; signaling

The long-term goal of my research program is to determine how learning about rewards and motivation to obtain them is encoded in neural activity in an area of the brain responsible for reward-seeking behaviours. The dopamine neurons of the ventral tegmental area (VTA) encode cues in the environment that predict stimuli of positive or negative valence, but how this occurs and if this changes with different motivational states is not well understood. One possibility is that neuropeptides can modulate dopamine neurons in a state-dependent manner. For example, our recent work has demonstrated that satiety peptides suppress the output of dopamine neurons. Furthermore, the neuropeptide orexin released from neurons of the lateral hypothalamus (LH), are activated in response to arousal, and plays a key role in motivating animals to seek rewards. The peptides orexin and dynophin are co-localized in LH neurons that project to the VTA. Interestingly, orexin action in the VTA is stimulatory whereas dynorphin action is inhibitory. Therefore, if both peptides are released simultaneously, it is unclear how reward-seeking effects of orexin are promoted. Understanding how this circuit functions adds a highly novel component to understanding the state-dependency of learning reward-predictive cues. We hypothesize that orexin and dynorphin are co-released in the VTA and modulate independent VTA projections to other brain regions such as the basolateral amygdala (BLA), nucleus accumbens (NAc) or medial prefrontal cortex (mPFC). To address this hypothesis, we propose 2 objectives:

我的研究计划的长期目标是确定如何将学习奖励和获得奖励的动机编码到负责寻求奖励行为的大脑区域的神经活动中。腹侧被盖区（VTA）的多巴胺神经元编码环境中的线索，预测正价或负价的刺激，但这种情况是如何发生的以及这种情况是否会随着不同的动机状态而变化尚不清楚。一种可能性是神经肽可以以状态依赖的方式调节多巴胺神经元。例如，我们最近的工作表明，饱腹感肽会抑制多巴胺神经元的输出。此外，下丘脑外侧 (LH) 神经元释放的神经肽食欲素在受到唤醒反应时被激活，在激励动物寻求奖励方面发挥着关键作用。肽类食欲素和强啡肽共定位于投射到 VTA 的 LH 神经元中。有趣的是，VTA 中的食欲素作用是刺激性的，而强啡肽的作用是抑制性的。因此，如果两种肽同时释放，尚不清楚食欲素的寻求奖赏作用是如何促进的。了解该回路的功能为理解学习奖励预测线索的状态依赖性添加了一个非常新颖的组成部分。我们假设食欲素和强啡肽在 VTA 中共同释放，并调节独立的 VTA 投射到其他大脑区域，如基底外侧杏仁核 (BLA)、伏隔核 (NAc) 或内侧前额叶皮质 (mPFC)。为了解决这个假设，我们提出两个目标：