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: 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=690276
• 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:***1) Objective 1: Determine if and how orexin and dynorphin independently modulate VTA DA BLA, VTA DA NAc or VTA DA mPFC. Ie. Are all actions of orexin in the VTA are equal?***2) Objective 2: Determine if endogenously co-released orexin and dynorphin can independently modulate excitatory synaptic transmission onto VTA DA neurons that project to either the BLA or the NAc and determine how this modulation contributes to motivated behaviour. ******The overarching goal of the research proposed here is to understand how the LH orexin/dynorphin input to the VTA modulates dopamine neuronal activity in a target-dependent manner. This circuit is an important part of how reward learning occurs and will integrate with the main themes of my lab. This work will be of wide interest because it touches on the foundations of motivation, arousal and reinforcement learning. In addition, the multifaceted nature of this research will provide trainees with extensive technical skills as well as collecting, analyzing and interpreting data.******Ultimately, my research program will further our understanding of how we encode salient cues that drive goal-directed behaviour. ********

我的研究计划的长期目标是确定学习奖励和获得奖励的动机是如何编码在大脑中负责寻求奖励行为的区域的神经活动中的。腹侧被盖区（VTA）的多巴胺神经元编码环境中的线索，预测刺激的积极或消极的效价，但这是如何发生的，如果这与不同的动机状态的变化还没有很好的理解。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，我们最近的工作已经证明，饱腹感肽抑制多巴胺神经元的输出。此外，从外侧下丘脑（LH）的神经元释放的神经肽食欲素，被激活，以响应唤醒，并在激励动物寻求奖励中起着关键作用。肽食欲素和强啡肽共定位于投射到腹侧被盖区的LH神经元中。有趣的是，食欲素在腹侧被盖区的作用是刺激的，而强啡肽的作用是抑制的。因此，如果两种肽同时释放，则不清楚食欲素的奖赏寻求效应是如何促进的。了解这个回路的功能为理解学习奖励预测线索的状态依赖性增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腹侧被盖区共同释放，并调节独立的腹侧被盖区投射到其他脑区，如基底外侧杏仁核（BLA），杏仁核（NAc）或内侧前额叶皮层（mPFC）。为了解决这一假设，我们提出了2个目标：* 1）目标1：确定食欲素和强啡肽是否以及如何独立地调节VTA DA BLA，VTA DA NAc或VTA DA mPFC。Ie.在腹侧被盖区中，食欲素的所有作用是否相等？* 2)目标二：确定内源性共同释放的食欲素和强啡肽是否可以独立地调节投射到BLA或NAc的腹侧被盖区DA神经元的兴奋性突触传递，并确定这种调节如何有助于动机行为。** 这里提出的研究的首要目标是了解LH食欲素/强啡肽输入腹侧被盖区如何以靶点依赖性方式调节多巴胺神经元活动。这个回路是奖励学习如何发生的重要组成部分，并将与我实验室的主要主题相结合。这项工作将引起广泛的兴趣，因为它涉及动机，唤醒和强化学习的基础。此外，这项研究的多方面性质将为学员提供广泛的技术技能以及收集，分析和解释数据。最终，我的研究计划将进一步了解我们如何编码驱动目标导向行为的显着线索。********