Target dependent effects of peptide signaling in the VTA

我的研究项目的长期目标是确定关于奖励的学习和获得奖励的动机是如何在大脑中负责寻求奖励行为的区域的神经活动中编码的。腹侧被盖区（VTA）的多巴胺神经元在环境中编码预测正或负价刺激的线索，但这是如何发生的，以及这是否随着不同的动机状态而变化，目前还不清楚。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，我们最近的工作已经证明，饱腹肽抑制多巴胺神经元的输出。此外，从外侧下丘脑（LH）神经元释放的神经肽食欲素在觉醒反应中被激活，并在激励动物寻求奖励方面发挥关键作用。肽促食欲素和动力肽共定位于LH神经元，投射到VTA。有趣的是，食欲素在VTA中的作用是刺激性的，而促啡肽的作用是抑制性的。因此，如果这两种多肽同时释放，如何促进食欲素的寻求奖励作用尚不清楚。了解这个回路如何运作，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。我们假设食欲素和肌啡肽在VTA中共同释放，并调节VTA向其他脑区（如基底外侧杏仁核（BLA）、伏隔核（NAc）或内侧前额叶皮层（mPFC））的独立投射。为了解决这一假设，我们提出了两个目标：***1)目标1：确定食欲素和动力啡肽是否以及如何独立调节VTA DA BLA， VTA DA NAc或VTA DA mPFC。Ie。食欲素在VTA中的所有作用都是一样的吗？***2)目的2：确定内源性共同释放的食欲素和运动啡肽是否可以独立调节向BLA或NAc投射的VTA DA神经元的兴奋性突触传递，并确定这种调节如何促进动机行为。******这里提出的研究的总体目标是了解LH食欲素/动力啡肽输入VTA如何以目标依赖的方式调节多巴胺神经元活动。这个回路是奖励学习发生的重要部分，将与我实验室的主题相结合。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受训人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加深我们对我们如何编码驱动目标导向行为的显著线索的理解。＊＊＊＊＊＊＊＊

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. ********