Using large scale electrophysiology to study the role of midbrain dopamine neurons underlying motivated behaviors

项目总结 许多精神疾病的一个核心特征是对预测关系的无序估计 在给定的提示和结果之间。这种未能评估和产生适当的行为反应 对于既有奖励又有厌恶的暗示是正确的。例如，在创伤后应激障碍中， 刺激可以引起强烈的厌恶动机反应，即使这些是在安全和 熟悉的背景。另一方面，在物质使用障碍中，以前与药物配对的线索可能会引发强烈的 渴望和引发复发，尽管这些线索是在从未使用过毒品的环境中遇到的。 因此，了解支持和调节线索触发的因素和神经系统是至关重要的 动机，希望找出潜在的治疗动机障碍的方法。体内的多巴胺神经元 众所周知，腹侧被盖区(VTA)负责与奖励相关的学习，但 VTA多巴胺神经元被厌恶刺激兴奋，这反对这些神经元在 奖励。然而，人们对VTA多巴胺神经元的这种异质性了解有限。 有助于动态控制奖励和厌恶，因为这些主要是在以下条件下进行评估的 动物学习的线索-结果关联是僵硬和稳定的，这阻碍了区分 值和价的编码。在这里，我提出了一种动态改变关系的新的行为方法 在逐个试验的基础上，在线索和奖励或厌恶结果之间进行比较，以了解贡献 VTA多巴胺神经元与灵活产生动机行为有关。这种行为方法将允许 我要测试VTA多巴胺神经元的定义子集是否编码长期运行的学习价值与 暗示的直接动机意义，否则是模棱两可的奖励或厌恶，这具有 对我们理解这些神经元在健康和疾病中的重要意义。主要目标是 (1)应用大规模电生理学方法研究投射中奖赏和厌恶的细节关联-- 确定的VTA多巴胺神经元，(2)评估不同的VTA多巴胺神经元对灵活的 对奖赏和厌恶的控制，以及(3)详细说明腹侧基底节输入对 VTA多巴胺神经元，使产生灵活的动机行为成为可能。总而言之， 拟议的研究为我提供了广泛的培训，将我的技能转化为老鼠，整合了光遗传学 与大规模记录方法，并开发了一种方法，用于记录细胞类型和 复杂行为期间的电路定义方式。大鼠脑VTA区多巴胺神经元功能的解构 对奖赏和厌恶的快速调节是我们理解这些贡献的重要一步 在精神疾病中的神经元，并具有产生新的干预和治疗的潜力。

PROJECT SUMMARY A core feature of a number of psychiatric illnesses is the disordered estimation of the predictive relationship between a given cue and an outcome. This failure to appraise and generate appropriate behavioral responses is true for cues that both are rewarding and aversive. For example, in post-traumatic stress disorders innocuous stimuli can elicit intense aversive motivational responses even though these were encountered in a safe and familiar context. On the other hand, in substance use disorders previously drug-paired cues can elicit intense craving and trigger relapse, despite these cues being encountered in settings where drug use never occurred. As a result, it is critical to understand the factors and neural systems that support and regulate cue-triggered motivations in the hope of identifying potential treatments for disorders of motivation. Dopamine neurons within the ventral tegmental area (VTA) are well known to be responsible for reward-related learning, yet subsets of VTA dopamine neurons are excited by aversive stimuli which opposes an exclusive role for these neurons in reward. However, there is limited understanding of how such heterogeneity in VTA dopamine neurons contributes to the dynamic control of reward and aversion as these are primarily assessed in conditions where animals learn cue-outcome associations that are rigid and stable which occlude the ability to differentiate the encoding of value and valence. Here, I propose a novel behavioral approach that dynamically alters the relations between cues and either rewarding or aversive outcomes on a trial-to-trial basis to understand the contribution of VTA dopamine neurons to the flexible generation of motivated behaviors. This behavioral approach will allow me to test whether defined subsets of VTA dopamine neurons encode the long-running learned value versus the immediate motivational significance of cues that are otherwise ambiguously rewarding or aversive which has important implications for our understandings of these neurons in health and disease. The primary goals are to (1) apply a large-scale electrophysiological approach to detail correlates of reward and aversion in projection- defined VTA dopamine neurons, (2) assess the contribution of distinct VTA dopamine neurons to the flexible control of reward and aversion, and (3) detail the computations supported by ventral basal ganglia inputs onto VTA dopamine neurons that make possible the generation of flexible motivated behavior. Collectively the proposed research provides me extensive training that translates my skills into mice, integrates optogenetics with large-scale recording approaches, and develops an approach for the recording of neurons in a cell-type and circuit-defined manner during complex behaviors. Deconstructing the function of VTA dopamine neurons in the rapid regulation of reward and aversion is a significant step in our understanding of the contributions of these neurons in psychiatric illness and has potential for generating novel interventions and therapies.