Context dependent modulations of dopamine signaling

多巴胺信号传导的上下文相关调节

• 批准号: 9153211
• 负责人: Naoshige Uchida
• 金额: $ 42.25万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9153211
• 关键词: Affect; Air; Anhedonia; Aversive Stimulus; Behavioral Paradigm; Brain; Complex; Cues; Data; Disease; Dopamine; Eating Disorders; Etiology; Event; Foundations; Goals; Health; Individual; Influentials; Lead; Learning; Liquid substance; Masks; Measures; Mental Depression; Mental disorders; Methods; Midbrain structure; Monkeys; Mus; Names; Odors; Oral cavity; Outcome; Paper; Parkinson Disease; Preventive; Probability; Punishment; Rewards; Schizophrenia; Signal Transduction; Sum; Testing; Therapeutic; Ventral Tegmental Area; Water; addiction; classical conditioning; design; dopamine system; dopaminergic neuron; expectation; high reward; neural circuit; response

Project Summary Dopamine is thought to be a key regulator of learning from appetitive as well as aversive events. It has been proposed that dopamine neurons signal value prediction error (VPE, often referred to as reward prediction error), or the difference between the values of actual and predicted outcomes. Although accumulating evidence supports this idea for reward, how dopamine neurons integrate information about aversive events remains highly controversial. Some studies have shown that aversive stimuli inhibit dopamine neurons, while others have suggested that aversive events activate at least some dopamine neurons. Others have argued that dopamine neurons largely ignore aversive events. In order to resolve the above controversy, this project aims to examine how dopamine neurons in the ventral tegmental area (VTA) convey information about aversive events . Our main hypothesis is that dopamine neurons alter the way they respond to rewarding and aversive stimuli depending on reward contexts. More specifically, we hypothesize that in low reward contexts, dopamine neurons faithfully signal value prediction errors by combining the value of both reward and aversion. In high reward contexts, we hypothesize that dopamine neurons acquire short-latency excitatory response to aversive stimuli and decrease their inhibitory responses to aversive stimuli, thereby diminishing their ability to signal value prediction errors. Aim 1 will test the specific hypothesis that dopamine neurons in VTA represent a combined value for reward and aversion along a one-dimensional value axis in a low reward context. Aim 2 will test the hypothesis that VTA dopamine neurons signal value prediction error in low but not high reward contexts. Aim 3 will test the hypothesis that expectation of an aversive stimulus reduces aversive stimulus- induced inhibition in a subtractive fashion in low reward contexts. Malfunction of the midbrain dopamine system is associated with a variety of pathological conditions including depression, anhedonia, apathy, schizophrenia, addiction, eating disorders and Parkinson's disease. In particular, aberrant dopamine responses to salient events have been implicated in addiction, schizophrenia and other mental disorders. This study will allow us to better understand situations in which dopamine neurons are activated by aversive events, and will serve as a foundation to understand dopamine signaling in health and disease.

项目概要 多巴胺被认为是从食欲和厌恶事件中学习的关键调节剂。它一直 提出多巴胺神经元信号值预测误差（VPE，通常称为奖励预测 误差），或实际结果值与预测结果值之间的差异。尽管不断积累证据 支持这种奖励的想法，多巴胺神经元如何整合有关厌恶事件的信息仍然存在 极具争议性。一些研究表明厌恶刺激会抑制多巴胺神经元，而另一些研究则表明 研究表明，厌恶事件至少会激活一些多巴胺神经元。其他人则认为 多巴胺神经元很大程度上忽略厌恶事件。为了解决上述争议，本项目旨在 研究腹侧被盖区（VTA）的多巴胺神经元如何传递有关厌恶的信息 事件。我们的主要假设是多巴胺神经元改变了它们对奖励和厌恶的反应方式 刺激取决于奖励环境。更具体地说，我们假设在低奖励环境中，多巴胺 神经元通过结合奖励和厌恶的值来忠实地发出值预测错误的信号。在高 在奖励环境中，我们假设多巴胺神经元获得对厌恶的短潜伏期兴奋反应 刺激并减少他们对厌恶刺激的抑制反应，从而削弱他们发出信号的能力 值预测错误。目标 1 将检验 VTA 中的多巴胺神经元代表的具体假设 在低奖励背景下沿一维价值轴奖励和厌恶的组合价值。目标2将 检验 VTA 多巴胺神经元在低奖励但不是高奖励中信号值预测误差的假设 上下文。目标 3 将检验以下假设：对厌恶刺激的预期会减少厌恶刺激—— 在低奖励环境中以减法方式诱导抑制。 中脑多巴胺系统的功能障碍与多种病理状况有关，包括 抑郁症、快感缺失、冷漠、精神分裂症、成瘾、饮食失调和帕金森病。在 特别是，对显着事件的异常多巴胺反应与成瘾、精神分裂症有关 以及其他精神障碍。这项研究将使我们能够更好地了解多巴胺神经元的情况 被厌恶事件激活，并将作为理解健康中的多巴胺信号传导的基础 和疾病。