Resolving the role of VTA dopamine and GABA neurons in associative learning

解析 VTA 多巴胺和 GABA 神经元在联想学习中的作用

• 批准号: 10749667
• 负责人: Margaret E Stelzner
• 金额: $ 3.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749667
• 关键词: Animals; Association Learning; Behavior; Behavioral; Brain region; Calcium; Color; Computing Methodologies; Conflict (Psychology); Consumption; Cues; Decision Making; Desire for food; Disease; Disinhibition; Dopamine; Elements; Environment; FLP recombinase; Fiber; Floor; Genetic; Goals; Halorhodopsins; Imaging Device; In Situ Hybridization; Learning; Motivation; Neurons; Outcome; Photometry; Play; Population; Prevalence; Process; Rattus; Rewards; Role; Shock; Signal Transduction; Stimulus; Sucrose; Synapses; Synaptic plasticity; Testing; Time; Training; Ventral Tegmental Area; Viral; calcium indicator; cost; dopaminergic neuron; experience; experimental study; food consumption; gamma-Aminobutyric Acid; in vivo; insight; motivated behavior; neurobiological mechanism; neurotransmission; novel; optogenetics; promoter; recruit; response; selective expression; sensor; tool; transmission process

PROJECT SUMMARY Associating stimuli in the environment to biologically relevant outcomes, such as reward or threat, is necessary to survive and foundational to decision making. Given the prevalence of disordered decision making, there is a pressing need to understand the basic neurobiological mechanisms of associative learning underlying cue-guided motivation and behavior. The Ventral Tegmental Area (VTA) is essential to this behavioral process through its two main neuronal subtypes: dopamine (DA) and GABA. GABA neurons synapse directly onto local DA neurons and modulate DA transmission. DA neurons increase activity to cue-reward associations, modulating firing based on the extent to which reward predicted matches reward expected in a phenomenon known as reward prediction error (RPE). GABA neurons also increase activity in reward learning and their signaling contributes to RPE DA dynamics. In contrast, DA neurons are inhibited in aversive contexts while GABA neurons increase activity. Given VTA GABA’s role in both appetitive and aversive processing, these neurons may be uniquely engaged to integrate valence in decision making. Understanding the role of these neurons in multi-valent learning is important, because behavior often takes place in situations of motivational conflict, where opposing goals (i.e., consuming food and avoiding threats) occur simultaneously, requiring the appetitive and aversive elements to be weighed and integrated to guide choices. This proposal will make use of new tools to target, record, and manipulate VTA DA and GABA neurons, to investigate their functional connectivity (Aim 1) and their roles in valence integration (Aim 2). First, I will optogenetically inhibit GABA neurons while recording the activity of VTA DA neurons through in vivo fiber photometry. These experiments will test the hypothesis that the VTA GABA modulates local DA neurons and this relationship can change with experience. I will also manipulate and record DA and GABA dynamics during a motivational conflict task in which there are two opposing goals (consuming sucrose and avoiding shock) to dissect the roles these populations play in valence integration. These studies will test the hypothesis that VTA DA and GABA neurons produce value and salience signals, respectively, that are collectively necessary to integrate valence, for dynamic reward seeking.

项目概要 将环境中的刺激与生物学相关的结果（例如奖励或威胁）联系起来是必要的 生存和决策的基础。鉴于决策混乱的普遍存在， 迫切需要了解联想学习的基本神经生物学机制 线索引导的动机和行为。腹侧被盖区（VTA）对于这一行为过程至关重要 通过其两种主要的神经元亚型：多巴胺 (DA) 和 GABA。 GABA 神经元直接突触到局部 DA 神经元并调节 DA 传输。 DA 神经元增加提示奖励关联的活动， 根据预测奖励与现象中预期奖励的匹配程度来调节激发 称为奖励预测误差（RPE）。 GABA 神经元也会增加奖励学习的活动及其 信号传导有助于 RPE DA 动态。相比之下，DA 神经元在厌恶的环境中受到抑制，而 GABA 神经元活性增加。鉴于 VTA GABA 在食欲和厌恶处理中的作用，这些 神经元可能在决策中独特地参与整合效价。了解这些的作用 多价学习中的神经元很重要，因为行为通常发生在动机的情况下 冲突，相反的目标（即消耗食物和避免威胁）同时发生，需要 权衡和整合食欲和厌恶因素以指导选择。该提案将使 使用新工具来定位、记录和操纵 VTA DA 和 GABA 神经元，以研究 它们的功能连接（目标 1）及其在价态整合中的作用（目标 2）。首先，我会 光遗传学抑制 GABA 神经元，同时通过体内纤维记录 VTA DA 神经元的活动 光度测定。这些实验将检验 VTA GABA 调节局部 DA 神经元和 这种关系会随着经验而改变。我还将在过程中操纵和记录 DA 和 GABA 动态 动机冲突任务，其中有两个相反的目标（消耗蔗糖和避免休克） 剖析这些群体在价态整合中发挥的作用。这些研究将检验 VTA 的假设 DA 和 GABA 神经元分别产生价值信号和显着信号，这些信号共同是 整合价，以实现动态奖励寻求。