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.

项目摘要 将环境中的刺激与生物相关的结果（如奖励或威胁）联系起来是必要的 生存和决策的基础。考虑到无序决策的普遍存在， 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。中脑被盖区（VTA）在这一行为过程中起着至关重要的作用 通过其两种主要的神经元亚型：多巴胺（DA）和GABA。GABA神经元直接与局部 DA神经元和调制DA的传输。DA神经元增加线索-奖励关联的活动， 基于预测的奖励与现象中预期的奖励相匹配的程度来调节放电 奖励预测误差（Reward Prediction Error，RPE）GABA神经元也增加奖励学习的活动， 信号传导有助于RPE DA动力学。相反，DA神经元在令人厌恶的环境中受到抑制， GABA神经元增加活动。鉴于VTA GABA在食欲和厌恶处理中的作用， 神经元可以独特地参与在决策中整合效价。了解这些角色 多价学习中的神经元是重要的，因为行为往往发生在动机的情况下， 冲突，其中对立的目标（即，食物和避免威胁）同时发生，需要 需要权衡和整合的欲望和厌恶因素，以指导选择。这一提议将使 使用新的工具来定位，记录和操纵VTA DA和GABA神经元，以研究 它们的功能连接性（目标1）和它们在价整合中的作用（目标2）。首先我会 光遗传学抑制GABA神经元，同时通过在体纤维记录VTA DA神经元的活性 测光法这些实验将检验VTA GABA调节局部DA神经元的假设， 这种关系可以随着经验而改变。我还将操纵和记录DA和GABA的动态， 一个动机冲突任务，其中有两个相反的目标（消耗蔗糖和避免休克）， 剖析这些群体在价整合中扮演的角色。这些研究将检验VTA的假设， DA和GABA神经元分别产生价值和显著性信号，这是共同需要的， 整合效价，用于动态奖励寻求。