Emergence of valence coding in the ventral striatum

腹侧纹状体价编码的出现

• 批准号: 10577864
• 负责人: VENKATESH N MURTHY
• 金额: $ 49.14万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10577864
• 关键词: Address; Air; Animals; Area; Association Learning; Aversive Stimulus; Axon; Behavior; Behavioral Paradigm; Binge Eating; Brain; Categories; Code; Cues; Decision Making; Disease; Dopamine; Drug Addiction; Event; Fiber; Foundations; Goals; Heterogeneity; Hot Spot; Image; Learning; Motivation; Mus; Nature; Neurons; Neurosciences; Odors; Olfactory Cortex; Olfactory tubercle; Outcome; Photometry; Physiology; Play; Population; Predictive Value; Process; Punishment; Research; Response to stimulus physiology; Rewards; Rodent; Role; Sensory; Shapes; Signal Transduction; Site; Stimulus; Testing; Training; Ventral Striatum; Ventral Tegmental Area; addiction; calcium indicator; cell type; cocaine self-administration; efficacious treatment; flexibility; maladaptive behavior; microendoscopy; nerve supply; neural; neural circuit; neuromechanism; neurotransmission; novel; olfactory bulb; optogenetics; piriform cortex; public health relevance; sensory input; sensory stimulus

Summary The ability to learn associations between a specific sensory stimulus and an outcome such as re- ward or punishment is a basic requirement for flexible behaviors. Malfunctions of this associative process may underlie various disorders such as drug addiction and binge eating. Rodents can learn novel stimulus-response associations after only a few repetitions, but the circuits that are modified during learning are largely unknown. The olfactory tubercle (OT), a part of the ventral stri- atum, is located at the interface between sensory and reward centers, receiving strong olfactory sensory input as well as dopaminergic innervation from the ventral tegmental area (VTA). It has been implicated in reward and is a recognized “hot spot” for cocaine self-administration. These ob- servations suggest that the OT is the site of heterosynaptic plasticity to establish valence represen- tation associated with odors. The PIs have developed a behavioral paradigm in mice that allows rapid and flexible association of arbitrary odor cues with reward or aversion. Using this behavior, they have found evidence for an explicit representation of reward in the OT. In this project, the PIs will test the hypothesis that neural activity in the OT is modified during learning to reflect the va- lence of stimuli, and that dopaminergic signals from the VTA play a key role in this learning. Aim 1: To determine whether OT neurons signal explicit (odor-independent) valence signals after learn- ing. Mice will be trained to learn the arbitrarily assigned valence of a panel of odors and record spiking activity using tetrodes from the OT in behaving animals. The hypothesis tested is that there is an explicit valence representation in the activity of OT neurons and this representation emerges rapidly when novel odor associations are learned. Aim 2: To determine how reward and aversion are represented in the OT. The PIs will use aversive and rewarding stimuli to ask whether OT neu- rons represent true valence signals, or if they signal motivational salience. The hypothesis is that OT activity will be modulated in opposite directions for rewarding and aversive cues, signaling ex- plicit valence, with potential heterogeneity across OT cell types and subregions. Aim 3: To deter- mine whether dopaminergic axons targeting OT carry valence related signals that evolve during learning. The PIs will use fiber photometry and microendoscopy to record valence-related activity of dopaminergic axons in the OT and optogenetics to stimulate these axons in behaving mice. The hypothesis is that the OT receives dopamine inputs that represent value prediction errors that can shape the valence-related activity of OT neurons. The research proposed has broad relevance for neuroscience because it will shed light on how reward-predicting signals are learnt and represent- ed in the brain, which could help devise treatments in abnormal conditions such as addiction.

概括 在特定的感觉刺激和结果（例如重新）之间学习关联的能力 病房或惩罚是灵活行为的基本要求。这种关联的故障 过程可能是各种疾病的基础，例如吸毒和暴饮暴食。啮齿动物可以 在仅重复几次后，学习新颖的刺激反应关联，但是电路是 在学习过程中进行的修改在很大程度上未知。嗅觉结节（OT），腹面的一部分 - atum，位于感觉中心和奖励中心之间的界面，获得强烈的嗅觉 感官输入以及腹侧对接区域（VTA）的多巴胺能神经。它有 他们被暗示是奖励，是可卡因自我管理的公认的“热点”。这些 食物表明，OT是杂突可塑性的位置，以建立价表示 - 与气味相关的趋势。 PI在小鼠中开发了行为范式，允许 任意气味线索与奖励或厌恶的快速而灵活的关联。使用此行为， 他们找到了明确表示OT中奖励的证据。在这个项目中，PI 将检验以下假设，即在学习过程中修改了OT中的中性活性以反映VA- VTA的刺激以及来自VTA的多巴胺能信号在这项学习中起着关键作用。目标1： 确定ot神经元是否在学习后是否表明明确（无味）价信号 ing。小鼠将接受培训，以学习一群气味的任意分配价和记录 在行为动物中使用来自OT的四极管的尖峰活动。检验的假设是 是OT神经元活动中的显式价表示，该表示形式出现 目标2：确定奖励和厌恶 在OT中表示。 PI将使用厌恶和有益的刺激来询问是否neu- Rons代表真正的价信号，或者如果它们表示动机显着性。假设是 OT活动将在相反的方向调节，以奖励和厌恶提示，并发出信号。 目标3：确定 - 矿山是否针对OT靶向OT的多巴胺能轴突携带价相关的信号 学习。 PI将使用纤维光度法和微观镜检查记录与价相关的活性 OT和光遗传学中的多巴胺能轴突刺激行为小鼠中的这些轴突。这 假设是OT接收多巴胺输入，代表价值预测错误，可以 塑造OT神经元的价相关活性。提出的研究对 神经科学是因为它会阐明如何学习奖励预测信号并代表 - 在大脑中，它可以帮助设计在异常情况（例如成瘾）中的治疗方法。