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 学习特定感官刺激与结果（例如重新定义）之间关联的能力 监护或惩罚是灵活行为的基本要求。该关联的故障 这个过程可能是各种疾病的根源，例如毒瘾和暴饮暴食。啮齿动物可以 仅经过几次重复就可以学习新的刺激-反应关联，但是这些电路 在学习过程中进行的修改很大程度上是未知的。嗅结节（OT），腹侧条纹的一部分 atum，位于感觉和奖励中心之间的界面，接收强烈的嗅觉 感觉输入以及来自腹侧被盖区（VTA）的多巴胺能神经支配。它有 与奖励有关，是公认的可卡因自我给药的“热点”。这些对象 观察表明 OT 是异质突触可塑性的位点，以建立价代表 与气味有关的状态。 PI 开发了一种小鼠行为范例，允许 将任意气味线索与奖励或厌恶快速而灵活地联系起来。利用这种行为， 他们发现了旧约中明确表示奖励的证据。在这个项目中，PI 将检验以下假设：OT 中的神经活动在学习过程中被修改以反映 va- 刺激的强度，来自 VTA 的多巴胺能信号在这种学习中发挥着关键作用。目标 1： 确定 OT 神经元在学习后是否发出明确的（与气味无关的）价信号 ing。小鼠将被训练学习一组气味的任意指定价并记录 使用来自 OT 的四极管对行为动物进行尖峰活动。检验的假设是 是 OT 神经元活动中的明确价态表示，并且这种表示出现 当学习到新的气味联想时，速度会很快。目标 2：确定奖赏和厌恶如何 都出现在旧约中。 PI 将使用令人厌恶和奖励的刺激来询问 OT 是否会产生负面影响。 rons 代表真正的价信号，或者它们是否表示动机显着性。假设是 OT 活动将向相反的方向调节，以获得奖励和厌恶的线索，发出前 明确的价态，在 OT 细胞类型和亚区域之间具有潜在的异质性。目标 3：阻止—— 探究针对 OT 的多巴胺能轴突是否携带在过程中进化的价相关信号 学习。 PI 将使用纤维光度测定法和显微内窥镜检查来记录与价相关的活动 OT 中的多巴胺能轴突和光遗传学刺激行为小鼠的这些轴突。这 假设是 OT 接收代表价值预测错误的多巴胺输入，这些错误可以 塑造 OT 神经元的价相关活动。拟议的研究具有广泛的相关性 神经科学，因为它将揭示奖励预测信号是如何学习和表示的—— 大脑中的信号，这可以帮助设计针对成瘾等异常情况的治疗方法。