Emergence of valence coding in the ventral striatum

腹侧纹状体价编码的出现

• 批准号: 10359091
• 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/10359091
• 关键词: Address; Air; Animals; Area; Association Learning; Aversive Stimulus; Axon; Behavior; Behavioral Paradigm; Binge Eating; Brain; Code; Cues; Decision Making; Disease; Dopamine; Drug Addiction; Event; Fiber; Foundations; Goals; Heterogeneity; Hot Spot; Image; Learning; Light; Motivation; Mus; Nature; Neurons; Neurosciences; Odors; Olfactory Cortex; Olfactory tubercle; Outcome; Photometry; Physiology; Play; Population; Process; Punishment; Research; Response to stimulus physiology; Rewards; Rodent; Role; Sensory; Shapes; Signal Transduction; Site; Stimulus; Synaptic plasticity; Testing; Training; Ventral Striatum; Ventral Tegmental Area; addiction; calcium indicator; cell type; classical conditioning; cocaine self-administration; efficacious treatment; flexibility; maladaptive behavior; microendoscopy; nerve supply; neural circuit; neuromechanism; novel; olfactory bulb; optogenetics; piriform cortex; public health relevance; relating to nervous system; sensory input; sensory stimulus; ward

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.

总结 学习特定感官刺激和结果之间联系的能力，如重新 监管或处罚是灵活行为的基本要求。此关联的故障 这一过程可能是各种疾病的基础，如药物成瘾和暴食。老鼠可以 学习新的刺激反应协会后，只有几次重复，但电路， 在学习过程中发生的变化在很大程度上是未知的。嗅结节（OT）是腹索的一部分， atum位于感觉和奖励中心之间的界面，接收强烈的嗅觉信号。 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 它与奖赏有关，是可卡因自我给药的公认“热点”。这些OB- servations表明，OT是异突触可塑性的网站，以建立代表价- 与气味有关的症状。PI已经在小鼠中开发了一种行为范例， 快速和灵活的任意气味线索与奖励或厌恶的关联。使用这种行为， 他们在旧约中发现了明确的奖赏表现的证据。在这个项目中， 将测试的假设，在OT的神经活动是修改在学习过程中，以反映价值- Lence的刺激，和多巴胺能信号从腹侧被盖区发挥了关键作用，在这种学习。目标1： 为了确定OT神经元在学习后是否发出明确的（气味独立的）效价信号， ing.将训练小鼠学习任意分配的一组气味的化合价，并记录 使用OT中的四极管在行为动物中进行尖峰活动。检验的假设是， 是OT神经元活动中的一种明确的效价表征， 当新的气味联想被学习时，速度很快。目标2：确定奖励和厌恶 在OT中有代表性。PI将使用厌恶和奖励刺激来询问OT neu是否存在。 rons代表真正的效价信号，或者它们是否表示动机显著性。前提是 OT活动将在相反的方向调制奖励和厌恶的线索，信号前， 明确的效价，具有跨OT细胞类型和亚区的潜在异质性。目标3：遏止- 我是否多巴胺能轴突靶向OT携带价相关的信号，演变过程中， 学习PI将使用纤维光度法和显微内窥镜记录与价相关的活性 多巴胺能轴突的OT和光遗传学刺激这些轴突在行为小鼠。的 一个假设是，OT接收多巴胺输入，这些输入表示值预测误差， 形成OT神经元的价相关活动。这项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现的- 艾德在大脑中，这可能有助于设计治疗异常情况，如成瘾。