Modulation of Sensory Representations in the Ventral Striatum

描述（由申请人提供）：药物成瘾是一种使人衰弱的疾病，会造成相当大的社会，心理和经济伤害。成瘾的标志性症状是对获得和消费毒品的强烈渴望，通常是由与毒品相关的感官线索引发的。引起这些症状的机制依赖于药物诱导的多巴胺增加-一种通常参与联想学习，奖励处理和动机的神经化学物质-不成比例地加强了药物配对的感觉体验。为了设计用于预防和治疗物质滥用的疗法，确定控制天然多巴胺介导的强化及其在成瘾中的扰动的神经机制是至关重要的。受滥用药物影响最严重的大脑区域是腹侧纹状体，多巴胺将中性感觉体验归因于腹侧纹状体 奖励性的，激励性的这种多巴胺依赖性转化涉及属于几个功能不同类别的大量神经元中神经活动的变化。然而，确定这些变化的确切性质-以及它们如何成为成瘾中线索触发行为出现的基础-由于腹侧纹状体无法进行大规模，高分辨率的神经活动监测而不可能。为了解决这一限制并鉴定使药物配对的感觉线索高度激励的多巴胺介导的转化，我们提出部署我们在麻醉小鼠中开发的独特手术方法，其将首次实现对腹侧纹状体中功能鉴定的神经元的活动的大规模监测。使用这种方法，再加上多光子群体成像，我们将在AIM I，确定感觉编码的腹侧纹状体的细分的一般原则，以及这种编码被修改的具体方式，通过急性管理可卡因和安非他明。然后在AIM II中，我们将通过将我们的成像方法与传统的经典条件反射方法相结合来解决自然奖励和滥用药物如何改变感觉经验的神经表征。拟议的项目将是第一个观察体内腹侧纹状体感觉编码的一般原则，通过监测大规模遗传学群体的活动， 识别出属于不同功能类别的神经元。总之，所提出的实验将揭示这种活动的变化特征，因为中性感官体验通过自然奖励学习获得动机价值，以及这种转变如何成为被成瘾干扰的联想学习的纹状体原则的基础。

DESCRIPTION (provided by applicant): Drug addiction is a debilitating disease that causes considerable social, psychological, and financial harm. The hallmark symptom of addiction, an intense desire to obtain and consume drugs, is often triggered by drug-associated sensory cues. The mechanism that gives rise to these symptoms relies on drug-induced increase in dopamine--a neurochemical normally involved in associative learning, reward-processing, and motivation--that disproportionately reinforces drug-paired sensory experience. In order to design therapies for preventing and treating substance abuse, it is crucial to determine the neural mechanisms that govern natural dopamine-mediated reinforcement and its perturbation in addiction. The brain region that is most critically affected by drugs of abuse is the ventral striatum, and it is within the ventral striatum that dopamine attributes neutral sensory experience with rewarding, motivational properties. This dopamine-dependent transformation involves changes in neural activity in large populations of neurons that belong to several functionally distinct classes. However determining the exact nature of these changes--and how they underlie the emergence of cue-triggered behaviors in addiction--has not been possible due to the inaccessibility of the ventral striatum to large-scale, high-resolution monitoring of neural activiy. To address this limitation and identify the dopamine- mediated transformation that renders drug-paired sensory cues highly motivating, we propose to deploy a unique surgical approach we have developed in the anesthetized mouse that will for the first time enable large- scale monitoring of activity in functionally identified neurons in the ventral striatum. Using this approach, coupled with multiphoton population imaging we will, in AIM I, determine general principles of sensory encoding in a subdivision of the ventral striatum, and the specific ways in which this encoding is modified by acute administration of cocaine and amphetamine. Then in AIM II, we will address how natural rewards and drugs of abuse alter neural representations of sensory experience by coupling our imaging approach with traditional classical conditioning approaches. The proposed project will be the first to observe general principles of sensory encoding in the ventral striatum in vivo by monitoring activity in large populations of genetically identified neurons belonging to functionally distinct classes. Together, the proposed experiments will reveal what features of this activity change as neutral sensory experience acquires motivational value through natural-reward learning and how this transformation underlies striatal principles of associative learning that are perturbed by addiction.