Modulation of Sensory Representations in the Ventral Striatum

描述(申请人提供)：毒瘾是一种衰弱的疾病，会造成相当大的社会、心理和经济损害。上瘾的标志性症状是获得和消费毒品的强烈愿望，通常是由与毒品相关的感官线索触发的。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--不成比例地加强与药物配对的感觉体验。为了设计预防和治疗药物滥用的疗法，确定控制自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，正是在腹侧纹状体内，多巴胺归因于中性感觉体验。 有回报，有动力的特性。这种多巴胺依赖的转变涉及到属于几个不同功能类别的大量神经元的神经活动的变化。然而，由于腹侧纹状体无法对神经活动进行大规模、高分辨率的监测，因此无法确定这些变化的确切性质--以及它们是如何导致成瘾中线索触发行为的出现的。为了解决这一限制并确定使药物配对感觉线索高度激发的多巴胺介导的转换，我们建议采用我们在麻醉小鼠中开发的一种独特的手术方法，该方法将首次能够大规模监测腹侧纹状体功能识别神经元的活动。使用这种方法，结合多光子群体成像，我们将在AIM I中确定腹侧纹状体细分的感觉编码的一般原理，以及这种编码被急性注射可卡因和苯丙胺改变的具体方式。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，解决自然奖励和滥用药物如何改变感觉体验的神经表征。这项拟议的项目将通过监测大量遗传群体的活动，首次在活体观察腹侧纹状体感觉编码的一般原理。 识别出属于不同功能类别的神经元。总之，拟议的实验将揭示当中性感觉体验通过自然奖赏学习获得动机价值时，这一活动的哪些特征发生变化，以及这种变化如何为受成瘾困扰的联想学习的纹状体原则奠定基础。

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.