Nucleus accumbens neuronal ensembles in drugs and natural rewards seeking.

无节制的奖赏寻求是饮食和物质使用障碍的共同中心特征，这些疾病暴露了 患者终生易复发。最近的研究表明，有益的经历会导致 同步激活伏核核心(NAcore)中的离散数量的神经元 与奖励相关的背景有因果关系。这项提议意在描述神经元集合的特征 是通过NAcore和邻近地区的奖励经验和寻找奖励和灭绝的代码建立的 电路。在整个提案中，特别强调比较特定于群体的变化 毒品(可卡因)和天然(蔗糖)之间的奖励，以解决成瘾药物是否篡夺 生物奖赏所使用的电路或涉及不同的电路机制。我将使用定向重组 在活跃群体(TRAP)策略中，特别是允许tdTomato标记的FosCreERxAi14小鼠系 在不同的行为中特别激活的神经元。K99的目标是解决以下问题 寻找可卡因和蔗糖的群体及其在同一动物中的共存 对已描述的奖励自我管理和线索诱导恢复的模型的创新版本 寻求(Aim1a)。新生成的FosCreERxAi14xD2GFP报告小鼠和RNAScope策略(培训 组件#1)将允许严格识别组成每个集合的细胞类型(目标1B)。 AMPA/NMDA比率的功能测量将是可塑性的标志(培训部分2) 在寻找奖赏的过程中，在标记的细胞内执行(目标2)。建议书的R00部分评估 在使用抑制和恢复线索的过程中，合奏的必要性和充分性(目标3A-B) 兴奋性设计者受体被一种设计者药物(DREADD)特异性地激活 集合细胞，以及特定于奖励的集合之间的功能联系(目标3C)。 将使用FosCreERxAi14xD2GFP报告小鼠和 RNAScope(目标4A)。最后，将完成关于寻找和灭绝的特定组合的投影轮廓 使用依赖于集合的逆转录病毒表达(Aim3B)，然后是集合和投影特异性 塑性测量(目标4C)。初步数据显示，可卡因、蔗糖和消亡 在NAcore中，合奏在很大程度上是不同的，但部分重叠的合奏，以及AAV目标 DREADD的表达仅限于系综。所获得的数据将为了解这些机制提供新的线索 维持对毒品和自然奖赏的不适应、奖赏导向的寻求和灭绝行为。 南卡罗来纳医科大学提供了一个很好的研究环境。在博士的指导下。 卡利瓦斯和我的指导委员会，我将体验高级技术培训和职业发展 成功完成此项目的指导，同时过渡到独立的教职员工职位，并进一步 研究潜在奖赏寻求的合奏的内在属性。

Unmanaged reward seeking is a shared central feature of eating and substance use disorders that expose patients to lifelong relapse vulnerability. Recent research shows that rewarding experiences induce synchronous activation of a discrete number of neurons in the nucleus accumbens core (NAcore) that are causally linked to reward-related contexts. This proposal intends to characterize the neuronal ensembles that are built through reward experience and code for reward seeking and extinction in the NAcore and adjacent circuitry. Throughout the proposal, special emphasis is given to comparing ensemble-specific changes between drugs (cocaine) and natural (sucrose) rewards to address whether or not addictive drugs usurp circuitry used by biological rewards or involve distinct circuitry mechanisms. I will use targeted recombination in active populations (TRAP) strategy, specifically the FosCreERxAi14 mouse line that allows tdTomato tagging of the neurons specifically activated during distinct behaviors. The K99 aims address the characterization of the cocaine- and sucrose-seeking ensembles and their colocalization within the same animal using an innovative version of the well-described model of reward self-administration and cue-induced reinstatement of seeking (Aim1A). The newly generated FosCreERxAi14xD2GFP reporter mice and RNAscope strategy (training component #1) will allow rigorous identification of the cell types comprising each ensemble (Aim 1B). Functional measurements of AMPA/NMDA ratios, a marker of plasticity (training component #2), will be performed within tagged cells during reward seeking (Aim 2). The R00 portion of the proposal evaluates necessity and sufficiency (Aims 3A-B) of the ensembles during cued-reinstatement using inhibitory and excitatory designer receptors exclusively activated by a designer drug (DREADD) specifically expressed in the ensemble cells, as well as the functional connection between reward-specific ensembles (Aim 3C). Characterization of the extinction ensemble will be achieved using FosCreERxAi14xD2GFP reporter mice and RNAscope (Aim 4A). Finally, ensemble-specific projections profiles of seeking and extinction will be completed using ensemble-dependent retroviral expression (Aim3B) followed by ensemble and projection specific plasticity measurements (Aim 4C). Preliminary data demonstrate that cocaine, sucrose and extinction ensembles form largely distinct but partly overlapping ensembles in the NAcore, and that AAV-targeted DREADD expression is restricted to the ensembles. The data obtained will shed new light on the mechanisms sustaining maladaptive reward-oriented seeking and extinction behaviors towards drugs and natural rewards. The Medical University of South Carolina provides an excellent research setting. Under the mentorship of Dr. Kalivas and my mentoring committee, I will experience advanced technical training and career development guidance to successfully complete this project while transitioning to an independent faculty position and further study of the intrinsic properties of ensembles underlying reward seeking.