Nucleus accumbens neuronal ensembles in drugs and natural rewards seeking.

无节制的奖励寻求是饮食和物质使用障碍的共同核心特征， 患者终身复发的脆弱性。最近的研究表明，奖励的经验诱导 同步激活的离散数量的神经元在核延髓核心（NAcore）， 与奖励相关的背景有因果关系。该建议旨在描述神经元集合的特征， 是通过奖励经验和代码的奖励寻求和灭绝在NAcore和邻近 电路在整个提案中，特别强调了比较特定于总体的更改 药物（可卡因）和天然（蔗糖）奖励之间的关系，以解决成瘾药物是否篡夺 生物奖励使用的电路或涉及不同的电路机制。我将使用靶向重组 在活动种群（TRAP）策略中，特别是允许tdTomato标记的FosCreERxAi 14小鼠系 在不同的行为中被激活的神经元。K99的目标是描述 可卡因和蔗糖寻求合奏和他们的共定位在同一动物使用一个 奖励自我管理和线索诱导恢复的良好描述模型的创新版本 寻找（目标1A）。新产生的FosCreERxAi 14 xD 2GFP报告基因小鼠和RNAscope策略（训练 组分#1）将允许严格鉴定包含每个系综的细胞类型（目标1B）。 AMPA/NMDA比率的功能测量，可塑性的标志物（训练成分#2），将被 在奖励寻求过程中在标记细胞内执行（目标2）。建议书的R 00部分评估 必要性和充分性（目标3A-B）的合奏在线索恢复使用抑制和 兴奋性设计受体专门激活的设计药物（DREADD），特异性表达于 系综细胞，以及奖励特定系综之间的功能连接（目标3C）。 将使用FosCreERxA 14 xD 2GFP报告小鼠实现消光系综的表征，并且 RNAscope（目标4A）。最后，将完成搜索和灭绝的特定集合投影剖面 使用系综依赖性逆转录病毒表达（Aim 3B），然后使用系综和投射特异性 塑性测量（目标4C）。初步数据显示可卡因蔗糖和灭绝 系综在NAcore中形成很大程度上不同但部分重叠的系综，并且AAV靶向 DREADD表达式仅限于集合。所获得的数据将揭示新的机制 对药物和自然奖励的寻求和灭绝行为。 南卡罗来纳州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，我将经历先进的技术培训和职业发展 指导成功完成这个项目，同时过渡到独立的教师职位，并进一步 研究奖励寻求背后的集合的内在属性。

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.