Commonalities and vulnerabilities in context-induced reward seeking and habits

项目摘要 青春期是一个神经生物学上独特的发育时期，其特征是高比率的 实验性药物使用和易患药物滥用障碍。青少年 物质滥用增加了终身成瘾的可能性，可卡因成瘾的出现是因为 例如，15-16%的青少年可卡因使用者将在10年内产生依赖性。 第一次曝光的年份因此，确定可卡因脆弱性的机制是一项至关重要的研究任务。 现在人们普遍认为，精神兴奋剂暴露重组树突棘在前额叶 皮质，但可卡因暴露对神经结构的长期后果是否有因果关系 在任何年龄都有成瘾的脆弱性代表了该领域的一场激烈辩论。这部分是因为很少有实验室 配备了在动物系统中模拟成瘾的工具，以捕获和计数树突棘， 操纵离散神经回路中树突棘结构的分子调节器， 因果关系。我们将准确地应用这些工具来确定组织和行为的影响， 青少年自我服用可卡因，最终目标是扭转早期服用可卡因的不良后果， 终生接触可卡因作为一个模型系统，我们使用小鼠，像人类一样，容易自我管理可卡因。 我们将重点介绍眶额皮质脑源性神经营养因子（BDNF）及其高亲和力的 受体trkB。出生后BDNF表达是青春期皮质脊柱发育的关键决定因素 和精致。然而，早期生活中暴露于刺激物会减少眶额皮质中的BDNF， 广泛涉及成瘾病理学。因此，BDNF系统可能是一个有希望的靶点， 青少年可卡因自我管理的组织和功能后果。 我们提出了3个离散实验，使用我的实验室已经建立的实验方案： 1)我们将分离和重建3D深层眶额皮质神经元从小鼠，有自我- 在青少年时期服用可卡因，然后表现出对可卡因的行为脆弱性或弹性 寻求和刺激-反应习惯的形成。我们假设可卡因的脆弱性 与眶额皮层深层神经简化有关。 2)我们将阻止青少年可卡因自我管理的长期行为影响（情境诱导）。 可卡因寻求和刺激反应习惯形成）与基于神经营养因子的干预策略。 具体来说，我们预计用新型trkB激动剂7，8-DHF治疗可卡因暴露的青春期小鼠将 消除幼年可卡因自我给药的长期负面影响。 3)最后，我们将测试一个神经解剖模型，其中眶额皮质BDNF缺乏导致 由于眶额杏仁核神经回路的扰动而导致的刺激反应习惯。 实质性的初步调查结果支持每一个目标，并将确保完成这一项目。

PROJECT SUMMARY Adolescence is a neurobiologically distinct developmental period characterized by high rates of experimental drug use and vulnerability to the development of substance abuse disorders. Adolescent substance abuse increases the likelihood of developing lifelong addiction, and cocaine addiction emerges with particular virulence-for example, 15-16% of adolescent cocaine users will develop dependence within 10 years of first exposure. Thus, identifying mechanisms of cocaine vulnerability is a critical research imperative. It is now widely accepted that psychostimulant exposure reorganizes dendritic spines within the prefrontal cortex, but whether the long-term consequences of cocaine exposure on neural structure are causally related to addiction vulnerability at any age represents a lively debate in the field. This is in part because few labs are equipped with the tools to model addiction in animal systems, to capture and enumerate dendritic spines, and to manipulate the molecular regulators of dendritic spine structure in discrete neurocircuits in order to isolate causal relationships. We will apply precisely these tools to identify the organizational and behavioral impact of adolescent cocaine self-administration, with the ultimate goal of reversing the adverse consequences of early- life cocaine exposure. As a model system, we use mice, which like humans, readily self-administer cocaine. We will focus on orbitofrontal cortical Brain-derived Neurotrophic Factor (BDNF) and its high-affinity receptor trkB. Postnatal BDNF expression is a critical determinant of adolescent cortical spine development and refinement. However, early-life stimulant exposure decreases Bdnf in the orbitofrontal cortex, a structure widely implicated in addiction pathology. Thus, BDNF systems may present a promising target in reversing the organizational and functional consequences of adolescent cocaine self-administration. We propose 3 discrete experiments using experimental protocols already established in my lab: 1) We will isolate and reconstruct in 3D deep-layer orbitofrontal cortical neurons from mice that had self- administered cocaine in adolescence and then showed either behavioral vulnerability or resilience to cocaine seeking and stimulus-response habit formation in adulthood. We hypothesize that cocaine vulnerability will be associated with neural simplification in deep-layer orbitofrontal cortex. 2) We will block the long-term behavioral effects of adolescent cocaine self-administration (context-induced cocaine seeking and stimulus-response habit formation) with neurotrophin-based intervention strategies. Specifically, we expect that treating cocaine-exposed adolescent mice with the novel trkB agonist 7,8-DHF will occlude the long-term negative impact of early-life cocaine self-administration. 3) Finally, we will test a neuroanatomical model in which orbitofrontal cortical Bdnf deficiency results in stimulus-response habits due to perturbations in an orbitofrontal-amygdala neurocircuit. Substantial preliminary findings support each aim and will ensure the completion of this project.