Commonalities and vulnerabilities in context-induced reward seeking and habits

描述（由申请人提供）：青春期是一个神经生物学上独特的发育期，其特征是高比例的实验性药物使用和易患药物滥用障碍。青少年药物滥用增加了发展终身成瘾的可能性，可卡因成瘾的出现特别明显，例如，15-16%的青少年可卡因使用者将在第一次接触可卡因后的10年内产生依赖性。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前额叶皮层内的树突棘，但可卡因暴露对神经结构的长期后果是否与任何年龄的成瘾易感性有因果关系，这在该领域引起了激烈的争论。这部分是因为很少有实验室配备了工具，可以在动物系统中模拟成瘾，捕获和计数树突棘，并在离散的神经回路中操纵树突棘结构的分子调节器，以便 来分离因果关系我们将准确地应用这些工具来识别组织 和行为的影响，青少年可卡因自我管理，最终目标是扭转不良后果的早期生活可卡因暴露。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。 我们将重点关注眶额皮质脑源性神经营养因子（BDNF）及其高亲和力受体trkB。出生后BDNF的表达是青春期皮质棘发育和完善的关键决定因素。然而，早期生活中的兴奋剂暴露减少了眶额皮质中的BDNF，这是一种广泛涉及成瘾病理学的结构。因此，BDNF系统可能是一个有前途的目标，在扭转青少年可卡因自我管理的组织和功能的后果。 我们提出了3个离散的实验，使用实验方案已经建立在我的实验室：1）我们将分离和重建在3D深层眶额皮质神经元的小鼠，有自我管理的可卡因在青春期，然后表现出行为脆弱性或恢复可卡因寻求和刺激反应习惯的形成在成年。我们假设可卡因的脆弱性将与深层眶额皮质的神经简化。 2)我们将阻断青少年可卡因自我管理的长期行为效应（情境诱导的可卡因寻求和刺激反应习惯的形成）与神经营养因子为基础的干预策略。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阻断早期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学模型，其中眶额皮质BDNF缺乏导致刺激反应习惯，由于在眶额杏仁核神经回路的扰动。 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。

DESCRIPTION (provided by applicant): 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 effecs 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.