Commonalities and vulnerabilities in context-induced reward seeking and habits

环境引起的奖励寻求和习惯的共性和弱点

基本信息

批准号：
8623540
负责人：
Shannon Leigh Gourley
金额：
$ 8.67万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8623540
关键词：
Addictive Behavior Address Adolescence Adolescent Adult Affinity Age Agonist Amygdaloid structure Anatomic Models Animals Behavioral Biological Biological Models Brain Brain-Derived Neurotrophic Factor Cardiovascular Diseases Cell Nucleus Cocaine Cocaine Dependence Cocaine Users Complex Decision Making Dendritic Spines Dependence Development Disease Dose Drug Addiction Drug usage Ensure Epidemiology Foundations Funding Gene Silencing Goals Habits Histology Human Infusion procedures Intervention Life Malignant Neoplasms Mediating Modeling Molecular Mus Neurons Neurosciences Neurotrophic Tyrosine Kinase Receptor Type 2 Operative Surgical Procedures Outcome Pathology Peer Review Pharmaceutical Preparations Positioning Attribute Prefrontal Cortex Preparation Process Protocols documentation Psychopathology Recording of previous events Recovery Relapse Reporting Research Response to stimulus physiology Rewards Self Administration Self-Administered Signal Transduction Site Speed Staging Structure Substance Addiction Substance abuse problem System Techniques Testing Therapeutic Time TimeLine Tissues Vertebral column Viral Virulence Work addiction adolescent substance abuse adverse outcome base behavior test brain tissue cocaine exposure computerized data processing cost expectation in vivo neurotrophic factor novel postnatal psychostimulant public health relevance relating to nervous system research study resilience tool

项目摘要

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.

项目摘要青春期是一个神经生物学上不同的发育周期，其特征是实验性药物使用和对滥用药物滥用疾病的发展的脆弱性。青少年滥用药物会增加终生成瘾的可能性，可卡因成瘾随着特定的毒力为例，15-16％的青少年可卡因用户将在10之内发展依赖性多年的首次曝光。因此，确定可卡因脆弱性的机制是一项关键的研究。现在，人们广泛认为，心理刺激性暴露会在前额叶内重新组织树突状刺皮质，但是可卡因暴露对神经结构的长期后果是否与因果关系相关在任何年龄段的成瘾脆弱性中都代表了该领域的一场活泼的辩论。这部分是因为很少有实验室配备了模拟动物系统成瘾的工具，以捕获和枚举树突状刺以及操纵离散神经信中树突状脊柱结构的分子调节剂，以分离因果关系。我们将精确地应用这些工具来确定青少年可卡因自我管理，其最终目标是扭转早期的不利后果生命可卡因暴露。作为模型系统，我们使用的小鼠很容易自动采用可卡因。我们将专注于轨道额皮质脑源性神经营养因子（BDNF）及其高亲和力受体TRKB。产后BDNF表达是青少年皮质脊柱发育的关键决定因素和改进。然而，早期寿命刺激性暴露降低了轨道皮层中的BDNF，一种结构广泛涉及成瘾病理。因此，BDNF系统可能会在逆转青少年可卡因自我管理的组织和功能后果。我们建议使用我的实验室中已经建立的实验协议提出3个离散实验： 1）我们将在具有自我的小鼠的3D深层轨道皮质神经元中隔离并重建，这些神经元具有自我在青春期施用可卡因，然后显示出对可卡因的行为脆弱性或韧性在成年期寻求和刺激反应习惯形成。我们假设可卡因脆弱性将是与深层眶额皮质中的神经简化有关。 2）我们将阻止青少年可卡因自我管理的长期行为影响（上下文诱导可卡因寻求基于神经营养的干预策略，寻求和刺激反应习惯形成）。具体而言，我们期望用新型的TrkB激动剂7,8-DHF治疗可卡因暴露的青少年小鼠遮住了早期可卡因自我管理的长期负面影响。 3）最后，我们将测试一个神经解剖模型，其中眶额皮质BDNF缺乏导致刺激性反应习惯是由于轨道额 - 杏仁核神经电路的扰动而引起的。实质性的初步发现支持每个目标，并确保该项目的完成。