Molecular and circuit-level synergies in decision-making after early-life cocaine

早期可卡因后决策中的分子和电路水平协同作用

基本信息

批准号：
8676766
负责人：
Shannon Leigh Gourley
金额：
$ 22.02万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2016-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8676766
关键词：
Actins Actomyosin Adolescence Adolescent Adolescent Development Adult Affinity Age Agonist Amphetamines Amygdaloid structure Animals Attention Behavioral Binding Brain Brain-Derived Neurotrophic Factor Cellular Morphology Cellular Structures Cocaine Cocaine Dependence Cocaine Users Confocal Microscopy Cytoskeleton Decision Making Dendritic Spines Dependence Development Dose Drug usage Epidemiology Etiology Exposure to Extracellular Matrix Proteins Gene Silencing Gene Transfer Genetic Goals Guanosine Triphosphate Phosphohydrolases Habits Human Infusion procedures Integrins Intervention Learning Life Long-Term Depression Long-Term Effects Mediating Mental Health Modeling Modification Molecular Morphology Mus Neurons Neurotoxins Neurotransmitters Neurotrophic Tyrosine Kinase Receptor Type 2 Operative Surgical Procedures Outcome Pattern Pharmaceutical Preparations Phase Play Population Positioning Attribute Prefrontal Cortex Property Protocols documentation Recording of previous events Relapse Research Resolution Response to stimulus physiology Role Self-Administered Signal Transduction Site Stimulus Stress Structure Substance abuse problem Synapses System Techniques Testing Therapeutic Training Vertebral column Viral Viral Vector Virulence addiction adolescent substance abuse adverse outcome cocaine exposure hippocampal pyramidal neuron in vivo innovation latrunculin A mRNA Expression neocortical neurobiological mechanism novel strategies postnatal psychostimulant public health relevance receptor relating to nervous system resilience response tool

项目摘要

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. 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. Cocaine and other amphetamine-like psychostimulants potently regulate dendritic spine morphology in the prefrontal cortex. Whether the long-term consequences of cocaine exposure on neural structure are causally related to adolescent vulnerabilities represents a lively debate in field, however direct evidence supporting any single position is limited. This is in part becaus few labs are equipped with the tools to model addiction in animal systems, to capture and enumerate dendritic spine structure, and to manipulate the molecular regulators of dendritic spine structure to isolate causal relationships. We will develop and refine tools by which to identify the impact of cocaine-induced dendritic spine reorganization on decision-making and cocaine vulnerability with the goal of reversing the adverse consequences of early-life cocaine exposure. Throughout, we will focus on ¿1-integrin systems. ¿1-integrin is a receptor for extracellular matrix proteins, and it is implicated in cocaine addiction in humans. Because of widespread expression throughout the CNS, ¿1-integrin is an unrealistic target in developing treatments for addiction; however its downstream effector in cortical neurons, p190RhoGAP, offers a promising target for intervention. p190RhoGAP stabilizes prefrontal cortical cell structure directly by inhibiting actomyosin contraction and indirectly by increasing mRNA expression of Brain-derived neurotrophic factor (Bdnf). Therefore, we propose to develop tools to: 1) inhibit p190RhoGAP function in vivo using viral vector approaches. This presents a significant advance beyond existing tools (the p190rhogap heterozygous mouse), which lack anatomical and temporal selectivity. 2) selectively manipulate the high-affinity BDNF receptor, trkB. This is essential because although BDNF is implicated in addiction etiology, its receptor target in this context remains unknown. This is despite the recent development of a brain-penetrant trkB agonist with therapeutic-like benefits in other mental health domains. 3) pharmacologically reverse the adverse consequences of early-life cocaine exposure. We will develop pharmacological interventions that act on regulators of the actin cytoskeleton (such as BDNF-trkB systems) rather than traditional neurotransmitter targets. We will apply these tools to mice administered cocaine in adolescence with the goal of blocking maladaptive decision-making in adulthood. We will identify correlative relationships between spine structure and behavioral outcomes using high-resolution confocal microscopy, and causal relationships by refining techniques by which to directly manipulate dendritic spine structure in vivo.

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时期，其特征是实验性药物使用率高且容易发生药物滥用。青少年药物滥用增加了终生成瘾的可能性，并且可卡因成瘾具有特殊的毒性。例如，15-16% 的青少年可卡因使用者会在首次接触后 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。可卡因和其他安非他明类精神兴奋剂有效调节前额叶皮层的树突棘形态，可卡因暴露对神经结构的长期影响是否与青少年的脆弱性存在因果关系，这在该领域引起了激烈的争论，但是支持任何单一立场的直接证据都存在。这在一定程度上是因为很少有实验室具备模拟动物系统成瘾、捕获和枚举树突棘结构以及操纵成瘾分子调节因子的工具。我们将开发和完善工具来识别可卡因引起的树突棘重组对决策和可卡因脆弱性的影响，目标是扭转生命早期接触可卡因的不利后果。，我们将重点关注 ¿ 1-整合素系统。 1-整合素是细胞外基质蛋白的受体，由于在中枢神经系统中广泛表达，它与人类的可卡因成瘾有关。 1-整合素是开发成瘾治疗方法的一个不切实际的目标；然而，它在皮质神经元中的下游效应器 p190RhoGAP 提供了一个有前途的干预目标，p190RhoGAP 通过直接抑制肌动球蛋白收缩和间接通过增加 Brain- 的 mRNA 表达来稳定前额皮质细胞结构。因此，我们建议开发工具来：1) 使用体内抑制 p190RhoGAP 功能。这比现有工具（p190rhogap 杂合小鼠）有显着进步，现有工具缺乏解剖学和时间选择性 2) 选择性地操纵高亲和力 BDNF 受体 trkB，因为尽管 BDNF 与成瘾病因有关。尽管最近开发出了一种在其他心理健康领域具有类似治疗作用的脑渗透性 trkB 激动剂，但其在这种情况下的受体靶点仍然未知。 3）在药理学上逆转生命早期接触可卡因的不良后果我们将开发作用于肌动蛋白细胞骨架调节剂（例如BDNF-trkB系统）而不是传统神经递质靶点的药物干预措施我们将把这些工具应用于服用可卡因的小鼠。我们将使用高分辨率共聚焦显微镜确定脊柱结构和结果之间的相关行为关系，并通过细化确定因果关系。直接操纵体内树突棘结构的技术。