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（由适用提供）：青少年可卡因用户将在初次接触的10年内发展依赖性。确定可卡因脆弱性的机制是一项重要的研究。可卡因和其他类似苯丙胺的精神刺激物可能在前额叶皮层中可能调节树突状脊柱形态。可卡因对中性结构的长期后果有时与青少年脆弱性有关，这在现场中是活泼的辩论，但是支持任何单一位置的直接证据受到限制。这部分是因为很少有实验室配备在动物系统中建模的工具，以捕获和枚举树突状脊柱结构，并操纵树突状脊柱结构的分子调节剂以隔离因果关系。我们将开发和完善这些工具，通过这些工具来确定可卡因引起的树突状脊柱重组对决策和可卡因脆弱性的影响，目的是扭转早期可卡因暴露的不利后果。在整个过程中，我们将专注于1-整合素系统。 1-整合素是细胞外基质蛋白的受体，它在人类的可卡因成瘾中暗示。由于整个中枢神经系统的宽度表达，因此1-整合素是发展成瘾治疗方法的不现实目标。然而，它在皮质神经元中的下游效应子P190RHOGAP为干预提供了有望的目标。 P190RHOGAP通过直接抑制肌动蛋白收缩并间接地稳定前额叶皮质细胞结构，并通过增加脑源性神经营养因子（BDNF）的mRNA表达而间接稳定。因此，我们建议使用病毒矢量方法在体内抑制P190RHOGAP功能的工具：1）抑制P190RHOGAP功能。这超出了现有工具（P190RHOGAP杂合小鼠）的重大进展，该工具缺乏解剖和临时选择性。 2）选择性操纵高亲和力BDNF受体TRKB。这是必不可少的，因为尽管BDNF是在成瘾病因中实施的，但其受体靶标在这种情况下仍然未知。尽管最近在其他心理健康领域中具有类似治疗的益处，但最近发展了脑培训剂TRKB激动剂。 3）药理扭转了早期可卡因暴露的不利后果。我们将开发出对肌动蛋白细胞骨架（例如BDNF-TRKB系统）而不是传统神经递质靶标的调节剂作用的药理干预措施。我们将将这些工具应用于青少年可卡因的小鼠，目的是阻止成年后的适应不良决策。我们将使用高分辨率共聚焦显微镜以及通过精炼技术直接操纵体内的树突状脊柱结构来确定脊柱结构和行为结果之间的相关关系。