ALTERING NEUROPLASTICITY DURING DEVELOPMENT

在发育过程中改变神经可塑性

• 批准号: 7389842
• 负责人: Delia M Vazquez
• 金额: $ 27.65万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-25 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7389842
• 关键词: Abstinence; Addictive Behavior; Adult; Affect; Animals; Anxiety; Behavior; Behavior Therapy; Behavioral; Breeding; Cell Proliferation; Cocaine; Condition; Development; Dose; Drug Exposure; Drug abuse; Drug usage; Event; Exposure to; Family; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Growth Factor; Hippocampus (Brain); Individual; Injection of therapeutic agent; Lead; Life; Link; Molecular; Morphology; Neonatal; Neuronal Plasticity; Newborn Infant; Nucleus Accumbens; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Predisposition; Psychotropic Drugs; Rate; Rattus; Relapse; Relative (related person); Research Personnel; Self Administration; Self-Administered; Staging; Stress; Substance abuse problem; Synapses; Testing; Weaning; addiction; animal breeding; base; day; dentate gyrus; drug seeking behavior; fetal; neonatal exposure; neural circuit; neurogenesis; postnatal; programs; protective effect; psychosocial; psychostimulant; relating to nervous system; response; social; social stress; stressor; trait

Altering Neuroplasticity During Development: Impact on Substance Abuse in the Adult. This project tests the hypothesis that mechanisms of neural plasticity are key determinants of all phases of addiction, including the initial susceptibility to drug-taking behavior. Therefore, it asks whether altering neural plasticity during development will in turn alter the behavioral response to cocaine and/or its neural consequences at various stages of drug exposure. It further asks whether the impact of this developmental manipulation will be different in animals selectively bred based on the novelty-seeking trait to be either high responders (HR) or low responders (LR). This trait has been linked to differences in both initial susceptibility to self-administer drugs and differences in hippocampal neurogenesis, with the HR animals being more prone to drug-taking and showing lower rates of neurogenesis. We propose to use a developmental manipulation that enhances hippocampal neurogenesis - i.e.the neonatal administration of the Fibroblast Growth Factor 2 (FGF2). Thus, HR-bred and LR-bred animals will either receive vehicle or a small dose of FGF2 on the first day of life. They will be raised to adulthood and then exposed to cocaine either through experimenter administration or self-administration, followed by various periods of abstinence. The impact of a social stressor on their behavior and neural responses will also be tested. We hypothesize that neonatal FGF2 treatment will lead to "protection" against drug abuse both under basal and under stress conditions. We further hypothesize that the protective effect will be more marked in the novelty-seeking HR-bred animals under basal conditions, and in the LR-bred animals under stress conditions. The neural dependent variables to be tested included hippocampal morphology and rates of neurogenesis. They also include assessment of gene expression in the hippocampus and nucleus accumbens (core and shell) using a panel of genes relating to neural plasticity, including the stress, growth factor and synaptic remodeling genes studied in the other three projects. The results of this project will yield information on antecedents of drug abuse vulnerability during early development in animals with differing genetic susceptibilities to drug seeking.

发育过程中改变神经可塑性：对成人药物滥用的影响。 该项目测试了这样的假设：神经可塑性机制是所有神经可塑性的关键决定因素 成瘾的各个阶段，包括最初对吸毒行为的敏感性。因此，它询问是否 改变发育过程中的神经可塑性反过来会改变对可卡因和/或其物质的行为反应 药物暴露不同阶段的神经后果。它还进一步询问这是否会产生影响 基于寻求新奇特征而选择性培育的动物的发育操纵将会有所不同 可以是高响应者 (HR) 或低响应者 (LR)。这一特征与最初的差异有关 HR 动物对自我给药药物的敏感性以及海马神经发生的差异 更容易吸毒并且神经发生率较低。 我们建议使用一种增强海马神经发生的发育操作 - 即 新生儿给予成纤维细胞生长因子 2 (FGF2)。因此，HR 繁殖和 LR 繁殖的动物将 在出生第一天接受赋形剂或小剂量的 FGF2。他们将被抚养长大并 然后通过实验者给药或自我给药暴露于可卡因，然后 不同时期的禁欲。社会压力源对他们的行为和神经反应的影响将 也进行测试。 我们假设新生儿 FGF2 治疗将导致“保护”免受药物滥用，无论是在 基础和应激条件下。我们进一步假设，保护作用在以下情况下会更加显着： 基础条件下寻求新奇的 HR 饲养的动物，以及压力下 LR 饲养的动物 状况。 要测试的神经因变量包括海马形态和发生率 神经发生。它们还包括对海马体和细胞核中基因表达的评估 伏隔核（核心和外壳）使用一组与神经可塑性相关的基因，包括压力、生长 其他三个项目中研究的因子和突触重塑基因。该项目的成果将产生 关于具有不同特征的动物在早期发育过程中药物滥用脆弱性的前因信息 对药物寻求的遗传敏感性。