ALTERING NEUROPLASTICITY DURING DEVELOPMENT

改变发育过程中的神经可塑性：对成人物质滥用的影响。 这个项目测试的假设，神经可塑性的机制是所有的关键决定因素， 成瘾阶段，包括对吸毒行为的最初易感性。因此，它问， 在发育过程中改变神经可塑性将反过来改变对可卡因和/或其 药物暴露不同阶段的神经后果。它进一步问，这一影响是否 在根据寻求新奇的特性选择性繁殖的动物中，发育操纵将是不同的， 高反应者（HR）或低反应者（LR）。这一特征与两种初始基因的差异有关。 HR动物对自我给药药物的敏感性和海马神经发生的差异 更容易吸毒，神经发生率更低。 我们建议使用一种促进海马神经发生的发育操作，即： 新生儿施用成纤维细胞生长因子2（FGF 2）。因此，HR繁殖和LR繁殖的动物将 在出生的第一天接受载体或小剂量的FGF 2。他们将被抚养成人， 然后通过实验者给药或自我给药暴露于可卡因， 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 也被测试。 我们假设新生儿FGF 2治疗将导致对药物滥用的“保护”， 基础和应力条件下。我们进一步假设，保护作用将更加显着， 在基础条件下寻求新奇的HR繁殖的动物，以及在应激条件下LR繁殖的动物 条件 待检验的神经因变量包括海马形态学和 神经发生他们还包括评估海马体和细胞核中的基因表达 使用一组与神经可塑性有关的基因，包括压力、生长、 因子和突触重塑基因的研究在其他三个项目。该项目的成果将产生 关于不同发育阶段动物早期药物滥用脆弱性的前因的信息 对药物寻求的遗传易感性

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.