Opiates and Adult Neurogenesis

描述(申请人提供)：药物依赖与边缘相关结构的体积减少、海马体形态改变以及边缘和海马体相关症状有关，如学习和记忆障碍。相反，海马体参与药物奖励和对药物寻求的复发。弄清药物诱导的海马神经适应的时间进程、程度和原因，识别海马神经适应如何影响成瘾行为，将极大地提高我们对成瘾的理解和治疗。海马体的一个值得注意的方面是它在整个生命过程中产生新神经元的能力。成人产生的神经元在功能上整合到海马区的电路中，似乎参与了海马区依赖的学习。包括吗啡在内的滥用药物会减少海马齿状回颗粒下区(SGZ)的神经发生。这增加了阿片剂诱导的神经发生改变导致认知障碍、持续服药或复发或以其他方式阻碍康复的可能性。我们将使用最先进的技术来测试这种可能性，以克服SGZ前体分析中的障碍，从而促进我们对阿片类药物和海马神经发生之间的关系的理解。目的1.确定吗啡自我给药和戒断如何改变成年海马神经发生的不同阶段。慢性但非急性的阿片类药物会减少成年海马区新细胞的诞生和神经元的生成。通过使用吗啡自我给药，我们将采取下一个基本步骤来理解这一作用：描绘阿片类药物和戒断对所有细胞阶段的准确影响，从干细胞和前体细胞的增殖到年轻神经元的成熟，以及最终存活到成熟。目的2.评估成年海马区神经发生改变与药物寻找的关系。在Aim 1和我们关于戒断后新神经元对寻求药物重要性的初步数据的指导下，我们将探索阿片类药物暴露如何改变自愿跑步和海马区依赖学习，以及跑步和学习如何影响寻求药物和阿片剂诱导的海马神经发生改变。目的3.评估成体产生的海马神经元参与药物/上下文关联。目前尚不清楚成人产生的神经元是否受到药物/上下文关联的影响或在其中起重要作用，药物/上下文关联对于恢复自我给药或条件性位置偏爱(CPP)至关重要。使用我们的新型转基因小鼠模型来诱导性和选择性地减少海马神经发生，我们将检验这一假设，即在关键的成熟窗口期间，药物/上下文关联激活成人产生的神经元。这些研究可能为治疗阿片成瘾或防止阿片类药物复发提供治疗方法。这些研究还将提高我们对阿片剂影响大脑功能和海马体功能的复杂机制的理解，并将深入了解海马体和成人神经发生在成瘾过程中的作用，这是成瘾研究特别是生物医学科学的关键问题。毒瘾是一种破坏性的疾病，其特征是强迫吸毒、高复吸倾向和认知缺陷。滥用毒品，包括海洛因，会导致海马体中新神经元的数量减少，海马体是大脑中对学习和记忆至关重要的区域。我们将探索阿片成瘾与成人海马神经发生之间的潜在相互关系，从而为成瘾大脑的结构和功能以及成人大脑中新神经元的功能提供亟需的洞察。

DESCRIPTION (provided by applicant): Drug dependence is linked to decreased volume of limbic-related structures, altered hippocampal morphology, and limbic- and hippocampal-related symptoms, such as deficits in learning and memory. Conversely, the hippocampus is involved in drug reward and relapse to drug seeking. Clarification of the time course, extent, and cause of drug-induced hippocampal neuroadaptations and identification of how hippocampal neuroadaptations impact addictive behaviors will greatly improve our understanding and treatment of addiction. A notable aspect of the hippocampus is its ability to generate new neurons throughout life. Adult-generated neurons are functionally integrated into hippocampal circuitry, and appear to be involved in hippocampal- dependent learning. Drugs of abuse, including morphine, decrease neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus. This raises the possibility that opiate-induced alteration in neurogenesis leads to cognitive deficits, continued drug taking or relapse, or otherwise impedes recovery. We will test this possibility using state-of-the-art techniques to overcome obstacles in SGZ precursor analysis and thus advance our understanding of the relationship between opiate and hippocampal neurogenesis. Aim 1. Determine how morphine self-administration and withdrawal alter discrete stages of adult hippocampal neurogenesis. Chronic, but not acute, opiates decrease the birth of new cells and generation of neurons in adult hippocampus. Using morphine self-administration, here we will take the next essential step in understanding this action: delineate the precise effects of opiates and withdrawal on all cellular stages, from proliferation of stem and precursor cells, to maturation of young neurons, and eventual survival to maturity. Aim 2. Assess how altered adult hippocampal neurogenesis relates to drug seeking. Guided by Aim 1 and our preliminary data on the importance of new neurons to drug seeking after withdrawal, we will explore how voluntary running and hippocampal-dependent learning are altered by opiate exposure, and how running and learning influence drug-seeking and opiate-induced alterations in hippocampal neurogenesis. Aim 3. Evaluate the involvement of adult-generated hippocampal neurons in drug/context association. It is unknown if adult-generated neurons are influenced by or important in the drug/context association critical for reinstatement to self-administration or conditioned place preference (CPP). Using our novel transgenic mouse models to inducibly and selectively reduce hippocampal neurogenesis, we will examine the hypothesis that adult-generated neurons are activated by drug/context associations during a critical maturation window. These studies may indicate therapeutic approaches for treating opiate addiction or preventing opiate relapse. These studies will also improve our understanding of the complex mechanisms by which opiates affect brain function hippocampal function, and will provide insight into the role of the hippocampus and adult neurogenesis in addictive processes, a critical issue for addiction research in particular and biomedical science in general. Drug addiction is a devastating disorder marked by compulsive drug use, high propensity to relapse to drug taking, and cognitive deficits. Drugs of abuse, including heroin, lead to a decrease in the number of new neurons in the hippocampus, a brain region important for learning and memory. We will explore the potentially reciprocal relationship between opiate addiction and adult hippocampal neurogenesis, thus providing much- needed insight into the structure and function of the addicted brain as well as the function of new neurons in the adult brain.