Opiates and Adult Neurogenesis

描述（由申请人提供）：药物依赖与边缘相关结构体积减少、海马形态改变以及边缘和海马相关症状（如学习和记忆缺陷）有关。相反，海马体参与药物奖励和药物寻求复发。阐明药物诱导的海马神经适应的时间过程、程度和原因，以及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电路中，并且似乎参与海马依赖性学习。滥用药物，包括吗啡，减少海马齿状回颗粒下区（SGZ）的神经发生。这增加了阿片类药物诱导的神经发生改变导致认知缺陷、持续吸毒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，从而推进我们对阿片类药物和海马神经发生之间关系的理解。目标1。确定吗啡自我给药和戒断如何改变成人海马神经发生的离散阶段。慢性，但不是急性，阿片类药物减少新细胞的诞生和成年海马神经元的产生。使用吗啡自我管理，在这里，我们将采取下一个重要步骤来理解这个行动：描绘阿片类药物和戒断对所有细胞阶段的确切影响，从干细胞和前体细胞的增殖，到年轻神经元的成熟，并最终存活到成熟。目标2.评估成年海马神经发生的改变与药物寻求的关系。目标1和我们的初步数据的重要性，新的神经元药物寻求后退出的指导下，我们将探讨如何自愿运行和海马依赖性学习改变阿片类药物暴露，以及如何运行和学习影响药物寻求和阿片诱导的海马神经发生的变化。目标3：评估成人产生的海马神经元在药物/背景关联中的参与。目前尚不清楚成人产生的神经元是否受到药物/背景关联的影响或在其中发挥重要作用，这些关联对于恢复自我给药或条件性位置偏好（CPP）至关重要。使用我们的新的转基因小鼠模型，诱导和选择性地减少海马神经发生，我们将研究的假设，成人产生的神经元被激活的药物/上下文协会在一个关键的成熟窗口。这些研究可能表明治疗阿片成瘾或预防阿片复吸的治疗方法。这些研究还将提高我们对阿片类药物影响大脑功能海马功能的复杂机制的理解，并将深入了解海马和成人神经发生在成瘾过程中的作用，这是成瘾研究和生物医学科学的关键问题。药物成瘾是一种毁灭性的疾病，其特征是强迫性药物使用、高复发倾向和认知缺陷。滥用药物，包括海洛因，会导致海马体中新神经元数量的减少，海马体是一个对学习和记忆很重要的大脑区域。我们将探讨阿片类药物成瘾和成年海马神经发生之间的潜在相互关系，从而提供急需的洞察成瘾大脑的结构和功能以及成年大脑中新神经元的功能。

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.