Regulation of adult neurogenesis by opiates

描述(由申请人提供)：药物依赖与边缘相关结构的体积减少和海马体形态改变有关。在临床上，药物依赖与边缘和海马区相关的症状有关，如情感和情绪的改变，以及学习和记忆的缺陷。弄清海马区结构和功能改变的时间进程、程度和原因可能有助于我们对成瘾的理解和治疗。海马可塑性的一个方面对成瘾研究可能很重要，那就是海马体在整个成年期生成新神经元的能力。有证据表明，新的海马神经元在功能上整合到海马神经元的回路中，并参与学习和记忆的各个方面。虽然关于是什么增加和减少了海马区新细胞的数量，人们已经了解了很多，但在确定成年海马区神经发生调控的细胞机制方面进展甚微。这项建议旨在探索阿片类药物如何调控成人神经发生，并探索阿片类药物诱导的成人神经发生改变的潜在后果。这一建议有三个方面：a)我们已经表明，慢性但不是急性的阿片类药物暴露抑制了成年海马区新神经元的诞生(Eisch等人，2000年)。我们将通过检测细胞周期中抑制和改变的时间进程来表征阿片剂对成年神经发生的抑制。我们还提供了成年海马区新生细胞亚群表达u-阿片受体的数据。我们将探索Mu-阿片受体的表达是否会在细胞周期中波动。B)我们提供的数据表明，慢性吗啡后，海马区某些细胞因子和生长因子减少。为了了解吗啡诱导的这些因子的变化如何改变成年神经发生，我们将确定这些变化相对于吗啡暴露的时间进程，并探索新生海马细胞是否表达这些细胞因子和生长因子的受体。C)我们提供的数据表明，吗啡诱导的成年海马神经发生减少与海马区功能降低有关。我们将充分探讨慢性吗啡引起的海马区功能障碍，特别是与吗啡引起的成年神经发生和海马区某些细胞因子和生长因子水平的变化有关。对阿片类药物诱导的成人神经发生变化的研究，对于检验新神经元对学习和记忆重要的假设具有重要的潜力。此外，理解阿片类药物如何抑制成年海马区的新神经元，可能会有助于阐明调控神经干细胞的基本机制。重要的是，这类研究将提高我们对鸦片类药物影响大脑功能的复杂机制的理解。

DESCRIPTION (provided by applicant): Drug dependence is linked to decreased volume of limbic-related structures and to altered hippocampal morphology. Clinically, drug dependence is associated with limbic- and hippocampal-related symptoms, such as alterations in affect and emotion, and deficits in learning and memory. Clarification of the time course, extent, and cause of the changes in hippocampal structure and function will likely improve our understanding and treatment of addiction. One aspect of hippocampal plasticity potentially important for addiction research is the ability of the hippocampus to make new neurons throughout adulthood. Evidence suggests that the new hippocampal neurons are functionally integrated into hippocampal circuitry, and are involved in aspects of learning and memory. While much has been learned about what increases and decreases the number of new cells in the hippocampus, little progress has been made in identifying the cellular mechanisms underlying the regulation of adult hippocampus neurogenesis. This proposal is designed to explore how opiates regulate adult neurogenesis, and to explore the potential consequences of opiate-induced alterations in adult neurogenesis. There are three aspects to this proposal: a) We have shown that chronic, but not acute, opiate exposure inhibits the birth of new neurons in the adult hippocampus (Eisch et al., 2000). We will characterize the opiate-induced inhibition of adult neurogenesis by examining the time course of inhibition and alterations in the cell cycle. We also present data that a subset of newly born cells in the adult hippocampus express mu-opioid receptors. We will explore if mu-opioid receptor expression fluctuates across the cell cycle. b) We present data that certain cytokines and growth factors are decreased in the hippocampus after chronic morphine. To understand how morphine-induced changes in these factors alter adult neurogenesis, we will determine the time course of these changes relative to morphine exposure and explore if newly born hippocampal cells express receptors for these cytokines and growth factors. c) We present data that the morphine-induced decrease in adult hippocampal neurogenesis correlates with decreased hippocampal function. We will fully explore the deficit in hippocampal functioning caused by chronic morphine, particularly in relation to morphine-induced changes in adult neurogenesis and hippocampal levels of certain cytokines and growth factors. Examination of opiate-induced alterations of adult neurogenesis holds significant potential for testing the hypothesis that new neurons are important for learning and memory. In addition, comprehension of how opiates act to inhibit new neurons in the adult hippocampus will likely shed light on the basic mechanisms regulating neural stem cells. Importantly, such studies will improve our understanding of the complex mechanisms by which opiates affect brain function.