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体积减少和海马形态改变有关。在临床上，药物依赖与边缘和海马体相关的症状有关，如情感和情绪的改变，以及学习和记忆的缺陷。阐明海马结构和功能变化的时间过程、程度和原因可能会提高我们对成瘾的理解和治疗。海马体可塑性的一个方面可能对成瘾研究很重要，那就是海马体在成年期产生新神经元的能力。有证据表明，新的海马体神经元在功能上与海马体回路相结合，并参与学习和记忆的各个方面。虽然关于海马中新细胞数量的增加和减少已经了解了很多，但在确定成人海马神经发生调节的细胞机制方面进展甚微。本研究旨在探讨阿片类药物如何调节成人神经发生，并探讨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)我们已经证明，慢性而非急性阿片类药物暴露会抑制成年海马中新神经元的生成（Eisch et al., 2000）。我们将通过检查抑制的时间过程和细胞周期的改变来描述阿片类药物诱导的成人神经发生的抑制。我们还提供的数据表明，成年海马中新生细胞的一个子集表达mu-阿片受体。我们将探讨mu-阿片受体的表达是否在细胞周期中波动。b)我们提供的数据表明，慢性吗啡后海马中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人神经发生，我们将确定这些变化相对于吗啡暴露的时间过程，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，吗啡诱导的成人海马神经发生减少与海马功能下降有关。我们将充分探讨慢性吗啡引起的海马功能缺陷，特别是吗啡诱导的成人神经发生和海马某些细胞因子和生长因子水平的变化。检查阿片类药物诱导的成人神经发生的改变，对于验证新神经元对学习和记忆很重要的假设具有重要的潜力。此外，了解阿片类药物如何抑制成人海马体中的新神经元，可能有助于阐明调节神经干细胞的基本机制。重要的是，这些研究将提高我们对阿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.