Regulation of adult neurogenesis by opiates

药物依赖与边缘相关结构的体积减少和改变有关 海马区形态。临床上，药物依赖与边缘和海马区相关。 症状，如情感和情绪的改变，以及学习和记忆障碍。澄清 海马体结构和功能改变的时间进程、程度和原因可能会有所改善 我们对成瘾的理解和治疗。海马区可塑性的一个方面可能很重要 对于成瘾的研究是指海马体在整个成年期制造新神经元的能力。 有证据表明，新的海马神经元在功能上整合到了海马神经元的回路中， 并参与学习和记忆的各个方面。虽然已经了解了很多关于什么增加和 减少海马体中新细胞的数量，但在识别 成年海马神经发生调控的细胞机制。这项建议是 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 阿片类药物诱导的成人神经发生的改变。这项建议包括三个方面： A)我们已经证明，慢性但非急性的阿片类药物暴露会抑制成人新神经元的诞生 海马体(Eisch等人，2000年)。我们将描述阿片剂对成体的抑制作用 通过检测细胞周期中抑制和改变的时间进程来研究神经发生。我们也 目前的数据显示，成年海马区新生细胞的一部分表达LX-阿片受体。我们 将探索LX-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，在海马区某些细胞因子和生长因子在 慢性吗啡。为了了解吗啡诱导的这些因素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和 探索新生海马体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以下因素相关 海马区功能下降。我们将充分探索脑缺血引起的海马区功能障碍。 慢性吗啡，特别是与吗啡引起的成人神经发生和发育的改变有关 海马区某些细胞因子和生长因子的水平。 对阿片类药物诱导的成人神经发生改变的检查具有显著的潜力 测试新神经元对学习和记忆重要的假设。此外，理解 阿片类药物如何作用于抑制成年海马区的新神经元，很可能有助于揭示 神经干细胞的调控机制。重要的是，这样的研究将提高我们对 鸦片类药物影响大脑功能的复杂机制。

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 lx-opioid receptors. We will explore if lx-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.