Regulation of Adult Neurogenesis by Methamphetamine

描述（由申请人提供）：我的近期目标是建立自己作为一个独立的研究人员在神经科学和细胞生物学领域，并获得培训的方法，如药物自我管理和动物行为。对于我的长期目标，我把自己看作是一名教员，在一个学术环境中，有一个既定的独立实验室，专注于神经科学，追求我对药物滥用和成人神经发生的兴趣。在美国，滥用精神兴奋剂甲基安非他明已达到流行病的程度，并造成严重的医疗和社会问题。人类滥用甲基苯丙胺会严重损害前额皮质和海马体，减少皮质和海马体的体积，并产生记忆缺陷。有趣的是，成年前体细胞的发生已被证明在哺乳动物大脑的增殖区域，即内侧前额叶皮质（mPFC）和海马颗粒下区（SGZ）。新生的前体细胞成熟为神经元或神经胶质细胞，并参与维持成年大脑的结构和功能。虽然甲基苯丙胺对RFC和海马的结构和功能的破坏性影响变得非常清楚，但关于甲基苯丙胺对成人胶质细胞生成和神经发生的影响的信息很少。本研究的目的是探讨甲基苯丙胺自身给药诱导的成年大鼠mPFC和海马细胞增殖、胶质细胞生成和神经发生减少的机制，并探讨甲基苯丙胺诱导的皮质和海马结构和功能改变之间的可能关系。重要的是，我们将使用临床相关的自我管理模式的甲基苯丙胺暴露，以实现我们的具体目标。首先，我们将确定甲基苯丙胺升级对细胞增殖和细胞死亡的有害影响，在升级的时间过程。其次，我们将探讨慢性甲基苯丙胺诱导的成年皮层和海马胶质细胞和神经发生减少的可能机制。第三，我们将揭示慢性甲基苯丙胺诱导的细胞发生和行为改变之间的关系。总之，我们的研究结果将提高我们对长期暴露于精神兴奋剂影响成人大脑功能的复杂机制的理解，并可能有助于产生更好的治疗甲基苯丙胺成瘾的疗法。

DESCRIPTION (provided by applicant): My immediate goal is to establish myself as an independent researcher in the fields of neuroscience and cell biology, and obtain training in methods such as drug self-administration and animal behavior. For my long- term goals, I see myself as a faculty member in an academic environment with an established independent laboratory focusing on neuroscience and pursuing my interests in drug abuse and adult neurogenesis. Abuse of the psychostimulant methamphetamine has reached epidemic proportions and poses significant medical and social problems in the United States. Methamphetamine abuse in humans severely damages the prefrontal cortex and hippocampus, reducing cortical and hippocampal volume and producing memory deficits. Interestingly, adult precursor cell genesis has been demonstrated in the proliferative regions of the mammalian brain, namely, the medial prefrontal cortex (mPFC) and the hippocampal subgranular zone (SGZ). The newly born precursors mature into neurons or glia and are implicated in maintaining adult brain structure and function. While the devastating effects of methamphetamine on the structure and function of the RFC and hippocampus are becoming very clear, very little information exists on the affects of methamphetamine on adult gliogenesis and neurogenesis. The objective of this proposal is to investigate the mechanisms underlying methamphetamine self-administration-induced decrease in cell proliferation, gliogenesis and neurogenesis in the adult rat mPFC and hippocampus and to explore a possible relationship between methamphetmine-induced alterations in cortical and hippocampal structure and function. Importantly, we will use a clinically relevant self-administration paradigm of methamphetamine exposure to implement our specific aims. First, we will determine the harmful effects of methamphetamine escalation on cell proliferation and cell death over an escalation time course. Second, we will explore a possible mechanism for chronic methamphetamine-induced decrease in adult cortical and hippocampal gliogenesis and neurogenesis. Third, we will uncover the relationship between chronic methamphetamine- induced alteration in cell genesis and behavior. Taken together, our findings will improve our understanding of the complex mechanisms by which chronic exposure to psychostimulants affect adult brain function and may help generate better therapies to treat methamphetamine addiction.