Regulation of Adult Neurogenesis by Methamphetamine

我的近期目标是成为神经科学和细胞生物学领域的一名独立研究员，并接受药物自我管理和动物行为等方法方面的培训。对于我的长期目标，我认为自己是一个学术环境中的教员，有一个成熟的独立实验室，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，精神刺激剂甲基苯丙胺的滥用已经达到了流行的程度，并造成了严重的医疗和社会问题。甲基苯丙胺在人类中的滥用严重损害了前额叶皮质和海马体，减少了皮质和海马体的体积，并产生记忆缺陷。有趣的是，在哺乳动物大脑的增殖区，即内侧前额叶皮质(MPFC)和海马亚颗粒带(SGZ)，已经证实了成体前体细胞的发生。新生的前体细胞成熟为神经元或神经胶质细胞，与维持成人大脑结构和功能有关。虽然甲基苯丙胺对RFC和海马区结构和功能的破坏性影响已经变得非常清楚，但关于甲基苯丙胺对成年神经胶质发生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我给药导致成年大鼠大脑皮质和海马区细胞增殖、胶质形成和神经发生减少的机制，并探讨甲基苯丙胺引起的皮质和海马区结构和功能改变之间的可能关系。重要的是，我们将使用与临床相关的甲基苯丙胺暴露自我管理范例来实现我们的具体目标。首先，我们将确定甲基苯丙胺在一段时间内升级对细胞增殖和细胞死亡的有害影响。其次，我们将探索慢性甲基苯丙胺导致成人大脑皮质和海马区胶质发生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改变与行为之间的关系。综上所述，我们的发现将提高我们对长期接触精神刺激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方法。

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.