Regulation of Adult Neurogenesis by Methamphetamine

甲基苯丙胺对成人神经发生的调节

• 批准号: 7315180
• 负责人: Chitra D Mandyam
• 金额: $ 15.2万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-25 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7315180
• 关键词: Adult; Affect; Animal Behavior; Apoptosis; Behavior; Birth; Brain; Brain-Derived Neurotrophic Factor; Cell Cycle Kinetics; Cell Death; Cell Proliferation; Cells; Cellular biology; Chitra; Chronic; Complex; Comprehension; Data; Drug abuse; Environment; Epidemic; Exposure to; Faculty; Fibroblast Growth Factor 2; GDNF gene; Goals; Hippocampus (Brain); Human; Insulin-Like Growth Factor I; Knowledge; Laboratories; Light; Liver Acinus Zone 3; Medial; Medical; Memory impairment; Methamphetamine; Methods; Neuroglia; Neurons; Neurosciences; Numbers; Pharmaceutical Preparations; Prefrontal Cortex; Principal Investigator; Proteins; Rattus; Regulation; Research; Research Personnel; Rodent; Science; Self Administration; Social Problems; Stem cells; Structure; Time; Training; United States; addiction; base; clinically relevant; drug of abuse; gliogenesis; granule cell; improved; insight; interest; member; methamphetamine exposure; nerve stem cell; neurogenesis; precursor cell; programs; psychostimulant; stimulant abuse

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.

描述（由申请人提供）：我的近期目标是使自己成为神经科学和细胞生物学领域的独立研究员，并获得药物自我给药和动物行为等方法的培训。对于我的长期目标，我将自己视为学术环境中的一名教员，拥有一个专注于神经科学的独立实验室，并追求我对药物滥用和成人神经发生的兴趣。精神兴奋剂甲基苯丙胺的滥用已达到流行程度，并在美国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，减少皮质和海马体体积并产生记忆缺陷。有趣的是，成体前体细胞的起源已在哺乳动物大脑的增殖区域得到证实，即内侧前额皮质（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，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影响的信息却很少。本提案的目的是研究甲基苯丙胺自我给药导致成年大鼠 mPFC 和海马细胞增殖、胶质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可能的关系。重要的是，我们将使用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升级过程中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诱导的成人皮质和海马胶质细胞生成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。总而言之，我们的研究结果将提高我们对长期接触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。