CA2+/CAMP SIGNALING IN DEVELOPMENT OF FOREBRAIN CIRCUITS

前脑回路发育中的 CA2 /CAMP 信号传导

• 批准号: 6528139
• 负责人: TONY AI PHAM
• 金额: $ 15.25万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6528139
• 关键词: biological signal transduction; cAMP response element binding protein; calcium flux; cyclic AMP; developmental neurobiology; gene expression; genetic regulation; genetically modified animals; laboratory mouse; neocortex; neural plasticity; neurogenesis; prosencephalon; synaptogenesis; thalamus

DESCRIPTION: The precise synaptic connectivity of neurons in the mammalian brain is the underlying cellular substrate that governs perception and behavior. The major psychiatric illnesses, such as schizophrenia and depression, may be caused by abnormalities in the connectivity of forebrain neurons. However, the molecular mechanisms that instruct the precise development of forebrain connectivity are largely unknown. This application examines the hypothesis that cellular processes mediated by calcium and cyclic AMP are critical for the refinement and maturation of neural circuits in the thalamus and neocortex, key forebrain structures that mediate conscious perception. Using the visual system as the experimental model, the specific aims of the research are: (1) to examine the mechanisms that drive calcium/cAMP-regulated gene expression during the development of neocortical and thalamic circuitry, (2) to examine the processes that lead to the down-regulation of neocortical calcium/cAMP-regulated gene expression with maturation, (3) to determine the impact of disruption of calcium/cAMP signaling on neocortical plasticity and thalamic connectivity, (4) to construct a transgenic mouse line that has a thalamus specific disruption of the calcium/cAMP-regulated transcription factor CREB. These experiments will help elucidate how calcium/cAMP signals translate sensory experience into patterns of gene expression, and determine the impact of disruption of calcium/cAMP signaling on neural connectivity. The investigator is a psychiatrist whose long-term interest is to understand how neuronal connectivity develops early in life and how it is modified by experience, with the hope that this knowledge will provide insight into the cellular and molecular abnormalities that underlie behavioral and perceptual disorders. He will have an appointment as assistant professor at the University of Washington School of Medicine. His transition towards research independence will be undertaken with mentoring from Dr. Daniel Storm and Dr. Mark Hamlin of the University of Washington. Also, several collaborations are planned, namely with Dr. Alcino Silva (UCLA), Dr. Barbara Gordon-Lickey (University of Oregon), and Dr. John Neumaier (University of Washington), that will result in a significant broadening of research experience.

描述：哺乳动物神经元的精确突触连接 大脑是基本的细胞底物，控制感知和 行为。主要的精神疾病，如精神分裂症和 抑郁症，可能是由前脑连通性异常引起的 神经元。然而，指导精确度 前脑连通性的发展在很大程度上是未知的。此应用程序 检验了细胞过程由钙和循环介导的假说 AMP对于神经回路的完善和成熟是至关重要的 丘脑和新皮质，调节意识的关键前脑结构 感知力。以视觉系统为实验模型，具体实现了 这项研究的目的是：(1)考察驱动机制 钙/cAMP调控基因在新皮质发育中的表达 和丘脑回路，(2)检查导致 对新皮质钙/cAMP调节基因表达的下调作用 成熟，(3)确定钙/cAMP信号中断的影响 关于新皮质可塑性和丘脑连通性，(4)构建 具有丘脑特异性干扰的转基因小鼠系 钙/cAMP调节的转录因子CREB。这些实验将会有所帮助 阐明钙/cAMP信号如何将感觉体验转化为模式 基因表达，并确定钙/cAMP干扰的影响 神经连通性的信号。 调查员是一位精神病学家，他的长期兴趣是了解 神经元连接是如何在生命早期发展起来的，以及它是如何被 经验，希望这些知识将提供对 构成行为和知觉基础的细胞和分子异常 精神错乱。他将被任命为该大学的助理教授 华盛顿医学院的。他向研究独立的转变 将由丹尼尔·斯托姆博士和马克·哈姆林博士进行指导 华盛顿大学。此外，还计划进行几项协作，即 与阿尔西诺·席尔瓦博士(加州大学洛杉矶分校)、芭芭拉·戈登-利基博士(俄勒冈大学)， 和John Neumaier博士(华盛顿大学)，这将导致 显著拓宽了研究经验。