Mapping Molecular and Cellular Responses to Odorants

描述(摘自申请者摘要)：本项目的目标是 在细胞和分子水平上描述嗅觉的特征。主要 嗅球的嗅神经元输入在空间上是有组织的 哺乳动物，我们假设这种空间组织保存在 更高水平的感觉处理。实验方法将基于 一种能提供时间和细胞分辨率的神经元激活分析方法 清醒的，行为自由的老鼠。蛋白在细胞内的表达和定位 荧光原位杂交法测定一个即刻早期基因Arc 而共聚焦显微镜将被验证为神经元激活的一种测量手段 嗅球。然后，神经元的激活模式将被确定 嗅球和前脑的其他区域对两个 结构上相关的气味物质。下一种结构上相关的气味物质 将通过提示条件作用被赋予行为意义；两者 训练中将使用欲望和厌恶的无条件刺激。 会话。条件反射后，脑内神经元的激活模式 对条件气味的反应将与幼稚的模式进行比较 鼠标以及由结构相关的分子产生的图案 这要么是行为中性的，要么是提供相反的行为 意义。总而言之，这些研究将为 嗅球的嗅觉和更高水平的感觉 以验证我们的假设。此外，这还构成了一个 定义在学习过程中修改的突触的重要一步 在哺乳动物中的过程，并开发一种转基因小鼠的功能测试 认知功能障碍与脑血管病模型的解剖学变化 阿尔茨海默病和其他神经退行性疾病。 在理查德·阿克塞尔医学博士赞助的这项研究过程中， 应聘者将接受创造性和严谨的分子方法培训 系统层面的神经科学问题。此外，应聘者将接受 哥伦比亚大学理查德·梅尤医学博士指导下的认知神经学 大学。

DESCRIPTION (from applicant's abstract): The goal of this project is to characterize olfactory perception at both cellular and molecular levels. Primary olfactory neuronal input is spatially organized in the olfactory bulb in mammals, and we hypothesize that this spatial organization is preserved at higher levels of sensory processing. The experimental approach will be based on an assay for neuronal activation that offers temporal and cellular resolution in awake, freely behaving mice. The expression and intracellular localization of an immediate early gene Arc, as determined by fluorescent in-situ hybridization and confocal microscopy will be validated as a measure of neuronal activation in the olfactory bulb. Then the pattern of neuronal activation will be determined in the olfactory bulb and other areas of the forebrain in response to two structurally related odorants. Next one of the structurally related odorants will be afforded a behavioral significance through cue conditioning; both appetitive and aversive unconditioned stimuli will be employed in the training sessions. Following conditioning, the pattern of neuronal activation in response to the conditioned odorant will be compared to the pattern in the naive mouse as well as to the pattern generated by the structurally related molecule that is either behaviorally neutral or afforded the opposite behavioral significance. Together, these studies will provide a functional map for olfactory perception in the olfactory bulb and higher levels of sensory processing in order to test our hypothesis. In addition, this constitutes an important step towards defining synapses that are modified during a learning process in mammals, and developing a functional assay in transgenic mice to correlate cognitive dysfunction with anatomical changes in disease models of Alzheimer's disease and other neurodegenerative diseases. During the course of this research sponsored by Richard Axel, M.D., the candidate will be trained in creative and rigorous molecular approaches to systems level neuroscience problems. Moreover, the candidate will be trained in cognitive neurology under the direction of Richard Mayeux, M.D. at Columbia University.