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Linking genes to higher brain function by way of cellular electrophysiology

通过细胞电生理学将基因与高级大脑功能联系起来

基本信息

批准号：
9111209
负责人：
GABY MAIMON
金额：
$ 50.85万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2018-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (Provided by the applicant) Abstract: Work in genetic model organisms has connected genes to behavior. Electrophysiology in awake, behaving animals has associated neuronal activity with cognition and action. This proposal lies at the interface of these two fields. We aim to reveal how genes, through their effects on cellular electrophysiology, influence higher brain function and behavior. We focus on a specific higher function, decision-making: the mental process that precedes and ultimately yields a behavioral choice. A healthy brain allows for choices that are adaptive and flexible. In drug addiction and mental illnesses such as depression, obsessive-compulsive disorder, and schizophrenia, behavioral choices are maladaptive, stereotypical, and repetitive. A deeper understanding of decision processes could improve the health of many. We propose to study decision-making in the fruit fly, Drosophila melanogaster, where there is a unique opportunity to form cross-disciplinary insights. We will use a new apparatus that allows us, for the first time, to record electrophysiological signals from genetically identified neurons in activly behaving fruit flies. Drosophila will perform simple choice tasks, like deciding to turn left or riht in response to visual stimuli. We will record and manipulate neuronal activity while the flies make up their mind or change their mind. After recordings, we will sequence RNA extracted from cells that govern decision-making to determine whether variability in their electrophysiological output, and variability in fly behavior, can be explained by the expression level of genes that regulate membrane and synaptic physiology. Drosophila offers a unique platform for this research program because behavioral paradigms, cell- type-specific genetic tools, and behavioral-physiology methods are mature. The work aims to reveal how genes, through their effect on cellular electrophysiology, influence decision-making, ultimately providing a foundation for more rational drug design for human mental illness.

描述（由申请人提供）翻译后摘要：遗传模型生物的工作已连接基因的行为。清醒的、有行为的动物的电生理学将神经元活动与认知和行动联系起来。这一建议处于这两个领域的交界处。我们的目标是揭示基因如何通过其对细胞电生理学的影响，影响更高的大脑功能和行为。我们专注于一个特定的更高功能，决策：先于并最终产生行为选择的心理过程。一个健康的大脑允许做出适应性和灵活性的选择。在药物成瘾和抑郁症、强迫症和精神分裂症等精神疾病中，行为选择是不适应的、刻板的和重复的。更深入地了解决策过程可以改善许多人的健康。我们建议研究决策的果蝇，果蝇，那里有一个独特的机会，形成跨学科的见解。我们将使用一种新的仪器，使我们能够第一次记录来自行为活跃的果蝇的遗传识别神经元的电生理信号。果蝇会执行简单的选择任务，比如根据视觉刺激决定向左转还是右转。我们将记录和操纵神经元活动，而苍蝇作出决定或改变主意。记录后，我们将对从控制决策的细胞中提取的RNA进行测序，以确定其电生理输出的变化以及苍蝇行为的变化是否可以通过调节膜和突触生理学的基因的表达水平来解释。果蝇为这项研究提供了一个独特的平台，因为行为范式，细胞类型特异性遗传工具和行为生理学方法已经成熟。这项工作旨在揭示基因如何通过对细胞电生理学的影响来影响决策，最终提供为人类精神疾病更合理的药物设计奠定了基础。