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

• 批准号: 8356038
• 负责人: GABY MAIMON
• 金额: $ 254.25万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356038
• 关键词: Animal Model; Animals; Behavior; Behavioral; Behavioral Paradigm; Brain; Cell Extracts; Cognition; Decision Making; Drosophila genus; Drosophila melanogaster; Drug Addiction; Drug Design; Electrophysiology (science); Foundations; Genes; Genetic; Genetic Models; HIV Infections; Health; Human; Lead; Left; Link; Mental Depression; Mental Processes; Mental disorders; Methods; Mind; Neurons; Obsessive-Compulsive Disorder; Output; Physiology; Process; Public Health; RNA Sequences; Research; Risk Behaviors; Schizophrenia; Signal Transduction; Synaptic Membranes; Time; Work; abstracting; awake; cell type; disability; flexibility; fly; improved; insight; programs; public health relevance; response; tool; visual stimulus

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. Public Health Relevance: A better understanding of how brains make choices could help modify risky behaviors that lead to HIV infection and drug addiction, which are major public health concerns. By providing a deeper understanding of decision-making circuits, the proposed work can ultimately yield insight into treatments for a variety of mental illnesses, such as depression, one of the leading causes of disability in the world.

描述(由申请人提供) 摘要：在遗传模型生物中的研究已经将基因与行为联系起来。清醒的、行为正常的动物的电生理学将神经元活动与认知和行动联系起来。这一建议位于这两个领域的交界处。我们的目标是揭示基因是如何通过对细胞电生理的影响来影响高级大脑功能和行为的。我们关注的是一种特定的更高级的功能--决策：先于并最终产生行为选择的心理过程。健康的大脑允许做出适应性和灵活性的选择。在吸毒成瘾和精神疾病中，如抑郁症、强迫症和精神分裂症，行为选择是不适应的、刻板印象的和重复的。更深入地了解决策过程可能会改善许多人的健康。我们建议研究果蝇的决策，在那里有一个独特的机会来形成跨学科的见解。我们将使用一种新的设备，首次允许我们记录活跃行为的果蝇的遗传识别神经元的电生理信号。果蝇将执行简单的选择任务，比如根据视觉刺激决定向左转或向右转。当苍蝇决定或改变主意时，我们将记录和操纵神经元的活动。录音后，我们将对从控制决策的细胞中提取的RNA进行测序，以确定它们电生理输出的可变性和苍蝇行为的可变性是否可以通过调节膜和突触生理的基因的表达水平来解释。果蝇为这一研究项目提供了一个独特的平台，因为行为范式、特定细胞类型的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的影响影响决策，最终提供 为更合理地设计治疗人类精神疾病的药物奠定基础。 与公共健康相关：更好地了解大脑是如何做出选择的，可以帮助改变导致艾滋病毒感染和吸毒成瘾的危险行为，这是主要的公共健康问题。通过提供对决策回路的更深入了解，拟议中的工作最终可以深入了解各种精神疾病的治疗方法，例如抑郁症，这是世界上导致残疾的主要原因之一。