Neural circuit mechanisms of odor localization in mice

小鼠气味定位的神经回路机制

• 批准号: 8678899
• 负责人: David Henry Gire
• 金额: $ 11.49万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-12 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8678899
• 关键词: Advisory Committees; Animal Behavior; Animals; Anterior; Anterior nares; Area; Back; Behavior; Behavioral; Bilateral; Brain; Cerebral cortex; Cerebral hemisphere; Committee Members; Contralateral; Cues; Dependovirus; Development Plans; Disease; Elements; Ensure; Environment; Feedback; Food; Goals; Head; Human; Image; Imaging Techniques; In Vitro; Indium; Interneurons; Investigation; Ipsilateral; Laboratories; Location; Mammals; Mediating; Mental disorders; Mentors; Methods; Monitor; Mus; Neurons; Odors; Outcome; Phase; Play; Presynaptic Terminals; Price; Process; Property; Relative (related person); Research; Research Personnel; Research Training; Resolution; Role; Schizophrenia; Sensory; Sensory Process; Slice; Smell Perception; Solid; Source; Specificity; Stimulus; Structure; Synapses; System; Techniques; Testing; Training; Universities; Viral; Work; autism spectrum disorder; awake; base; calcium indicator; career; career development; design; driving behavior; experience; information processing; inhibitory neuron; medical schools; meetings; multi-photon; neural circuit; neuromechanism; olfactory bulb; olfactory nuclei; operation; optogenetics; patch clamp; public health relevance; relating to nervous system; response; sensory integration; tool; transmission process

DESCRIPTION (provided by applicant): One of the primary functions of the brain is to integrate and process sensory input into a form that can guide the behavior of an animal within its environment. Combining sensory information in such a way that the source of a given stimulus can be located is a key aspect of this function. I propose to study the integration and processing of bilateral sensory information as it applies to odor localization in mice. Mice are macrosmotic creatures, and employ their sense of smell to detect conspecifics, food, and predators at a distance. Odor source localization is thus a vital ability for mice. Despite its ethological importance, the neural mechanisms that support odor localization are largely unknown. Research in this proposal will focus upon a cortical structure, the anterior olfactory nucleus (AON), which has been hypothesized to play a central role in odor localization by processing bilateral olfactory information and transmitting this information across the two hemispheres of the brain. First, work performed during the mentored phase will define a functional role for inter-hemispheric feedback projections from the AON to earlier olfactory structures. This will be accomplished by both monitoring the odor responses of these neurons and controlling their activity during odor localization tasks. Selective monitoring of AON feedback projections will be accomplished through cutting edge multiphoton imaging techniques, and the role of these neurons in odor localization will be directly tested using optogenetic strategies. Training in these two techniques will greatly contribute to the experimental repertoire of the candidate. After obtaining this information, work during the independent phase will employ these techniques to elucidate the mechanisms through which bilateral input is processed in the AON, focusing upon the role of inhibitory neurons. Taken together, the results of these studies will define how feedback from the cortex and local cortical inhibitory processing work together to combine bilateral sensory information in such a way that the source of an odor can be identified. By defining the mechanisms used to integrate sensory information in support of an ethologically relevant function, this work will provide a firm basis fr the general understanding of information processing within neural circuits as it occurs during natural sensory-driven behavior. Defining such fundamental mechanisms of neural circuit processing will be instrumental for the understanding and treatment of disorders that alter sensory integration, such as schizophrenia and autism spectrum disorders. Candidate's immediate and long-term career goals The candidate, Dr. David Gire, has experience with research in the olfactory system at both the circuit and systems level, providing a solid background in the methods and concepts related to this proposal. The long term goal of Dr. Gire's career is to define the neural circuit mechanisms used by animals as they process odor cues to obtain information about their environment. To conduct this work, in addition to his current experience, Dr.Gire will need to obtain training in techniques that will allow him to study neural circuit dynamics with high specificity and resolution while these circuits are used to process sensory information in awake, behaving animals. The research training provided in this proposal will involve methods designed to monitor and control specific neural circuit elements in behaving animals. These techniques include multi-photon imaging, head-restrained behavior, precise odor stimulation, and optogenetics. Combined training in these techniques will provide the final set of tools necessary for Dr. Gire to begin an independent research career with a focus upon neural circuit operation in awake, behaving animals. Key elements of the research career development plan The research described in the mentored phase of this proposal will be carried out in the laboratory of Dr. Venkatesh Murthy at Harvard University. The Murthy lab has demonstrated excellence in key areas of the proposal, including multiphoton imaging and optogenetic investigation of the olfactory system. The candidate has also assembled an Advisory Committee to support the successful completion of the training and research in this proposal. This committee includes Drs. Ed Boyden (MIT), Naoshige Uchida (Harvard), and Rachel Wilson (Harvard Medical School). Each committee member will provide specific research expertise and training to the candidate, including direct training in each of the committee members' laboratories. While in the mentored phase, the candidate will meet frequently with his mentor and committee in order to ensure progress with regard to both the research goals of the proposal as well as the candidate's advancement towards becoming an independent investigator. As the candidate begins his independent career, his Advisory Committee will continue to offer support and advice regarding early career issues, which will further support the transition of the candidate to independence.

描述(申请人提供)：大脑的主要功能之一是将感官输入整合和处理成一种形式，可以指导动物在其环境中的行为。以能够定位给定刺激源的方式组合感觉信息是这一功能的一个关键方面。我建议研究双侧感觉信息的整合和处理，因为它适用于小鼠的气味定位。老鼠是大型动物，利用它们的嗅觉来察觉特定物种、食物和远处的捕食者。因此，气味来源定位对小鼠来说是一项至关重要的能力。尽管它在行为学上很重要，但支持气味定位的神经机制在很大程度上是未知的。这项提议的研究将集中在皮质结构，前嗅核(AON)，它被假设在气味定位中发挥核心作用，通过处理双侧嗅觉信息并将这些信息传递到大脑的两个半球。首先，在指导阶段进行的工作将确定从AON到早期嗅觉结构的大脑半球间反馈投射的功能作用。这将通过监测这些神经元的气味反应并在气味定位任务中控制它们的活动来实现。对AON反馈投射的选择性监测将通过尖端的多光子成像技术完成，这些神经元在气味定位中的作用将直接使用光发生策略进行测试。这两种技巧的训练将对候选人的实验技能有很大帮助。在获得这些信息后，在独立阶段的工作将使用这些技术来阐明在AON中处理双边输入的机制，重点是抑制性神经元的作用。总而言之，这些研究的结果将定义来自大脑皮层的反馈和局部皮质抑制处理如何协同工作，以一种可以识别气味来源的方式将双边感觉信息结合在一起。通过定义整合感觉信息以支持行为学相关功能的机制，这项工作将为一般理解神经回路中的信息处理提供坚实的基础，因为它发生在自然感觉驱动的行为中。确定神经回路处理的这种基本机制将有助于理解和治疗改变感觉整合的障碍，如精神分裂症和自闭症谱系障碍。候选人的近期和长期职业目标候选人David Gire博士在电路和系统层面的嗅觉系统研究方面拥有丰富的经验，为与这项提议相关的方法和概念提供了坚实的背景。盖尔博士职业生涯的长期目标是确定动物在处理气味线索以获取环境信息时所使用的神经回路机制。为了进行这项工作，除了他目前的经验之外，Gire博士还需要接受技术培训，以便他能够研究 具有高特异性和高分辨率的神经回路动力学，而这些回路用于处理清醒的、行为正常的动物的感觉信息。这项提案中提供的研究培训将涉及旨在监测和控制动物行为中特定神经回路元件的方法。这些技术包括多光子成像、头抑制行为、精确气味刺激和光遗传学。这些技术的综合培训将为吉尔博士开始独立的研究生涯提供必要的最后一套工具，重点是清醒、行为正常的动物的神经回路操作。研究职业发展计划的主要内容本提案指导阶段所述的研究将在哈佛大学Venkatesh Murthy博士的实验室进行。Murthy实验室在该提案的关键领域展示了卓越的表现，包括多光子成像和嗅觉系统的光遗传学研究。候选人还组建了一个咨询委员会，以支持顺利完成本提案中的培训和研究。该委员会包括麻省理工学院的埃德·博伊登博士、哈佛大学的内田直树博士和哈佛医学院的瑞秋·威尔逊博士。每个委员会成员将为候选人提供具体的研究专业知识和培训，包括在每个委员会成员的实验室进行直接培训。在指导阶段，候选人将经常与他的导师和委员会会面，以确保在提案的研究目标以及候选人成为独立调查员方面取得进展。随着候选人开始其独立职业生涯，他的咨询委员会将继续就早期职业问题提供支助和咨询，这将进一步支持候选人向独立过渡。