Neural circuit mechanisms of odor localization in mice

小鼠气味定位的神经回路机制

基本信息

批准号：
9198435
负责人：
David Henry Gire
金额：
$ 24.9万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-12 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198435
关键词：
Accelerometer 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 Imaging Techniques In Vitro Injectable Interneurons Investigation Ipsilateral Laboratories Location Mammals Mediating Mental disorders Mentors Methods Monitor Mus Neurons Odors Olfactory Pathways Outcome Phase Play Presynaptic Terminals Price Process Property 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 calcium indicator career career development design experience information processing inhibitory neuron medical schools multiphoton imaging neural circuit neuromechanism olfactory bulb olfactory nuclei operation optogenetics patch clamp public health relevance relating to nervous system response sensory input sensory integration source localization tool transmission process

项目摘要

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（由申请人提供）：大脑的主要功能之一是将感觉输入整合并处理成可以指导动物在其环境中的行为的形式。以可以定位给定刺激源的方式组合感觉信息是该功能的一个关键方面。我建议研究双边感觉信息的整合和处理，因为它适用于小鼠的气味定位。小鼠是宏观嗅觉动物，它们利用嗅觉来探测远处的同种动物、食物和捕食者。因此，气味源定位对于小鼠来说是一项至关重要的能力。尽管其在行为学上很重要，但支持气味定位的神经机制在很大程度上还是未知的。该提案的研究将集中在皮质结构，即前嗅核（AON），假设它通过处理双侧嗅觉信息并将该信息跨大脑两个半球传输，在气味定位中发挥核心作用。首先，指导阶段进行的工作将定义从 AON 到早期嗅觉结构的半球间反馈投射的功能角色。这将通过监测这些神经元的气味反应并在气味定位任务期间控制它们的活动来实现。 AON 反馈投影的选择性监测将通过尖端的多光子成像技术来完成，并且这些神经元在气味定位中的作用将使用光遗传学策略直接测试。这两种技术的培训将极大地有助于候选人的实验能力。获得这些信息后，独立阶段的工作将采用这些技术来阐明 AON 中处理双边输入的机制，重点关注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皮层的反馈和局部皮层抑制处理如何协同工作，以结合双边感觉信息，从而识别气味的来源。通过定义用于整合感觉信息以支持行为学相关功能的机制，这项工作将为自然感觉驱动行为期间发生的神经回路内信息处理的一般理解提供坚实的基础。定义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统合的疾病，例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 博士拥有电路和系统层面嗅觉系统研究经验，为与该提案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定义动物在处理气味线索以获取有关环境的信息时使用的神经回路机制。为了开展这项工作，除了目前的经验之外，Gire 博士还需要获得技术培训，以便他能够学习具有高特异性和分辨率的神经回路动力学，而这些回路用于处理清醒、行为动物的感觉信息。该提案中提供的研究培训将涉及旨在监测和控制行为动物的特定神经回路元件的方法。这些技术包括多光子成像、头部约束行为、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提供最后一套必要的工具，让他开始独立的研究生涯，重点关注清醒、行为动物的神经回路操作。研究职业发展计划的关键要素本提案指导阶段描述的研究将在哈佛大学 Venkatesh Murthy 博士的实验室中进行。 Murthy 实验室在该提案的关键领域表现出了卓越的能力，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，以支持成功完成本提案中的培训和研究。该委员会包括博士。 Ed Boyden（麻省理工学院）、Naoshige Uchida（哈佛大学）和 Rachel Wilson（哈佛医学院）。每位委员会成员将为候选人提供具体的研究专业知识和培训，包括在每位委员会成员的实验室进行直接培训。在指导阶段，候选人将经常与其导师和委员会会面，以确保在提案的研究目标以及候选人成为独立研究者方面取得进展。当候选人开始独立职业生涯时，他的咨询委员会将继续就早期职业问题提供支持和建议，这将进一步支持候选人向独立过渡。