Neural circuit mechanisms of odor localization in mice

描述（由申请人提供）：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。以这样一种方式组合感官信息，从而可以定位给定刺激的来源，这是该功能的一个关键方面。我建议研究双侧感觉信息的整合和加工，因为它适用于小鼠的气味定位。老鼠是大型生物，利用它们的嗅觉来探测远处的同类、食物和捕食者。因此，气味源定位是小鼠的一项重要能力。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。本提案的研究将集中在皮层结构，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和控制它们在气味定位任务中的活动来完成。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通过光遗传学策略直接测试。这两种技术的训练将大大有助于候选人的实验曲目。在获得这些信息后，独立阶段的工作将采用这些技术来阐明双侧输入在AON中处理的机制，重点关注抑制性神经元的作用。综上所述，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共同工作，以这样一种方式将双边感觉信息结合起来，从而可以识别气味的来源。通过定义用于整合感官信息以支持行为学相关功能的机制，这项工作将为理解自然感觉驱动行为中神经回路中的信息处理提供坚实的基础。确定这种神经回路处理的基本机制将有助于理解和治疗改变感觉统合的疾病，如精神分裂症和自闭症谱系障碍。候选人David Gire博士在嗅觉系统的电路和系统层面都有研究经验，为本提案相关的方法和概念提供了坚实的背景。吉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。为了开展这项工作，除了他目前的经验外，吉尔博士还需要接受技术方面的培训，以便进行研究

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.