CRCNS: Multiple roles of inhibition in the olfactory system

描述（由申请人提供）：合作研究：本项目的计算模型将在Bazhenov博士的实验室（加州大学河滨分校）开发。实验工作将在Stopfer博士的实验室（NIH）进行；Stopfer博士是该提案的联合调查员。智力价值：结合实验计算方法将用于揭示昆虫嗅觉系统中气味编码的机制。本研究的主要目的是：1)利用新的实验技术和建模方法，解决昆虫嗅觉过程中同步性和振荡性在气味加工中的意义这一长期存在的问题；2)阐明抑制在形成嗅觉神经元反应中的多种复杂作用。在实验中，蝗虫和苍蝇将被用作研究这些不同形式的抑制的模型，这些实验涉及同时从触角叶（AL）、蘑菇体（MB）和侧角进行的细胞内和多单位记录。蝗虫提供了许多优势，包括在技术上相对容易进行某些类型的录音。只有在苍蝇身上才有新的遗传工具，可以对我们的假设进行更详细、更具体的测试。我们的团队之前也开发了蝗虫AL和MB的模型。在这里，我们建议扩展这些模型，以研究反馈和前馈抑制如何帮助区分相似的气味，在一系列浓度中实现最佳的气味表示，并最大限度地减少输入波动的影响。虽然我们现有的模型提供了预测和指导，但它们还没有与电生理和行为数据融合。此外，我们的一个实验室的新实验结果（如在苍蝇AL中发现气味引起的振荡，以及对蝗虫MB中反馈和前馈抑制的相对作用的重新评估）和其他小组（如在蝗虫MB中发现STDP）使得有必要对许多先前的假设进行批判性的重新评估。我们建议通过一系列精心设计的实验来探索瞬态振荡同步和脉冲重合延迟在不同气味和不同气味浓度编码中的作用。加强公众健康：至少有300万美国人患有化学感觉障碍；随着老龄化人口的增加，这一数字可能还会增长。嗅觉障碍导致无法检测诸如天然气和变质食物等危害。嗅觉也是帕金森病等神经退行性疾病发病的重要早期信号。更广泛的影响：虽然本研究计划的具体目标是了解昆虫嗅觉中抑制回路的基本作用，但基于我们模型的研究可以应用于研究其他感觉回路，以了解和预测振荡和同步的机制。这包括睡眠节律和丘脑皮质系统的节律性癫痫活动，Bazhenov的实验室对此进行了深入研究。我们的一个实验室（Bazhenov）持续招收本科生（目前有4名学生）在实验室进行研究。该项目将涉及UCR的两名少数民族本科生——Martina Mikhail和Adam Jivraj。自2011年1月以来，Martina一直在UCR PI实验室工作。她最近获得了加州少数民族参与联盟（CAMP）项目的暑期奖学金。我们希望其他本科生参与这个项目，作为他们在实验室研究训练的一部分。这个新项目的结果将是

DESCRIPTION (provided by applicant): Collaborative research: Computational models for this project will be developed in Dr. Bazhenov's laboratory (UC Riverside). Experimental work will be conducted in Dr. Stopfer's laboratory (NIH); Dr. Stopfer is serving as a co-Investigator for this proposal. Intellectual merit: A combined experimental-computational approach will be used to reveal mechanisms of odor coding in the insect olfactory system. The main goals of the study are: 1) To resolve, using new experimental techniques and modeling approaches, a long-standing question about the significance of synchrony and oscillation in the odor processing in insect olfaction; 2) To clarify manifold and complex roles of inhibition in shaping responses of olfactory neurons. The locust and fly will be used as models for studying these different forms of inhibition in experiments involving simultaneous intracellular and multiunit recordings from Antennal Lobe (AL), Mushroom Bodies (MB) and Lateral Horn. The locust offers many advantages including the relative technical ease of making certain types of recordings. New genetic tools available only in the fly permit more detailed and specific tests of our hypotheses. Our group also has previously developed models of the locust AL and MB. Here we propose to extend these models to investigate how feedback and feed-forward inhibition may help to discriminate between similar odors, to achieve optimal odor representation across a range of concentrations, and to minimize the effects of input fluctuations. Although our existing models provide predictions and guidance, they do not yet converge with electrophysiological and behavioral data. Further, new experimental results from one of our laboratories (such as the discovery of odor-elicited oscillations in the fly AL and a reevaluation of the relative role of feedback and feed-forward inhibition in the locust MB) and other groups (such as the discovery of STDP in the locust MB) make necessary a critical re-evaluation of many previous hypotheses. We propose to achieve this with a set of carefully designed experiments to explore roles of transient oscillatory synchronization and spike coincidence detention in coding of different odors and different odor concentrations. Enhancing public health: At least 3,000,000 Americans suffer from chemosensory disorders; this number is likely to grow as the aging segment of the population increases. Olfactory impairment leads to an inability to detect hazards such as natural gas and spoiled food. Olfaction is also an important early signal of the onset of neurodegenerative diseases such as Parkinson's Disease. Broader impacts: Although the specific goal of this research proposal is to understand fundamental roles of inhibitory circuits in insect olfaction, research based on our models could be applied to study other sensory circuits, to understand and predict mechanisms responsible for oscillations and synchrony. This includes sleep rhythms and rhythmic epileptiform activity in the thalamocortical system, which have been intensively studied in Bazhenov's laboratory. One of our laboratories (Bazhenov) continuously involves undergraduate students (currently 4 students) to conduct research in the lab. This project will involve two minority undergraduate students - Martina Mikhail and Adam Jivraj - at the UCR. Martina has been working in the UCR PI lab since January 2011. She was recently awarded a summer fellowship from CAMP (California Alliance for Minority Participation) program. We expect other undergraduate students to be involved to this project as a part of their research training in the lab. Results from this new project will be included in an undergraduate lab class - Computational Neurobiology (CBNS 130L) - that is taught by the UCR PI. Furthermore, the UCR PI plans to develop a new graduate level interdisciplinary course "Computational Neuroscience of the Olfactory System" that would teach students by modeling design based on example of insect olfactory system. The relative simplicity of insect olfactory circuits allows presenting students with a complete model of olfactory processing, and to introduce fundamental ideas of synchrony and oscillations. All of the software for running the models will be made available online. UCR PI is involved in a new initiative of designing "Institute for the Application of Mathematics" at UCR that will provide cross-disciplinary training in mathematics and neuroscience. Results of this project will be used in such training. Bazhenov and postdocs employed on this award will be involved in outreach programs at UCR such as the UCR ALPHA Center (http://alphacenter.ucr.edu/mission.html) that is a facility for establishing long term engagements between faculty/campus personnel and K-12 education We will participate in the development of Web content related to this project that will become part of the ALPHA Center website. UCR participates in the Brain Awareness Week (BAW) program and we will continue this tradition by presenting results of this study during BAW events. Our other laboratory (Stopfer) regularly employs high school and college interns, and regularly provides public demonstrations of sensory science. This practice will be continued and the results of this project will be used in such events.