Biophysical mechanisms that contribute to multiple output channels in the olfactory bulb

有助于嗅球多个输出通道的生物物理机制

• 批准号: 9788033
• 负责人: Shelly T Jones
• 金额: $ 3.31万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788033
• 关键词: Alzheimer' s Disease; Animals; Anterior; Apical; Binding; Biophysical Process; Brain; Cells; Cellular Morphology; Chemicals; Colorado; Computer Simulation; Coupling; Data; Dendrites; Dependence; Electric Stimulation; Electron Microscopy; Electrophysiology (science); Functional disorder; Gap Junctions; Goals; Human; Interneurons; Ion Channel; Knock-out; Knockout Mice; Lead; Location; Measures; Mediating; Medical; Mentors; Modeling; Morphology; Mus; Nasal Epithelium; Neurobiology; Neurologic Symptoms; Neurosciences; Odors; Olfactory Pathways; Output; Parkinson Disease; Pharmacology; Process; Property; Publishing; Reaction Time; Research; Research Training; Response to stimulus physiology; Role; Signal Transduction; Site; Slice; Smell Perception; Sodium; Sodium Channel; Stimulus; Synapses; Technical Expertise; Testing; Training; Universities; Visual system structure; Work; autism spectrum disorder; base; biophysical properties; collaborative environment; connexin 36; density; experience; experimental study; in vivo; knockout animal; meetings; mitral cell; multidisciplinary; nervous system disorder; neural circuit; olfactory bulb; olfactory nuclei; olfactory sensory neurons; optogenetics; patch clamp; piriform cortex; predicting response; programs; receptor; response; sensory system; stimulus sensitivity; voltage

Project Summary Odor molecules bind to olfactory sensory neurons (OSNs) in the nasal epithelium, which synaptically excite two classes of excitatory output cells in the olfactory bulb, tufted cells (TCs) and mitral cells (MCs). In vivo, TCs and MCs respond differently to odorant stimulation: TCs have broader tuning profiles, faster response times, and are more sensitive to low odor concentrations than MCs. This effectively creates two output channels from the olfactory bulb, that carry different information about the odor to the cortex. This proposal seeks to identify mechanisms that underlie the difference in TC and MC responses to OSN activation. A central focus will be on a potential shunting function of connexin-36 (Cx36)-mediated gap junctions, which appear to be much more highly expressed in MCs than TCs, but the proposal will also examine a number of other potential contributing factors such as inhibition and active conductances in dendrites. Aims 1 and 2 of the proposal will test the predictions of different mechanisms with experiments in olfactory bulb slices. These include the relationship between the intensity of an applied OSN stimulus (optogenetic or electrical) and the current and voltage responses of MCs and TCs (Aim 1), and also the sensitivity of the stimulus-response relationships to manipulations that modulate each mechanism (Aim 2). The manipulations employed in Aim 2 will include Cx36 KO mice and pharmacological blockade of GABAA receptors and voltage-gated sodium channels. Aim 3 will use computational modeling to explore whether the identified mechanisms from Aims 1 and 2 are sufficient to explain the difference between TC and MC responses. Aim 3 will also test alternative mechanisms that are difficult to manipulate experimentally, for example the contribution of cellular morphology. TRAINING AND ENVIRONMENT: To achieve the project’s goal, the applicant will develop expertise in sensory systems neuroscience, through regular meetings with her sponsor Dr. Nathan Schoppa (an expert in olfaction) and co-sponsor Dr. Joel Zylberberg (a computational neuroscientist with expertise in the visual system). Dr. Zylberberg’s expertise in a sensory system besides olfaction will help the applicant maintain perspective on how the specific circuit mechanisms studied within the proposal can generalize to other sensory systems. The applicant will also develop technical expertise in patch-clamp electrophysiology in brain slices and computational modeling, through experience and guidance of her mentors. The research training will take place at University of Colorado, Anschutz Medical Campus (UCAMC) in a collaborative environment that provides multidisciplinary training, covering the breadth of neurobiology. Relevant to the proposal, UCAMC has an especially strong research program in the chemical senses.

项目概要 气味分子与鼻上皮细胞中的嗅觉感觉神经元 (OSN) 结合，从而刺激两个突触 嗅球中的兴奋性输出细胞有簇状细胞（TC）和二尖瓣细胞（MC）。在体内，TCs 和 MC 对气味刺激的反应不同：TC 具有更广泛的调节特性、更快的响应时间，并且 与 MC 相比，对低气味浓度更敏感。这有效地创建了两个输出通道 嗅球，将有关气味的不同信息传递到皮层。该提案旨在确定 TC 和 MC 对 OSN 激活反应差异的机制。中心重点将是 连接蛋白 36 (Cx36) 介导的间隙连接的潜在分流功能，这似乎更多 在 MC 中的表达量高于 TC，但该提案还将研究一些其他潜在的贡献 树突中的抑制和活性电导等因素。该提案的目标 1 和 2 将测试 通过嗅球切片实验预测不同机制。这些包括关系 施加的 OSN 刺激（光遗传学或电）的强度与电流和电压之间的关系 MC 和 TC 的反应（目标 1），以及刺激-反应关系的敏感性 调节每个机制的操作（目标 2）。 Aim 2 中采用的操作将包括 Cx36 KO 小鼠和 GABAA 受体和电压门控钠通道的药理学阻断。目标 3 将使用 计算模型来探索目标 1 和 2 中确定的机制是否足以 解释 TC 和 MC 反应之间的差异。目标 3 还将测试替代机制 难以通过实验操作，例如细胞形态的贡献。 培训和环境：为了实现项目的目标，申请人将发展感官方面的专业知识 系统神经科学，通过与她的赞助商 Nathan Schoppa 博士（嗅觉专家）定期会面 共同发起人 Joel Zylberberg 博士（一位在视觉系统方面具有专业知识的计算神经科学家）。博士。 Zylberberg 在嗅觉之外的感官系统方面的专业知识将帮助申请人保持对如何 该提案中研究的具体电路机制可以推广到其他感觉系统。这 申请人还将开发脑切片膜片钳电生理学的技术专业知识和 通过导师的经验和指导进行计算建模。研究培训将举行 在科罗拉多大学安舒茨医学校区 (UCAMC) 的协作环境中， 多学科培训，涵盖神经生物学的广度。与该提案相关，UCAMC 有一个 尤其是在化学意义上的强大研究计划。