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

项目摘要 气味分子与鼻上皮中的嗅觉感觉神经元（OSN）结合， 嗅球中的兴奋性输出细胞，簇状细胞（TC）和僧帽细胞（MC）的类别。在体内，TC和 MC对气味刺激的反应不同：TC具有更宽的调谐曲线，更快的响应时间，并且 对低浓度的气味比MC更敏感。这有效地从 嗅球，将不同的气味信息传递到皮层。该建议旨在确定 TC和MC对OSN激活的反应差异的机制。一个中心的重点将是 连接蛋白36（Cx 36）介导的间隙连接的潜在分流功能，似乎比 在MC中的表达高于TC，但该提案还将研究其他一些潜在的贡献 抑制和树突中的活性电导等因素。提案的目标1和2将检验 预测不同的机制与实验嗅球切片。其中包括关系 在施加的OSN刺激（光遗传学或电）的强度与电流和电压之间 MC和TC的反应（目标1），以及刺激-反应关系对 调节每个机制的操作（目标2）。目标2中采用的操作将包括Cx 36 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 计算建模，以探索目标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，申请人将发展感官专业知识， 系统神经科学，通过定期会议与她的赞助商博士内森Schoppa（嗅觉专家） Joel Zylberberg博士（在视觉系统方面具有专长的计算神经科学家）。博士 Zylberberg在嗅觉之外的感觉系统方面的专业知识将帮助申请人保持对如何 该建议中研究的特定回路机制可以推广到其他感觉系统。的 申请人还将发展脑切片中膜片钳电生理学的技术专长， 计算建模，通过经验和指导她的导师。研究培训将在 在科罗拉多大学安舒茨医学院（UCAMC）的协作环境中， 多学科培训，涵盖神经生物学的广度。与该提案相关的是，UCAMC有一个 特别是在化学方面的研究项目。

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.