CRCNS: Higher-order feature detection in olfactory bulb

描述（由申请方提供）：嗅球外网状层（EPL）中二尖瓣细胞和颗粒细胞之间的相互作用改变了二尖瓣细胞动作电位的时间，从而影响嗅球输出至其多个靶点的信息。由这一提议的两个合作PI中的每一个产生的理论和实验结果表明，这种强大的和可塑的EPL网络并不负责通常归因于它的简单的“对比度增强”功能（相反，这主要发生在肾小球层）。相反，EPL的相互作用进行额外的，随后的操作气味表示，介导的气味感知和代表性的变化，部分基于个别动物的气味学习的历史。具体来说，我们在这里提出，计算在EPL服务，使二尖瓣细胞输出模式选择性的某些高阶特征的气味在同一意义上说，在初级视觉皮层的神经元是选择性的高阶视觉功能，如边缘和方向-也就是说，他们反映了共同激活的某些时空组合的受体，共同的特点是一个有意义的气味。在这里，我们建议开发详细的理论模型，这一假设及其影响，并测试其主要的关键预测实验。目前形式的模型预测：（1）尽管颗粒细胞可以被二尖瓣细胞侧树突兴奋，而不管它们的物理接近性如何，但二尖瓣细胞中的尖峰时间仅受到物理相邻颗粒细胞的抑制的影响，（2）颗粒细胞需要同时激活特定的传入神经（肾小球）输入，以引起全细胞再生反应，从而引起侧抑制。这种架构对我们将在目标1中开发的气味表征的处理具有重大意义。为了测试该模型，我们将使用颗粒细胞的空间选择性光遗传学激活和沉默来确定颗粒细胞对二尖瓣细胞活性的影响是否依赖于物理接近（Aim 2），使用嗅球肾小球的光学刺激来测量引起颗粒细胞中的尖峰所需的传入活动模式的形式和特异性（Aim 3），并通过测量竞争气味表征的感知效果来测试模型关于嗅球可塑性结构的假设（目标4）。本申请的智力价值源自其使用最先进的计算建模来构建所提出的实验并解释其结果，沿着使用新开发的实验技术来解决关于EPL功能和处理的长期问题，本文所述的理论已经构建并呈现可测试性。PI Cleland和Schaefer之间的合作对于该提案的成功至关重要，因为PI Schaefer的实验技术能够独特地测试PI Cleland理论模型的预测。PI的交叉能力提高了这种合作的效率：PI Schaefer在计算和行为方法方面都有能力，并在他的研究中利用这两种方法，而PI Cleland在电生理方法方面有能力，并在他的研究中利用它们。这种合作将使这两个机构的学生和博士后受益，将他们整合到一个真正的跨学科框架中，包括实验和计算方法，并通过在实验室之间旅行来促进他们的交叉培训。因此，这一建议的更广泛的影响包括来自不同背景的学生在协调的理论和实验技术的交叉培训，以及暴露他们到美国和德国的实验室。这两个专业学院都有在妇女代表性仍然不足的领域培训本科生和妇女的悠久历史。该提案还规定大学生研究人员可大量参与。

DESCRIPTION (provided by applicant): Reciprocal interactions between mitral and granule cells in the olfactory bulb external plexiform layer (EPL) modify the timing of mitral cell action potentials and thereby influence the information that the olfactory bulb exports to its multiple targets. Theoretical and experimental results produced by each of the two collaborating PIs of this proposal have shown that this powerful and plastic EPL network is not responsible for the simple "contrast-enhancement" function often attributed to it (instead, this largely occurs in the glomerular layer). Rather, EPL interactions perform additional, subsequent operations on odor representations that mediate changes in odor perception and representation based in part on an individual animal's history of odor learning. Specifically, we here propose that computations in the EPL serve to render mitral cell output patterns selective for certain higher-order features of odors in the same sense that neurons in primary visual cortex are selective for higher-order visual features such as edge and orientation - that is, they reflect the co-activation of certain spatiotemporal combinations of receptors that together are characteristic of a meaningful odor. We here propose to develop detailed theoretical models of this hypothesis and its implications and to test its main critical predictions experimentally. The model in its present form predicts (1) that whereas granule cells can be excited by mitral cell lateral dendrites irrespective of their physical proximity, spike timing in mitral cells is affected only by inhibition from physically neighboring granule cells, and (2) that granule cells require the simultaneous activation of specific sets of afferent (glomerular) inputs in order to evoke a whole-cell regenerative response and thereby evoke lateral inhibition. This architecture has substantial implications for the processing of odor representations that we will develop in Aim 1. To test this model, we will determine whether granule cell effects on mitral cell activity depend on physical proximity using spatially selective optogenetic activation and silencing of granule cells (Aim 2), measure the form and specificity of the afferent activity patterns required to evoke spikes in granule cells using optical stimulation of olfactory bulb glomeruli (Aim 3), and test the model's assumptions regarding the structure of olfactory bulb plasticity by measuring the perceptual effects of competing odor representations (Aim 4). The intellectual merit of this application derives from its use of state-of-the-art computational modeling to structure the proposed experiments and interpret their results, along with the use of newly-developed experimental techniques to address the longstanding questions about EPL function and processing that the theory described herein has framed and rendered testable. The collaboration between PIs Cleland and Schaefer is essential to the success of this proposal, as PI Schaefer's experimental techniques are uniquely able to test the prediction of PI Cleland's theoretical models. The efficiency of this collaboration is enhanced by the cross-competence of the PIs: PI Schaefer is competent in both computational and behavioral approaches and utilizes both in his research, whereas PI Cleland is competent in electrophysiological approaches and utilizes them in his research. This collaboration will benefit students and postdocs at both institutions by integrating them into a genuinely interdisciplinary framework encompassing both experimental and computational approaches, and facilitating their cross-training by enabling travel between labs. Consequently, the broader impacts of this proposal include the cross-training of students from diverse backgrounds in coordinated theoretical and experimental techniques as well as exposing them to both American and German laboratories. Both PIs have a strong history of training undergraduates and women in areas in which women remain underrepresented. This proposal also provides for the substantial participation of undergraduate researchers.