CRCNS: Higher-order feature detection in olfactory bulb

描述(由申请人提供)：嗅球外丛层(EPL)中的二尖瓣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，从而影响嗅球输出到其多个靶点的信息。这项提议的两个合作PI各自产生的理论和实验结果表明，这个强大而可塑性的EPL网络并不负责通常被归因于它的简单的“对比度增强”功能(相反，这主要发生在肾小球层)。相反，EPL交互作用对气味表征执行额外的、后续的操作，这些操作部分基于单个动物的气味学习历史来调节气味感知和表征的变化。具体地说，我们在这里提出，EPL中的计算有助于使二尖瓣细胞输出模式对气味的某些高阶特征具有选择性，就像初级视觉皮质中的神经元对高阶视觉特征(如边缘和方向)具有选择性一样-也就是说，它们反映了某些受体的时空组合的共同激活，这些受体共同具有有意义的气味的特征。我们建议为这一假说及其含义建立详细的理论模型，并对其主要的关键预测进行实验检验。目前的模型预测：(1)尽管颗粒细胞可以被二尖瓣细胞侧树突激发，而无论它们的物理距离如何，二尖瓣细胞的棘波计时只受物理上相邻的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(肾小球)输入，以引起全细胞再生反应，从而引起侧向抑制。这个体系结构对我们将在目标1中开发的气味表征的处理具有实质性的影响。为了测试这个模型，我们将使用颗粒细胞的空间选择性光遗传激活和沉默来确定颗粒细胞对二尖瓣细胞活动的影响是否依赖于物理接近(目标2)，测量通过光学刺激嗅球肾小球来唤起颗粒细胞尖峰所需的传入活动模式的形式和特异性(目标3)，并通过测量相互竞争的气味表征的感知效应来测试模型关于嗅球可塑性结构的假设(目标4)。本申请的智力优点来自于它使用最先进的计算建模来组织所提出的实验并解释它们的结果，以及使用新开发的实验技术来解决关于EPL功能和处理的长期存在的问题，这里描述的理论已经构建并使其可测试。PI Cleland和Schaefer之间的合作对这一提议的成功至关重要，因为Pi Schaefer的实验技术是唯一能够测试Pi Cleland理论模型的预测的技术。这种协作的效率通过PI的交叉能力得到提高：Pi Schaefer擅长计算和行为方法，并在他的研究中使用这两种方法，而Pi Cleland擅长电生理方法，并在他的研究中使用它们。这种合作将使两所大学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，并通过允许实验室之间的旅行促进他们的交叉培训。因此，这一建议的更广泛影响包括对来自不同背景的学生进行协调理论和实验技术的交叉培训，并使他们接触到美国和德国的实验室。这两家私人投资机构都有在妇女任职人数不足的领域培训本科生和妇女的良好历史。这项建议还规定了本科生研究人员的大量参与。

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.