Synaptic and circuit mechanisms of olfactory processing

描述(由申请人提供)：感官处理的早期阶段对各种感官模式提出了类似的问题--例如，控制增益和最小化噪音。目前尚不清楚解决这些问题的计算是如何在细胞和突触水平上实现的。早期的嗅觉系统是研究这些问题的一个有用的准备，因为它的区隔结构。所有表达相同气味感受器的嗅觉感受器神经元(ON)聚集在同一隔室(肾小球)，肾小球通过抑制性和兴奋性侧向连接连接。这种结构提出了关于这个回路中突触相互作用的体内功能的具体问题。具体地说，为什么每个肾小球上都聚集了这么多的角质细胞？突触后神经元如何在时间域整合汇聚的ORN棘波？当肾小球之间的连接消失时会发生什么？不同的肾小球处理通道对其前馈输入是否执行不同的计算？为什么局部神经元(LN)之间会有如此大的差异？为什么同时拥有兴奋性和抑制性LN是有用的？这些问题将通过有针对性的遗传操作、活体全细胞记录和果蝇触角叶的钙成像来解决。果蝇的触角叶是解决这些问题的一个很好的模型，因为它与它的脊椎动物同源物嗅球有很强的相似性。此外，它还可以进行目前在其他制剂中不可能进行的实验。具体地说，有可能从基因上操纵特定的突触，使用体内细胞内电生理测量来验证这些扰动的细胞相关性，并检查这些扰动对完整电路的功能后果。在这些研究中，遗传工具将被用来(1)操纵ORN的收敛和连贯，(2)选择性地取消侧向兴奋、侧向突触前抑制和侧向突触后抑制，(3)刺激特定的LN群体，以及(4)监测和操纵侧抑制的空间扩散。这些操作中的大多数都是由于最近关于这个系统生物学的发现而成为可能的。这些研究中的所有技术都在实验室中常规使用，因此它们的可行性得到了证明。这些研究的结果应该会阐明体内感觉回路中突触整合的一般原理。也就是说，这些研究应该有助于澄清神经电路如何使其信噪比最大化，不同的电路模块如何执行专门的计算，为什么局部中间神经元如此多样化，以及为什么侧向兴奋和侧向抑制经常共存。更具体地说，这些研究应该澄清在脊椎动物和更简单的模式生物中嗅觉处理的突触基础。了解大脑是如何处理气味的应该有助于设计所谓的“人造鼻子”，这种传感器旨在分析在医学诊断中有重要应用的有机挥发性物质。

DESCRIPTION (provided by applicant): The early stages of sensory processing pose similar problems for various sensory modalities-for example, controlling gain and minimizing noise. It is not clear how the computations that solve these problems are implemented at the level of cells and synapses. The early olfactory system is a useful preparation for investigating these issues because of its compartmental architecture. All the olfactory receptor neurons (ORNs) that express the same odorant receptor converge on the same compartment (glomerulus), and glomeruli are linked by both inhibitory and excitatory lateral connections. This architecture raises specific questions about the in vivo function of synaptic interactions in this circuit. Specifically, why do so many ORNs converge on each glomerulus? How do postsynaptic neurons integrate converging ORN spikes in the time domain? What happens when the connections between glomeruli are abolished? Do different glomerular processing channels perform different computations on their feedforward inputs? Why is there such diversity among local neurons (LNs)? Why would it be useful to have both excitatory and inhibitory LNs? These questions will be addressed using targeted genetic manipulations, in vivo whole-cell recordings, and calcium imaging in the Drosophila antennal lobe. The Drosophila antennal lobe is a good model for addressing these questions because it bears a strong similarity to its vertebrate homolog, the olfactory bulb. Moreover, it enables experiments that are currently not possible in other preparations. Specifically, it is possible to genetically manipulate specific synapses, validate the cellular correlates of these perturbations using in vivo intracellular electrophysiological measurements, and examine the functional consequences of these perturbations for the intact circuit. In these studies, genetic tools will be used (1) to manipulate ORN convergence and coherence, (2) to selectively abolish lateral excitation, lateral presynaptic inhibition, and lateral postsynaptic inhibition, (3) to stimulate specific LN populations, and (4) to monitor and manipulate the spatial spread of lateral inhibition. Most of these manipulations were made possible by recent discoveries about the biology of this system. All the techniques in these studies are routinely used in the laboratory, and thus their feasibility is proven. The results of these studies should illuminate general principles underlying synaptic integration in sensory circuits in vivo. Namely, these studies should help clarify how neural circuits can maximize their signal-to-noise ratio, how different circuit modules might perform specialized computations, why local interneurons are so diverse, and why lateral excitation and lateral inhibition often co-exist. More specifically, these studies should clarify the synaptic basis of olfactory processing, in vertebrates as well as in simpler model organisms. Understanding how the brain processes odors should aid the design of so-called "artificial noses", sensors designed to analyze organic volatiles which have important applications in medical diagnosis.