Network anatomy of olfactory processing

描述(申请人提供)：了解信息是如何在神经元回路中处理的是神经科学的中心问题，也是理解大脑如何工作的关键。神经元的功能从根本上取决于它在网络中的连接方式。因此，了解网络连通性-电路结构-与细胞功能之间的关系将有助于我们理解神经元和网络是如何转换信息来带来感知和行为的。大规模电子显微镜的最新进展使我们能够开始详细绘制神经网络解剖图。果蝇的嗅觉回路是一个很好的模型系统，因为它包含的神经元数量相对较少，体积很小，现有的工具可以进行基因靶向标记，而且我们对这个系统中神经元功能特性的了解正在迅速扩大。我们将利用这些关键优势来了解嗅觉网络组织的基本规则。这一提议将首次产生大规模的EM数据集，在这些数据集中，可以重建远程神经元连接，并与其体内生理学已知或可以在不同动物中进行检查的识别细胞相对应。具体地说，我们将研究投射神经元与前大脑两个靶区--侧角和蘑菇体--高阶神经元的连接的收敛和发散。我们假设侧角神经元从相同类型的投射神经元接受固定的和会聚的连接。有趣的是，侧角的神经元最近被认为与先天嗅觉行为有关。相比之下，我们假设蘑菇体神经元，已知对嗅觉学习至关重要，与投射神经元具有更多的随机和较少的刻板印象的连接。这些都是关于神经元网络的结构和功能的基本问题，这些网络在苍蝇的嗅觉系统中是唯一可以接近的。最后，通过了解神经元网络连接的基本原理，我们将准备好比较患病和健康的大脑，以评估神经退行性疾病模型中的电路结构是如何受到影响的，从而合理地设计治疗策略。

DESCRIPTION (provided by applicant): Understanding how information is processed in neuronal circuits is a central question in neuroscience and key to understanding how the brain works. A neuron's function is fundamentally dependent on how it is connected within its network. Therefore, understanding the relationship between network connectivity - circuit structure - and cellular function will help us to understand how neurons and networks transform information to bring about perception and behavior. Recent advances in large-scale electron microscopy have allowed us to begin detailed mapping of neural network anatomy. The olfactory circuit of Drosophila melanogaster is an excellent model system for this purpose because it contains a relatively small number of neurons in a small volume, existing tools allow genetically-targeted labeling, and our knowledge about functional properties of neurons in this system is rapidly expanding. We will exploit these key advantages to understand the rules underlying olfactory network organization. This proposal would generate for the first time, large-scale EM datasets in which long-range neuronal connectivity can be reconstructed and corresponded to identified cells whose in vivo physiology is known or can be examined in different animals. Specifically, we will examine the convergence and divergence of projection neuron connectivity to higher-order neurons in two target regions of the protocerebrum, the lateral horn and the mushroom body. We hypothesize that lateral horn neurons receive stereotyped and convergent connectivity from projection neurons of the same type. Interestingly, neurons in the lateral horn have recently been implicated in innate olfactory behaviors. In contrast, we hypothesize that mushroom body neurons, known to be crucial for olfactory learning, have more random and less stereotyped connectivity with projection neurons. These are fundamental questions about the structure and function of neuronal networks that are uniquely approachable in the olfactory system of the fly. Finally, by understanding the basic principles of neuronal network connectivity we will be poised to compare diseased and healthy brains to assess how circuit structure is affected in models of neurodegenerative disorders to rationally design treatment strategies.