Synaptic and circuit mechanisms of olfactory processing

嗅觉处理的突触和电路机制

• 批准号: 8039809
• 负责人: Rachel Wilson
• 金额: $ 35.6万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039809
• 关键词: Address; Affect; Animal Model; Architecture; Axon; Brain; Calcium; Cells; Chemicals; Dependency; Diagnosis; Disease; Drosophila genus; Genetic; Goals; Homologous Gene; Human; Image; Interneurons; Laboratories; Lateral; Link; Lobe; Maps; Measurement; Measures; Mediating; Medical; Modality; Modeling; Monitor; Morphology; Neurodegenerative Disorders; Neurons; Noise; Nose; Odorant Receptors; Odors; Olfactory Receptor Neurons; Patients; Physiological; Play; Population; Preparation; Presynaptic Terminals; Problem Solving; Process; Recruitment Activity; Relative (related person); Role; Sensory; Sensory Process; Shapes; Signal Transduction; Smell Perception; Source; Staging; Structure; Synapses; System; Systems Biology; Techniques; Testing; Time; Ursidae Family; Vertebrates; Whole-Cell Recordings; base; biodefense; design; genetic manipulation; in vivo; insight; neural circuit; olfactory bulb; olfactory disorder; postsynaptic; presynaptic; research study; response; sensor; synaptic function; tool

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. PUBLIC HEALTH RELEVANCE: Understanding olfactory processing should help treat olfactory disorders in human patients, and could aid in understanding why these disorders are often early warning signs of neurodegenerative diseases. Furthermore, understanding how the brain processes odors has contributed valuable insights to the design of so-called "artificial noses", sensors designed to detect and discriminate between specific volatile chemicals. These sensors have important applications in medical diagnosis and biodefense.

描述（由申请人提供）：感觉处理的早期阶段对各种感觉方式提出了类似的问题，例如控制增益和最小化噪声。目前尚不清楚解决这些问题的计算是如何在细胞和突触层面实现的。早期的嗅觉系统因其区室结构而成为研究这些问题的有用准备。所有表达相同气味受体的嗅觉受体神经元（ORN）聚集在同一个区室（肾小球）上，肾小球通过抑制性和兴奋性侧向连接相连。这种结构提出了有关该电路中突触相互作用的体内功能的具体问题。具体来说，为什么每个肾小球上会汇聚如此多的 ORN？突触后神经元如何在时域中整合会聚的 ORN 尖峰？当肾小球之间的连接被取消时会发生什么？不同的肾小球处理通道是否对其前馈输入执行不同的计算？为什么局部神经元（LN）之间存在如此多的多样性？为什么同时具有兴奋性和抑制性 LN 会有用？这些问题将通过有针对性的基因操作、体内全细胞记录和果蝇触角叶的钙成像来解决。果蝇触角叶是解决这些问题的一个很好的模型，因为它与其脊椎动物同源物嗅球具有很强的相似性。此外，它使得目前其他制剂无法进行的实验成为可能。具体来说，可以对特定突触进行基因操作，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影响。在这些研究中，遗传工具将用于 (1) 操纵 ORN 收敛和一致性，(2) 选择性地消除横向兴奋、横向突触前抑制和横向突触后抑制，(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。大多数这些操作都是由于最近对该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，因此其可行性得到了证明。这些研究的结果应该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阐明神经回路如何最大化其信噪比，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，以及为什么横向兴奋和横向抑制经常共存。更具体地说，这些研究应该阐明脊椎动物以及更简单的模型生物中嗅觉处理的突触基础。了解大脑如何处理气味应该有助于设计所谓的“人造鼻子”，这种传感器旨在分析有机挥发物，在医学诊断中具有重要应用。 公共健康相关性：了解嗅觉处理应该有助于治疗人类患者的嗅觉障碍，并有助于理解为什么这些障碍往往是神经退行性疾病的早期预警信号。 此外，了解大脑如何处理气味为所谓的“人造鼻子”的设计提供了宝贵的见解，这种传感器旨在检测和区分特定的挥发性化学物质。 这些传感器在医学诊断和生物防御方面具有重要应用。