The Receptor Basis for Serotonergic Modulation of Olfaction Across Multiple BrainAreas

跨多个脑区嗅觉的血清素调节的受体基础

• 批准号: 10424907
• 负责人: Andrew M Dacks
• 金额: $ 7万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10424907
• 关键词: Address; Affect; Atlases; Behavior; Behavioral Assay; Biological Models; Biophysics; Brain; Brain region; Cells; Code; Complex; Drosophila genus; Electrophysiology (science); Goals; Horns; Image; Individual; Interneurons; Invertebrates; Knowledge; Lateral; Lobe; Modeling; Nervous system structure; Neuromodulator; Neurons; Neuropil; Odors; Olfactory Pathways; Output; Physiological; Population; Positioning Attribute; Process; Property; Regulation; Research; Resolution; Role; Sensory; Serotonin; Smell Perception; Synapses; System; Testing; Transgenic Organisms; base; biophysical properties; cholinergic; connectome; dynamic system; experimental study; flexibility; innovation; knock-down; nanometer resolution; nervous system disorder; neuronal excitability; neuroregulation; olfactory bulb; patch clamp; presynaptic; receptor; receptor expression; reconstruction; response; sensory system; serotonin receptor; tool

Project Summary. Sensory networks continuously fine-tune how they process information to meet ongoing physiological demands. The nervous system achieves this flexibility via the release of “neuromodulators” which alter the biophysical and synaptic properties of individual neuron classes within a network. This adjusts the influence of each class to optimize network dynamics for the appropriate context. Neuromodulation is ubiquitous and many neurological disorders result from, or are associated with, dysfunctional neuromodulatory systems. Despite the importance of neuromodulation for healthy sensory processing, our ability to predict the consequences of neuromodulation is limited by the diversity of modulatory receptors expressed by different classes of neurons. Each receptor has different effects and each class of neuron supports different features of sensory coding, so the effects of neuromodulation can be complex. We propose to address this issue in a genetically tractable model with fewer neurons and modulatory receptors; the olfactory system of Drosophila. The objective of this application is to determine how serotonin (5-HT) receptor subtypes affect key neuronal classes and the consequences for olfactory processing and odor-guided behavior. The long-term goal of this research is to determine the mechanistic basis for neuromodulation of sensory network dynamics. In vertebrate and invertebrate olfactory systems, the effects of 5-HT on odor-evoked responses vary across different neuron classes. However, it is difficult to determine how 5-HT alters olfactory processing without knowing the consequences of activating the 5-HT receptors expressed by each class. We recently completed a comprehensive atlas of 5-HT receptor expression within the olfactory system, so we now propose to manipulate the expression of individual 5-HT receptors in specific classes of neurons to determine how 5-HT affects individual neuron classes, the consequences for odor coding across olfactory brain regions and odor- guided behavior. In addition, we will use one of the first whole brain, nanometer resolution EM connectomes to establish single cell resolution connectivity rules of 5-HT neurons with each olfactory neuron class examined in this proposal. In Specific Aim 1 we will determine the receptor basis for the effects of 5-HT on local inhibitory networks within the first olfactory neuropil (the antennal lobe or “AL”). In Aim 2 we will determine the contribution of direct modulation of cholinergic AL output neurons to the overall effects of 5-HT on olfactory information sent to downstream processing stages. Finally, in Aim 3 we will determine how 5-HT receptors modulate GABAergic AL output neurons that promote olfactory attraction. These experiments will establish how the overall effects of 5-HT emerge from neuron class-specific expression of 5-HT receptors, thus addressing a critical gap in our knowledge of healthy sensory processing.

项目摘要。感官网络不断微调它们处理信息的方式，以满足正在进行的 生理需求。神经系统通过释放“神经调节剂”来实现这种灵活性。 改变网络中单个神经元类别的生物物理和突触属性。这将调整 每一类的影响，以针对适当的环境优化网络动态。神经调节是 无处不在的许多神经疾病是由神经调节功能障碍引起的，或与之相关 系统。尽管神经调节对健康的感觉处理很重要，但我们预测 神经调节的后果受到不同基因表达的调节受体的多样性的限制 神经元的类别。每种受体都有不同的作用，每类神经元支持不同的功能 感觉编码，所以神经调节的影响可能是复杂的。我们建议通过一项 具有较少神经元和调节感受器的遗传易驯化模型；果蝇的嗅觉系统。 这项应用的目的是确定5-羟色胺(5-HT)受体亚型如何影响关键神经元 类以及嗅觉处理和气味引导行为的后果。这样做的长期目标是 研究目的是确定感觉网络动力学的神经调节的机制基础。 在脊椎动物和无脊椎动物的嗅觉系统中，5-羟色胺对气味诱发反应的影响各不相同 跨越不同的神经元类别。然而，很难确定5-羟色胺如何改变嗅觉处理。 而不知道激活每个类别表达的5-羟色胺受体的后果。我们最近 完成了嗅觉系统内5-羟色胺受体表达的全面图谱，因此我们现在提出 操纵特定类别神经元中单个5-羟色胺受体的表达，以确定5-羟色胺如何 影响单个神经元类别，气味编码跨嗅觉大脑区域和气味的后果- 引导性行为。此外，我们将使用第一批全脑、纳米分辨率的EM连接器之一来 建立5-羟色胺神经元的单细胞分辨连通性规则 这项提议。在特定的目标1中，我们将确定5-羟色胺对局部抑制作用的受体基础 第一嗅神经束(触角叶或“AL”)内的网络。在目标2中，我们将确定 胆碱能AL输出神经元直接调制在5-羟色胺对嗅觉整体效应中的作用 发送到下游处理阶段的信息。最后，在目标3中，我们将确定5-羟色胺受体如何 调节GABA能AL输出神经元，促进嗅觉吸引。这些实验将确定 5-羟色胺的整体效应是如何从5-羟色胺受体的神经元类别特异性表达中显现出来的 解决我们对健康感觉处理知识的一个关键差距。