Optogenetic studies of mouse olfaction

小鼠嗅觉的光遗传学研究

• 批准号: 8371241
• 负责人: VENKATESH N MURTHY
• 金额: $ 33.92万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8371241
• 关键词: Afferent Neurons; Aging; Alzheimer' s Disease; Animals; Architecture; Area; Autistic Disorder; Axon; Behavior; Brain; Brain Diseases; Brain Stem; Breathing; Breeding; Cells; Characteristics; Chemicals; Code; Decision Making; Dendrites; Devices; Disease; Dissection; Elements; Feedback; Food; Functional disorder; Future; Goals; Health; Human; In Vitro; Indium; Individual; Interneurons; Investigation; Ion Channel; Lateral; Light; Mammals; Methods; Metric; Molecular Genetics; Mus; Neurons; Nose; Odorant Receptors; Odors; Olfactory Cortex; Olfactory Epithelium; Optics; Output; Partner in relationship; Pattern; Pheromone; Positioning Attribute; Preparation; Process; Property; Proteins; Reagent; Research; Resolution; Retina; Retinal Ganglion Cells; Sampling; Sensory; Single Parent; Slice; Smell Perception; Solutions; Specificity; Stimulus; Structure; Surface; Synapses; System; Technology; Testing; Time; Transgenic Mice; Vertebrates; Visual; Visual system structure; digital; extracellular; granule cell; information processing; millisecond; mouse model; nervous system disorder; neural circuit; novel; olfactory bulb; optogenetics; piriform cortex; postsynaptic; public health relevance; receptive field; receptor; relating to nervous system; research study; response; sensory system; theories; tool; visual receptive field; vomeronasal organ

DESCRIPTION (provided by applicant): The function of a neural circuit is constrained by the properties of individual neurons and their wiring. In many sensory systems, the responses of the circuit elements vary systematically with physical position, leading to a topographic representation of the stimulus space. Sensory representation in the olfactory system has been harder to decipher, in part due to the difficulty in finding appropriate metrics to characterize the odor space and in sampling this space densely. Progress has also been slowed by technological limitations in probing and controlling individual circuit elements in early olfactory circuits. In this proposal, we aim to develop new methods that will greatly aid the dissection of functional neural circuits in the olfactory system in mice. Mice rely on olfaction to find food, choose mates and avoid predators. In mammals, olfactory sensory neurons send their axons to the olfactory bulb (OB), where there is a characteristic physical layout of inputs in the glomerular layer. Each glomerulus receives convergent afferents from a large number of olfactory sensory neurons expressing the same odorant receptor, so each point on the surface of the OB has a specific chemical response spectrum. The principal neurons in the OB, the mitral and tufted (M/T) cells, typically have a single primary dendrite that projects to a single glomerulus. M/T cells also receive lateral GABAergic inputs from a variety of interneurons in the glomerular and external plexiform layers, thus allowing them to sample information from several functionally diverse glomeruli. Odor processing in the OB is also strongly modulated by feedback from the cortex as well as brainstem neuromodulatory centers. Here, we propose to develop new reagents and methods that will accelerate the pace of research into mammalian olfaction. Our experiments will be guided by three specific aims. Aim 1: To generate transgenic mouse lines that express the light-activated ion channel channelrhodopsin specifically in olfactory sensory neurons, rendering the input layer of the olfactory bulb (glomeruli) optically excitable. Aim 2: To demonstrate the feasibility of using this mouse model to study functional connectivity in the OB and its downstream target areas using in vitro slice preparation and digital mirror device technology. Aim 3: To demonstrate the feasibility of constructing glomerular receptive fields of neurons in the OB and its target brain areas in the intact, freely breathing mouse. Tools developed here will help advance our understanding of odor coding. In addition, since the olfaction is often used as a sensory gateway to study higher brain function such as decision making, our tools will also have broader use. Finally, by crossing these "opto-olfactory" mice with other mouse models of disease, we can catalyze studies of sensory dysfunction in brain disorders such as autism and Alzheimer's disease.

描述（由申请人提供）：神经回路的功能受单个神经元及其布线的特性约束。在许多感觉系统中，电路元件的响应随物理位置而系统地变化，从而导致刺激空间的地形表示。嗅觉系统中的感觉表征一直难以破译，部分原因是难以找到合适的度量来表征气味空间，并且难以密集地对该空间进行采样。在早期嗅觉回路中，探测和控制单个回路元件的技术限制也减缓了进展。在这项提案中，我们的目标是开发新的方法，这将大大有助于在小鼠嗅觉系统的功能神经回路的解剖。 老鼠依靠嗅觉来寻找食物、选择配偶和躲避捕食者。在哺乳动物中，嗅觉感觉神经元将其轴突发送到嗅球（OB），在那里肾小球层中存在输入的特征性物理布局。每个肾小球都接收来自大量表达相同气味受体的嗅觉感觉神经元的会聚传入，因此OB表面上的每个点都有特定的化学反应谱。OB中的主要神经元，即二尖瓣和簇状（M/T）细胞，通常具有单个初级树枝状突起，投射到单个肾小球。M/T细胞也接受来自肾小球和外网状层中各种中间神经元的外侧GABA能输入，从而使它们能够从几个功能不同的肾小球中采集信息。嗅球中的气味处理也受到来自皮层和脑干神经调节中心的反馈的强烈调制。 在这里，我们建议开发新的试剂和方法，将加快研究哺乳动物嗅觉的步伐。我们的实验将以三个具体目标为指导。目标1：产生转基因小鼠品系，表达光激活离子通道channelrhodopsin特异性在嗅觉感觉神经元，使嗅球（肾小球）的输入层光学兴奋。目标二：证明使用该小鼠模型使用体外切片制备和数字镜像设备技术研究OB及其下游靶区的功能连接的可行性。目标三：目的：在自由呼吸的完整小鼠模型上，建立OB及其靶脑区神经元肾小球感受野的可行性。 这里开发的工具将有助于促进我们对气味编码的理解。此外，由于嗅觉通常被用作研究决策等高级大脑功能的感觉门户，我们的工具也将有更广泛的用途。最后，通过将这些“光-嗅觉”小鼠与其他疾病小鼠模型杂交，我们可以促进对自闭症和阿尔茨海默病等大脑疾病中感觉功能障碍的研究。