Area postrema neurons that mediate nausea-associated behaviors

介导恶心相关行为的后区神经元

基本信息

批准号：
10440136
负责人：
STEPHEN Daniel LIBERLES
金额：
$ 63.29万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10440136
关键词：
Ablation Afferent Neurons Agonist Anatomy Atlases Axon Behavior Brain Cancer Patient Cell Nucleus Cell Surface Receptors Cells Conditioned Reflex Cues Data Educational process of instructing Esthesia GCG gene GDF15 gene Genetic Hormones Image In Vitro Infection Intervention Knock-in Mouse Knockout Mice Lesion Malaise Measures Mediating Molecular Monitor Nausea Neurons Organ Pathway interactions Patients Pharmaceutical Preparations Poison Publishing Role Signal Transduction Stimulus Structure Structure of area postrema Testing Therapeutic Therapeutic Intervention Toxin Treatment Protocols Visceral behavioral response cell type cohort excitatory neuron experimental study genetic approach genetic signature ghrelin in vivo inhibitory neuron novel optogenetics pathogen receptor response sensory input sensory mechanism single-cell RNA sequencing success tool transcriptome transcriptome sequencing

项目摘要

Project Summary Nausea is an unpleasant sensation of visceral malaise, with underlying molecular and neuronal pathways remaining mysterious. Current anti-nausea medications display variable success across patient cohorts, with nausea being the major reason why cancer patients cannot adhere to treatment regimens. New strategies for nausea intervention are needed, and may be enabled by a mechanistic understanding of how the sensation of nausea arises. Classical studies involving brain lesion and stimulation revealed a tiny brain structure termed the area postrema that mediates nausea responses to several visceral threats. The area postrema is a circumventricular organ containing brain-resident sensory neurons that are anatomically poised to receive inputs from both circulating factors and vagal afferents. However, the diversity of area postrema cell types and receptors was previously uncharted. In preliminary data, we built an area postrema cell atlas through single-nucleus RNA sequencing, revealing four excitatory and three inhibitory neuron types. Transcriptome analysis revealed signature genes expressed in different neuronal clusters, as well as many cell surface receptors that guide cellular responses. We generated Cre knock-in mice for genetic access to various area postrema neurons, and adapted approaches for cell-specific chemogenetics, optogenetics, ablation, imaging, and anatomical mapping. We found two excitatory neuron types (clusters 2 and 4) that provide powerful aversion teaching signals, and one (cluster 1) that does not. In Aim 1, we will use genetic tools to ask whether cell clusters 2 and 4, and the receptors they express, mediate behavioral responses to a panel of nausea-inducing stimuli. In Aim 2, we will measure the responses of cell clusters 2 and 4 to humoral factors, genetically defined vagal afferents, and various nausea- inducing stimuli. In Aim 3 we will investigate the roles of newly charted inhibitory neurons in the area postrema, which project locally and are excellent candidates to suppress nausea or other area postrema-mediated behaviors. Together, these experiments will reveal the basic organization of area postrema circuitry, and provide a framework towards understanding and therapeutically controlling nausea.

项目摘要恶心是内脏不适的一种不愉快的感觉，有基本的分子和神经元途径仍然是神秘的。当前的抗Nausea药物在患者队列中显示出可变的成功，恶心是癌症患者无法遵守治疗方案的主要原因。新的策略需要恶心干预，可以通过对感觉的感觉来实现恶心出现。涉及脑部病变和刺激的经典研究表明，大脑结构很小介导恶心的反应对几种内脏威胁的区域。区域是一个包含脑居住的感觉神经元的旋转器官，这些神经元在解剖上准备接收来自循环因素和迷走神经传入的输入。但是，区域后细胞类型的多样性和受体以前未知。在初步数据中，我们通过单核RNA测序构建了一个区域Postrema细胞地图集，揭示了四种兴奋性和三种抑制性神经元类型。转录组分析揭示了表达的签名基因在不同的神经元簇以及许多引导细胞反应的细胞表面受体。我们生成的CRE敲入小鼠，用于遗传进入各个区域Postrema神经元，并适应方法用于细胞特异性化学遗传学，光遗传学，消融，成像和解剖图。我们找到了两个兴奋性神经元类型（簇2和4），可提供强大的厌恶教学信号，一个（群集1）那不是。在AIM 1中，我们将使用遗传工具询问细胞簇2和4以及受体是否表达，介导对诱发恶心刺激的小组的行为反应。在AIM 2中，我们将衡量细胞簇2和4对体液因素的反应，遗传定义的迷走神经传入以及各种恶心诱导刺激。在AIM 3中，我们将研究新图表的抑制性神经元在该地区Postrema的作用，哪个项目在本地项目，是抑制恶心或其他区域Postrema介导的出色候选者行为。这些实验将共同揭示区域postrema电路的基本组织，以及提供一个框架，以理解和治疗控制恶心。