Molecular and genetic dissection of brain circuits controlling fever

控制发烧的脑回路的分子和遗传解剖

基本信息

批准号：
10589104
负责人：
Catherine Dulac
金额：
$ 39.2万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10589104
关键词：
Ablation Adipose tissue Affect Animals Area Atlases Attenuated Awareness Behavior Behavioral Body Temperature Brain Cells Collaborations Data Dedications Desire for food Diagnosis Dinoprostone Dissection Dorsal Exhibits Fever Fluorescent in Situ Hybridization Future Gene Expression Generations Genes Genetic Goals Human Hypothalamic structure Immediate-Early Genes Immune Immune response Immune signaling Immunologic Factors In Situ Infection Inflammatory Injections Innate Immune Response Lethargies Libraries Lipopolysaccharides Medial Mediating Methods Middle Hypothalamus Modeling Molecular Mus Nervous System Neural Pathways Neuroglia Neurons Optics Patients Physiologic Thermoregulation Physiological Physiology Population Preoptic Areas Prostaglandin Receptor Prostaglandins Proteins Role Stereotyping Symptoms Synapses Temperature Testing Thermogenesis Universities Viral acute infection adaptive immune response associated symptom attenuation behavioral response cell type cytokine experimental study fighting genetic approach genetic information genetic technology imaging modality inducible Cre inhibitor insight neural circuit neuronal circuitry novel novel strategies novel therapeutic intervention paracrine paraventricular nucleus pathogen promoter response single-cell RNA sequencing therapeutic development tool treatment strategy

项目摘要

PROJECT SUMMARY ABSTRACT During an infection, animals exhibit adaptive changes in behavior and physiology aimed at increasing survival. Although many causes of acute infection exist, a similar set of stereotyped symptoms occur, which includes increased body temperature or fever, decreased appetite and increased lethargy. Both warm- and cold-blooded animals generate a fever in response infection suggesting that fever circuits are hard-wired and highly conserved, yet exactly how the nervous system alters body temperature and associated behavior in response to infection remains unknown. We have identified a population of neurons in the preoptic area of the hypothalamus that are highly activated following administration of inflammatory lipopolysaccharides (LPS). Due to the close proximity between the organum vasculosum of the laminae terminalis (OVLT), where inflammatory cytokines enter the brain to affect nearby cells, and neurons of the preotpic area regulating normal body temperature, and our preliminary data, we propose that these newly identified LPS-sensitive neurons control fever initiation during an immune response. We will use chemogenetic activation and cell ablation approaches to demonstrate that this population plays a role in increasing body temperature and in affecting other fever-associated behaviors upon LPS injection. Further, we have recently developed new approaches for molecular characterization of genetically defined cell populations in situ using single-cell RNA sequencing (scRNA-seq) and multiplex, error-robust, fluorescent in situ hybridization (MERFISH) to generate a spatially-resolved and functionally-aware atlas of the preoptic area. We will apply a similar strategy to characterize fever-inducing neurons as well as surrounding non- neuronal cell types that are likely to play a role in fever generation through paracrine mechanisms. Finally, we propose to use viral-mediated tracing and functional tools to determine the direct and indirect circuit mechanisms by which LPS-sensitive neurons and their targets exert control over body temperature and fever-related behaviors. Our data will lead to a molecular and functional characterization of LPS-sensitive neurons in the preoptic area and to a better understanding of how inflammatory sickness symptoms, such as fever and related behavioral changes, are regulated in the brain. These efforts have direct implications for understanding the mechanisms underlying human sickness, and may inform new therapeutic strategies for the treatment of fever and associated symptoms.

项目概要摘要在感染期间，动物表现出行为和生理的适应性变化，旨在提高生存率。尽管存在许多急性感染的原因，但也会出现一系列类似的刻板症状，其中包括体温升高或发烧、食欲下降和嗜睡增加。动物因感染而发烧，这表明发烧回路是硬连线的并且高度保守的，但神经系统究竟如何改变体温和相关行为以响应我们已经确定了下丘脑视前区的一群神经元的感染情况。由于紧密的关系，在施用炎性脂多糖（LPS）后会被高度激活。终板血管器 (OVLT) 之间的邻近性，其中炎症细胞因子进入大脑影响附近细胞和视前区神经元调节正常体温，根据我们的初步数据，我们建议这些新发现的 LPS 敏感神经元在我们将使用化学遗传学激活和细胞消融方法来证明这一点。人群在体温升高和影响其他与发烧相关的行为方面发挥着作用此外，我们最近开发了基因分子表征的新方法。使用单细胞 RNA 测序 (scRNA-seq) 和多重、抗误差、荧光原位杂交（MERFISH）生成空间分辨和功能感知的图谱我们将应用类似的策略来表征发热诱导神经元以及周围的非神经元。可能通过旁分泌机制在发烧产生中发挥作用的神经元细胞类型。提议使用病毒介导的追踪和功能工具来确定直接和间接回路机制 LPS敏感神经元及其靶标通过这种方式控制体温和发烧相关的我们的数据将导致 LPS 敏感神经元的分子和功能表征。视前区并更好地了解炎症性疾病症状（例如发烧和相关）如何行为变化在大脑中受到调节，这些努力对于理解行为具有直接影响。人类疾病的机制，并可能为治疗发烧提供新的治疗策略以及相关症状。