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.

项目摘要摘要在感染期间，动物暴露了旨在增加生存的行为和生理学的自适应变化。尽管存在许多急性感染原因，但也会出现类似的刻板印象，其中包括体温或发烧升高，食欲改善并增加了嗜睡。温暖和冷血动物发烧的反应感染，表明发烧电路是硬连线和高度的保守但恰恰是神经系统如何改变身体的时间和相关行为。感染仍然未知。我们已经确定了下丘脑前区域的神经元群在炎性脂多糖（LPS）给药后，高度激活。由于关闭 laminae末端（OVLT）的细胞器血管之间的接近，其中炎症细胞因子输入大脑以影响附近的细胞，以及调节正常身体时间的神经元的神经元，并我们的初步数据，我们建议这些新鉴定的LPS敏感神经元控制发烧免疫反应。我们将使用化学发生激活和细胞消融方法来证明这一点人口在增加身体时间效果和影响其他发烧相关行为方面发挥作用 LPS注入。此外，我们最近开发了用于遗传学分子表征的新方法使用单细胞RNA测序（SCRNA-SEQ）和多路复用，误解，原位定义的细胞群荧光原位杂交（Merfish）以生成空间分辨和功能意识的地图集前区域。我们将采用类似的策略来表征诱导发烧的神经元以及周围的非 - 神经元细胞类型可能通过旁分泌机制在发烧中发挥作用。最后，我们建议使用病毒介导的跟踪和功能工具来确定直接和间接电路机制 LPS敏感的神经元及其靶标通过其对体温和发烧相关的控制行为。我们的数据将导致LPS敏感神经元的分子和功能表征术前区域，并更好地了解炎症性疾病症状，例如发烧和相关症状行为变化在大脑中受到调节。这些努力对理解人类疾病的基础机制，可能为发烧的新治疗策略提供信息和相关症状。