权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

ODOR BLOCKING OF STRESS

消除压力的气味

基本信息

批准号：
10350667
负责人：
Linda B Buck
金额：
$ 61.87万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10350667
关键词：
Animals Area Behavior Blood Brain CRH gene Cells Characteristics Chemicals Chronic stress Complex Corticotropin-Releasing Hormone Data Disease Enterobacteria phage P1 Cre recombinase Foundations Fright Genetic Recombination Hormones Human Hypothalamic structure Instinct Knowledge Link Maps Mediating Mental disorders Methods Molecular Molecular Genetics Mus Nature Neural Pathways Neurons Nose Odors Olfactory Cortex Olfactory Pathways Outcome Physical Restraint Physiological Play Population Process Rodent Role Series Signal Transduction Smell Perception Stereotyping Stimulus Stream Stress Synapses Tracer Travel activity marker biological adaptation to stress environmental chemical experimental study human disease hypothalamic-pituitary-adrenal axis innovation insight mad itch virus neural circuit neuromechanism neurotropic virus novel optogenetics presynaptic relating to nervous system response sensory stimulus single-cell RNA sequencing stressor tool transcriptome

项目摘要

ABSTRACT The mammalian olfactory system detects a multitude of volatile chemicals perceived as scents. In animals, it also detects predator odorants that stimulate instinctive fear responses essential to survival. These defensive responses include increases in blood levels of stress hormones, which result from activation of the HPA (hypothalamic-pituitary-adrenal) axis. A small subset of corticotropin releasing hormone (CRH) neurons in the hypothalamus of the brain plays a key role in the HPA axis. Stressful stimuli increase blood levels of stress hormones in humans as well as in rodents, suggesting the evolutionary conservation of mechanisms underlying physiological responses to fear and stress. Moreover, chronic stress has been linked to some human diseases and dysregulation of the HPA axis is seen in certain human psychiatric conditions, further suggesting that an understanding of the neural mechanisms that control stress hormones in rodents might ultimately provide insights relevant to human disease. The stereotyped nature of stress hormone responses to predator odors in mice suggests the existence of genetically determined neural circuits that convey predator odor signals from the nose through higher olfactory areas to CRH neurons. Consistent with this idea, we recently discovered that a small brain area that occupies less than 5% of the olfactory cortex plays a key role in stress hormone responses to volatile predator odorants detected in the nose. Surprisingly, we and others have obtained evidence that certain common odorants can block stress hormone responses to a predator odor. Our studies further indicate that some odorants also block stress hormone responses to a potent non-olfactory stressor, physical restraint. We propose a series of experiments to investigate the neural circuit mechanisms underlying these unexpected effects of common odorants on stress. In the proposed studies, we will employ a combination of tools to investigate where and how common odorants act in the brain to modulate stress. These include the charting of neural pathways using neurotropic viruses that travel across one or multiple synapses, induction of Cre recombinase expression in stressor- and blocking odorant-responsive neurons, single cell transcriptome analysis to define neurons involved in stress responses and their blocking by common odorants, and chemogenetic and optogenetic silencing of subsets of neurons in specific brain areas. Together, these studies should provide important insights into how odors that appear innocuous can have profound modulatory influences on physiological responses to fear and stress that can be important to survival but, when dysregulated, can predispose to disease.

抽象的哺乳动物的嗅觉系统可以检测到多种被视为气味的挥发性化学物质。在动物身上，它还可以检测捕食者的气味，这些气味会刺激生存所必需的本能恐惧反应。这些防守反应包括血液中应激激素水平升高，这是由 HPA 激活引起的（下丘脑-垂体-肾上腺）轴。促肾上腺皮质激素释放激素 (CRH) 神经元的一小部分大脑的下丘脑在 HPA 轴中起着关键作用。压力刺激会增加血液中的压力水平人类和啮齿动物的激素，表明机制的进化保守性对恐惧和压力的潜在生理反应。此外，慢性压力与某些因素有关。人类疾病和 HPA 轴失调在某些人类精神疾病中可见，进一步这表明，了解啮齿类动物控制应激激素的神经机制可能会最终提供与人类疾病相关的见解。应激激素反应的刻板性质老鼠身上的捕食者气味表明存在遗传决定的传达捕食者气味的神经回路气味信号从鼻子通过较高的嗅觉区域到达 CRH 神经元。与这个想法相一致，我们最近发现，占嗅觉皮层不到 5% 的一小块大脑区域在应激激素对鼻子中检测到的挥发性捕食者气味的反应。令人惊讶的是，我们和其他人获得的证据表明某些常见的气味剂可以阻止应激激素对捕食者气味的反应。我们的研究进一步表明，一些气味剂还会阻止应激激素对强效非嗅觉的反应。压力源、身体约束。我们提出了一系列实验来研究神经回路机制常见气味剂对压力的这些意想不到的影响是潜在的。在拟议的研究中，我们将采用结合多种工具来研究常见气味剂在大脑中的作用位置以及如何调节压力。其中包括使用嗜神经病毒绘制神经通路图，这些病毒穿过一个或多个突触，在应激源和阻断气味反应神经元中诱导 Cre 重组酶表达，单细胞转录组分析可定义参与应激反应的神经元及其常见的阻断气味剂，以及特定大脑区域神经元子集的化学遗传学和光遗传学沉默。一起，这些研究应该提供重要的见解，让我们了解看似无害的气味如何产生深远的影响。对恐惧和压力的生理反应的调节影响对于生存来说可能很重要，但是当失调，容易患病。