ODOR BLOCKING OF STRESS

摘要 哺乳动物的嗅觉系统探测到大量被感知为气味的挥发性化学物质。在动物身上，它 还能检测到捕食者的气味，这些气味会刺激对生存至关重要的本能恐惧反应。这些防御性的 反应包括血液中应激激素水平的增加，这是由于HPA激活引起的。 (下丘脑-垂体-肾上腺)轴。下丘脑中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。应激性刺激会增加血液中的应激水平 人类和啮齿动物体内的荷尔蒙，表明机制的进化保守 对恐惧和压力的潜在生理反应。此外，慢性压力与一些 人类疾病和HPA轴调节失调可见于某些人类精神疾病，此外 这表明，对控制啮齿动物应激激素的神经机制的了解可能会 最终提供与人类疾病相关的见解。应激激素反应的刻板印象 老鼠身上的捕食者气味表明，存在由基因决定的神经回路，这些神经回路传递捕食者 气味信号从鼻子通过高级嗅觉区传递到CRH神经元。与这一理念一致，我们 最近发现，一个占嗅觉皮质不到5%的小脑区在 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 有证据表明，某些常见的气味可以阻止应激激素对捕食者气味的反应。我们的 进一步的研究表明，一些气味物质也能阻止压力荷尔蒙对强效非嗅觉物质的反应。 压力源，身体上的约束。我们提出了一系列实验来研究神经回路机制。 在这些常见气味对压力的意想不到的影响下。在建议的研究中，我们会采用 研究常见气味在大脑中的哪里以及如何作用以调节压力的工具的组合。 其中包括使用嗜神经性病毒跨越一个或多个 突触，应激源-Cre重组酶表达的诱导和气味反应神经元的阻断， 单细胞转录组分析确定参与应激反应的神经元及其被普通药物阻断 气味，以及化学发生和光发生沉默的特定大脑区域的神经元亚群。一起， 这些研究应该会提供重要的见解，让我们了解看起来无害的气味是如何产生深远影响的 对恐惧和压力的生理反应的调节影响，这对生存可能很重要，但当 调节失调，容易得病。

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.