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.