Olfactory and neuropeptide inputs to appetite neurons in the arcuate nucleus.

The sense of smell has potent effects on appetite, but the underlying neural mechanisms are largely a mystery. The hypothalamic arcuate nucleus contains two subsets of neurons linked to appetite: AgRP (agouti-related peptide) neurons, which enhance appetite, and POMC (pro-opiomelanocortin) neurons, which suppress appetite. Here, we find that AgRP and POMC neurons receive indirect inputs from partially overlapping areas of the olfactory cortex, thus identifying their sources of odor signals.

Odor blocking of stress hormone responses.

Scents have been employed for millennia to allay stress, but whether or how they might do so is largely unknown. Fear and stress induce increases in blood stress hormones controlled by hypothalamic corticotropin releasing hormone neurons (CRHNs). Here, we report that two common odorants block mouse stress hormone responses to three potent stressors: physical restraint, predator odor, and male-male social confrontation.

A psychological stressor conveyed by appetite-linked neurons.

Mammals exhibit instinctive reactions to danger critical to survival, including surges in blood stress hormones. Hypothalamic corticotropin-releasing hormone neurons (CRHNs) control stress hormones but how diverse stressors converge on CRHNs is poorly understood. We used sRNA profiling to define CRHN receptors for neurotransmitters and neuromodulators and then viral tracing to localize subsets of upstream neurons expressing cognate receptor ligands.

Connect-seq to superimpose molecular on anatomical neural circuit maps.

The mouse brain contains about 75 million neurons interconnected in a vast array of neural circuits. The identities and functions of individual neuronal components of most circuits are undefined. Here we describe a method, termed "Connect-seq," which combines retrograde viral tracing and single-cell transcriptomics to uncover the molecular identities of upstream neurons in a specific circuit and the signaling molecules they use to communicate.

Combinatorial effects of odorants on mouse behavior.

The mechanisms by which odors induce instinctive behaviors are largely unknown. Odor detection in the mouse nose is mediated by >1, 000 different odorant receptors (ORs) and trace amine-associated receptors (TAARs). Odor perceptions are encoded combinatorially by ORs and can be altered by slight changes in the combination of activated receptors.

A specific area of olfactory cortex involved in stress hormone responses to predator odours.

Instinctive reactions to danger are critical to the perpetuation of species and are observed throughout the animal kingdom. The scent of predators induces an instinctive fear response in mice that includes behavioural changes, as well as a surge in blood stress hormones that mobilizes multiple body systems to escape impending danger. How the olfactory system routes predator signals detected in the nose to achieve these effects is unknown.

Single-cell transcriptomics reveals receptor transformations during olfactory neurogenesis.

The sense of smell allows chemicals to be perceived as diverse scents. We used single-neuron RNA sequencing to explore the developmental mechanisms that shape this ability as nasal olfactory neurons mature in mice. Most mature neurons expressed only one of the ~1000 odorant receptor genes (Olfrs) available, and at a high level.

Olfactory receptor genes expressed in distinct lineages are sequestered in different nuclear compartments.

The olfactory system translates a vast array of volatile chemicals into diverse odor perceptions and innate behaviors. Odor detection in the mouse nose is mediated by 1,000 different odorant receptors (ORs) and 14 trace amine-associated receptors (TAARs). ORs are used in a combinatorial manner to encode the unique identities of myriad odorants.

Olfactory receptor patterning in a higher primate.

The mammalian olfactory system detects a plethora of environmental chemicals that are perceived as odors or stimulate instinctive behaviors. Studies using odorant receptor (OR) genes have provided insight into the molecular and organizational strategies underlying olfaction in mice. One important unanswered question, however, is whether these strategies are conserved in primates.

A pharmacological network for lifespan extension in Caenorhabditis elegans.

One goal of aging research is to find drugs that delay the onset of age-associated disease. Studies in invertebrates, particularly Caenorhabditis elegans, have uncovered numerous genes involved in aging, many conserved in mammals. However, which of these encode proteins suitable for drug targeting is unknown.

A large-scale analysis of odor coding in the olfactory epithelium.

Mammals can perceive and discriminate myriad volatile chemicals as having a distinct odor. Odorants are initially detected by odorant receptors (ORs) on olfactory sensory neurons (OSNs) in the nose. In the mouse, each OSN expresses one of ∼1000 different OR genes.

A high-throughput screen for chemicals that increase the lifespan of Caenorhabditis elegans.

One long-term goal of aging research is to find drugs that can delay aging and the onset of age-associated diseases. With this in mind, we screened 88,000 chemicals for the ability to increase the lifespan of Caenorhabditis elegans nematodes. We found that mianserin, a serotonin receptor antagonist used as an antidepressant in humans, can increase C.

Formyl peptide receptors are candidate chemosensory receptors in the vomeronasal organ.

The identification of receptors that detect environmental stimuli lays a foundation for exploring the mechanisms and neural circuits underlying sensation. The mouse vomeronasal organ (VNO), which detects pheromones and other semiochemicals, has 2 known families of chemoreceptors, V1Rs and V2Rs. Here, we report a third family of mouse VNO receptors comprising 5 of 7 members of the formyl peptide receptor (FPR) family.

An antidepressant that extends lifespan in adult Caenorhabditis elegans.

The mechanisms that determine the lifespan of an organism are still largely a mystery. One goal of ageing research is to find drugs that would increase lifespan and vitality when given to an adult animal. To this end, we tested 88,000 chemicals for the ability to extend the lifespan of adult Caenorhabditis elegans nematodes.

A second class of chemosensory receptors in the olfactory epithelium.

The mammalian olfactory system detects chemicals sensed as odours as well as social cues that stimulate innate responses. Odorants are detected in the nasal olfactory epithelium by the odorant receptor family, whose approximately 1,000 members allow the discrimination of a myriad of odorants. Here we report the discovery of a second family of receptors in the mouse olfactory epithelium.

Combinatorial effects of odorant mixes in olfactory cortex.

In mammals, each odorant is detected by a combination of different odorant receptors. Signals from different types of receptors are segregated in the nose and the olfactory bulb, but appear to be combined in individual neurons in the olfactory cortex. Here, we report that binary odorant mixes stimulate cortical neurons that are not stimulated by their individual component odorants.

Feedback loops link odor and pheromone signaling with reproduction.

Pheromones can have profound effects on reproductive physiology and behavior in mammals. To investigate the neural circuits underlying these effects, we used a genetic transneuronal tracer to identify neurons that synapse with GnRH (LHRH) neurons, the key regulators of reproduction. We then asked whether the connected neurons are presynaptic or postsynaptic to GnRH neurons and analyzed their responses to chemosensory cues.

Odor maps in the olfactory cortex.

In the olfactory system, environmental chemicals are deconstructed into neural signals and then reconstructed to form odor perceptions. Much has been learned about odor coding in the olfactory epithelium and bulb, but little is known about how odors are subsequently encoded in the cortex to yield diverse perceptions. Here, we report that the representation of odors by fixed glomeruli in the olfactory bulb is transformed in the cortex into highly distributed and multiplexed odor maps.

Olfactory receptors and odor coding in mammals.

Humans and other mammals perceive a vast number of volatile chemicals as having distinct odors. This ability derives from the existence of a large family of olfactory receptors that number about 350 in man and 1000 in mice. Individual odorants activate distinct combinations of olfactory receptors, generating an immense array of combinatorial receptor codes that define odorant identities.