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Mechanisms Underlying the Sense of Smell and Aging

Research Summary

Linda Buck's laboratory is investigating the mechanisms that underlie odor perception and pheromone sensing in mammals. They are interested in how the olfactory system detects myriad environmental chemicals and how the brain translates those chemicals into diverse odor perceptions and behaviors. They are also interested in the mechanisms that underlie aging.

Odor Detection in the Nose
The mammalian olfactory system detects a multitude of chemicals perceived as odors as well as social cues that alter behavior or physiology. In initial studies, we discovered the odorant receptor (OR) family, a family of unprecedented size and diversity that mediates odor detection in the nose and is evolutionarily conserved in vertebrates.

By analyzing genome sequence data, we identified close to 1,000 intact OR genes in mice and 350 in humans. OR genes are distributed over the majority of chromosomes at ~50 different loci in each species. This configuration may prevent a catastrophic loss of OR genes by unequal crossing over, a potential danger if all OR genes were clustered at one locus.

Diversity and specificity in odor detection.

One key question is how the OR family encodes odor identities. We found that it does so via a combinatorial strategy. Different odorants are detected, and thereby encoded, by different combinations of ORs, but one OR can serve as one component of the codes for multiple odorants. This strategy is capable of generating millions of different odor codes and explains how we can discriminate even closely related odorants. Our recent studies further indicate that ORs are extremely diverse in their recognition profiles, that receptor code size varies among odorants, and that most ORs are "narrowly tuned" to recognize odorants with similar structures and, in some cases, similar perceived odor subqualities.

Another intriguing question is how the nervous system organizes information from 1,000 different ORs. Our group and another first examined the nose and its synaptic target, the olfactory bulb of the brain. These studies suggested that each sensory neuron in the nose expresses a single OR gene. Thousands of neurons with the same OR are randomly scattered within one of several nasal zones, possibly reflecting the need for a stochastic OR gene choice mechanism. However, their axons converge in a few, apparently OR-specific, glomeruli in the bulb, an arrangement that might maximize odor sensitivity by the integration of signals from the same OR in downstream bulb neurons. Recent reports suggest that OR inputs then return to being highly distributed in the olfactory cortex, potentially allowing for the integration of signals from different components of an odorant's combinatorial receptor code at this level. We are currently using single-cell transcriptomics to investigate the mechanisms that shape the organization of OR inputs and how that organization generates odor perceptions of different valence.

TAARs, a Second Family of Chemosensory Receptors in the Nose
The large size of the OR family and its combinatorial use in odor coding would seem to easily account for odor discrimination. However, we found a second family of 14 nasal receptors, called trace amine-associated receptors (TAARs).  Like ORs, TAARs are evolutionarily conserved in vertebrates, suggesting they may have distinct functions. We identified ligands for a few TAARs, all volatile amines. Several were reported to be in mouse urine, hinting that TAARs might detect social cues. Consistent with this idea, one TAAR preferentially responded to adult male mouse urine, suggesting that it discerns both gender and sexual status. TAAR ligands in mouse or predator urine have now been reported to elicit innate attractive or aversive behavior. Our recent finding that a human TAAR responds to rotten fish suggests a possible sentinel function to prevent the ingestion of pathogen-harboring food and a conserved role for TAARs in innate aversion. We are currently investigating the neural circuits that underlie TAAR-induced innate responses in mice.

Pheromone Detection in the Vomeronasal Organ
The vomeronasal organ (VNO) is an accessory olfactory structure in the nasal septum historically associated with pheromone sensing. We found that VNO sensory neurons lack the G protein to which ORs couple and instead express two other G proteins, each in a different zone. Work in our lab and others identified two families of >100 receptors differentially expressed in these zones, as well as a small family of VNO formyl peptide receptors (FPRs). We found minute fractions of VNO neurons activated by extremely low concentrations of different pheromones or certain odorants. This suggested that some VNO receptors might be highly specific for single ligands and, in addition, that selected odorants might induce innate responses via the VNO, possibly allowing the coordination of social behaviors with environmental cues.

Neural Circuits That Induce Innate Responses to Olfactory Stimuli
The receptors and neural circuits that elicit instinctive responses to pheromones and predator odors are largely a mystery. We previously expressed a genetic transneuronal tracer we had developed in hypothalamic gonadotropin releasing hormone (GnRH) neurons, which control pheromone effects on sex hormones. These studies indicated that GnRH neurons directly synapse with ~50,000 neurons in 53 brain areas with diverse functions. They suggested that GnRH neurons integrate information from multiple brain areas about the internal and external environment and then modulate multiple other brain areas, perhaps to optimize reproductive success. These and other studies also suggested that GnRH neurons receive sensory input not only from the VNO, as previously thought, but also the nose. We are now using neurotropic viruses we have developed to investigate the receptors and neural circuits that underlie instinctive responses to pheromones and predator odors.

Our laboratory is also interested in aging. One long-term goal of aging research is to identify drugs that would delay age-associated disease. Some aging mechanisms seen in the short-lived nematode Caenorhabditis elegans are evolutionarily conserved in mice. Nematodes and mice also have many homologous proteins with related functions, suggesting that drugs found to increase nematode lifespan might point to drugs with similar effects in mice.

We screened 88,000 small molecules for the ability to increase C. elegans lifespan and found more than 100 that did so. Further investigation of one led to the discovery that a human antidepressant (mianserin) increases nematode lifespan by ~30 percent. Mianserin antagonizes neuromodulator receptors similar to those it blocks in humans and appears to increase lifespan via mechanisms linked to dietary restriction. By screening >1,000 chemicals with identified mammalian targets, we later uncovered additional compounds that increase nematode longevity. The identified compounds are candidates for testing on mammalian cells. In a different vein, we have embarked on experiments to use single-cell analyses to investigate the mechanisms that underlie aging in the mammalian brain.

This research was supported in part by grants from the National Institutes of Health, the Department of Defense, and the Ellison Medical Foundation.

As of October 8, 2014

Scientist Profile

Fred Hutchinson Cancer Research Center
Molecular Biology, Neuroscience