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Mechanisms of Olfaction and Aging
Summary: Linda Buck's laboratory is investigating the mechanisms that underlie odor and pheromone sensing and the determinants of aging and lifespan.
Odor and Pheromone Sensing in Mammals
The olfactory system of mammals detects a multitude of structurally diverse chemicals in the external environment. Most of these compounds are perceived as odors, but some, such as pheromones and predator odors, stimulate hormonal changes or instinctive behaviors.
We previously elucidated how odorants are initially detected in the nose, how the unique identities of individual odorants are encoded, and how those identities are represented in the olfactory epithelium (OE) of the nose and the olfactory bulb (OB) of the brain. Those studies showed that odorant detection in mice is mediated by ~1,000 different odorant receptors (ORs). Each OE neuron uses only one type of OR to detect odorants. Thousands of neurons with the same OR are randomly interspersed within several expression zones in the OE, but in the OB, their axons all converge with precision in a few glomeruli at two locations that are nearly identical among individuals. The result is a virtually stereotyped map of OR inputs in which each glomerulus and its associated relay neurons are dedicated to one OR.
We found that the OR family is used in a combinatorial manner to encode the unique identities of diverse odorants. The code for an odorant in the nose is thus a dispersed ensemble of neurons, each with one OR component of the odorant's receptor code; in the bulb, it is a specific combination of glomeruli whose spatial arrangement is similar among individuals. Even a slight change in an odorant's structure can change its combinatorial receptor code. This explains how we can discriminate closely related odorants and perceive such odorants as having odors as different as sweaty versus orange. Numerous questions remain to be explored, including how olfactory signals ultimately generate diverse odor perceptions and have the capacity to evoke memories with rich emotional overtones.
Many mammals have an accessory olfactory structure, the vomeronasal organ (VNO), that is involved in pheromone detection and transmits information to brain areas different from those that receive odor signals from the OE. Efforts in our lab and others showed that the VNO has two zones and expresses two different families of receptors with more than 100 members each, the V1R and V2R families. We found that individual mouse pheromones activate only a minute fraction of VNO neurons, suggesting that these compounds might be detected by one or a few dedicated receptors rather than a complex combination of receptors, as seen for odorants. To explore the neural circuits that mediate the effects of pheromones on reproduction, we prepared mice expressing a transneuronal tracer in GnRH neurons, a small subset of hypothalamic neurons that serve as master regulators of reproductive hormones and are also linked to sexual behaviors. We found that the 800 GnRH neurons in mice communicate with ~50,000 other neurons in dozens of functionally diverse brain areas, including those associated with sexual behaviors. We also obtained evidence that GnRH neurons receive signals derived not only from the VNO, but also from the OE. Catherine Dulac's lab (HHMI, Harvard University), using a different approach, concurrently reported that GnRH neurons receive signals from the OE.
How are pheromones detected in the OE? By conducting a broad search for additional types of receptors in the OE, we identified trace amine-associated receptors (TAARs) as a second family of chemosensory receptors in the OE. Searching for odorants detected by TAARs, we identified volatile amines recognized by several of these receptors. Interestingly, amines detected by at least three TAARs are present in mouse urine, a rich source of social cues. One TAAR detects a compound present in urine from stressed animals, while two others detect compounds enriched in male versus female urine, and one of these is reportedly a pheromone. TAARs are evolutionarily conserved from fish to humans, suggesting that they serve a function distinct from that of ORs. Our studies suggest that this function may be linked to the detection of social cues.
Determinants of Aging and Lifespan
Our laboratory is also keenly interested in the mechanisms that underlie aging, a subject that we began to explore about six years ago. Previous studies of the short-lived nematode Caenorhabditis elegans uncovered a number of genes that can influence the lifespan of this organism. Moreover, it has become increasingly evident that at least some aging mechanisms are likely to be evolutionarily conserved and that studies of aging in C. elegans may therefore lead to a better understanding of aging in higher organisms, such as humans.
We reasoned that if we could identify chemicals that would increase C. elegans lifespan, studies of the endogenous targets of these chemicals might provide additional insights into the underlying mechanisms of aging and also point to drugs that might be tested in mammals. By conducting a high-throughput screen of 88,000 diverse small molecules, we identified more than 100 compounds that increase C. elegans lifespan when given only during adulthood.
Further investigation of one compound led to the finding that the animal's lifespan can be increased about 30 percent by mianserin, a drug used as an antidepressant in humans. This effect requires a specific serotonin receptor, SER-4, as well as SER-3, a receptor for another neurotransmitter, octopamine. Similar to its antagonistic effects on certain serotonin receptors in humans, the drug inhibits both SER-3 and SER-4 in vitro, although it is a more potent antagonist of SER-4 than SER-3. Testing of mianserin on dietary-restricted nematodes or those with mutations in genes associated with aging suggested that the drug increases lifespan via mechanisms linked to dietary restriction. Curiously, however, the drug does not appear to reduce food intake. It has been suggested that serotonin and octopamine act as physiological antagonists in C. elegans, with serotonin signaling the presence of food and octopamine signaling its absence. One possible explanation for our findings is that the greater inhibitory effect of mianserin on SER-3 than SER-4 mimics a reduction in food intake and thereby triggers aging mechanisms associated with dietary restriction.
We are currently analyzing the effects of other chemicals and drugs we have found to increase C. elegans lifespan. By testing the compounds on known aging mutants and dietary-restricted animals, and by then testing them in different combinations with one another, we hope to gain insight into whether they act on previously identified aging pathways and, if not, whether their mechanisms of action are related. A further, longer-term goal is to identify the targets of these longevity-increasing compounds in the animal. Finally, we hope to test some of the compounds we identify, or their analogs, for the ability to delay aging and the onset of age-associated diseases in mice.
This research was supported in part by grants from the National Institutes of Health, the Department of Defense, and the Ellison Medical Foundation.
Last updated: November 24, 2008
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