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Olfaction and Aging
Summary: Linda Buck's laboratory is investigating the molecular and cellular logic of olfaction and the determinants of aging and life span.
Odor Perception in Mammals
Humans and other mammals can perceive a vast array of chemicals as having a distinct odor and distinguish among those with nearly identical structures. To gain insight into how this is accomplished, we are using the mouse as a model system to investigate how odorants are initially detected and then translated into diverse perceptions in the brain.
In initial studies, we discovered the odorant receptor (OR) family, which is responsible for odor detection in the nose and has about 1,000 members in mice and 350 in humans. We found that ORs are used in a combinatorial manner to detect individual odorants and encode their unique identities, a strategy that explains how a multitude of odorants can be discriminated and how changing a minor structural feature of an odorant or its concentration can alter its perceived odor.
Using OR genes as molecular tools, we have investigated how sensory signals derived from different ORs are organized in the nasal olfactory epithelium (OE) and its synaptic target, the olfactory bulb (OB), as well as at the next level of the olfactory system, the olfactory cortex (OC). In the OE, each of 5 million olfactory sensory neurons expresses a single OR gene. Neurons with the same OR are randomly dispersed throughout one of several OE zones, but their axons all converge in a few specific OB glomeruli, creating a stereotyped map of OR inputs. The OC also has a stereotyped spatial map of OR inputs, but here signals from one OR are targeted to 5–6 loose clusters of neurons. In sharp contrast to the OE and OB, where different OR inputs are strictly segregated, inputs from different ORs partially overlap in the OC and single neurons may receive inputs from combinations of different ORs. Functional studies further showed that different odorants activate distinct, but partially overlapping, patterns of sparsely distributed OC neurons. Together these findings indicate that odor identities are deconstructed into OR-specific channels in the OE, which are maintained in a different format in the OB and then transformed into highly multiplexed arrays of OR inputs and odor representations in the cortex.
Based on the patterning of OR inputs and odor responses in the cortex, we speculated that OC neurons might act as coincidence detectors whose activation requires combinatorial OR inputs. If so, a binary mix of odorants should activate OC neurons beyond those activated by either odorant alone because the mix would create new combinations of OR inputs. Using subcellular patterns of Arc mRNA induced by temporally spaced stimuli, we found that many OC neurons are indeed activated by a binary mix of odorants, but neither of its components, something that is not seen with OB neurons. The synthetic ability evident in the OC but not the OB may represent a first step in the reconstruction of an odorant's identity from its deconstructed features, which are carried by combinations of OR inputs.
Pheromones, Hormones, and Behavior
The olfactory system detects not only odorants but also pheromones that elicit hormonal changes or instinctive behaviors. While odorants are detected in the OE, pheromones are thought to be detected primarily in an accessory olfactory structure, the vomeronasal organ (VNO). Efforts in our lab and others uncovered two different families of ~150 VNO receptors. Using calcium imaging, we found that individual pheromones may be detected by only one or a few VNO receptors rather than a combination of receptors, as in the OE. Moreover, some VNO neurons detect extremely low concentrations of certain odorants, suggesting that, like pheromones, some odorants may elicit innate responses via the VNO.
To investigate the neural circuits that underlie pheromone effects on reproduction, we made mice expressing a genetic transneuronal tracer in GnRH neurons, a small subset of hypothalamic neurons that control reproductive hormones and are also linked to sexual behaviors. The relative locations of GnRH axons, tracer-labeled neurons, and neurons containing c-Fos in response to pheromones allowed identification of neurons presynaptic versus postsynaptic to GnRH neurons, as well as those capable of transmitting pheromone signals to GnRH neurons. These studies suggest that the reproductive neural circuitry of the brain is stereotyped and enormously complex, with 800 GnRH neurons communicating with 50,000 other neurons in functionally diverse brain areas, including those associated with sexual behaviors. These studies further suggest that GnRH neurons have bidirectional communication with both VNO- and OE-recipient brain areas and are capable of receiving pheromone signals not only from the VNO, but also from the OE.
We recently identified a second family of chemosensory receptors in the OE that may play a role in pheromone detection. These receptors, called trace amine-associated receptors (TAARs), have expression patterns resembling those of ORs, with each of 14 mouse TAARs expressed in a unique subset of OE neurons lacking other TAARs and ORs. Screening of more than 200 diverse odorants identified ligands for several TAARs, all of which are volatile amines. Remarkably, ligands for at least three mouse TAARs are present in mouse urine, a rich source of social cues. One is elevated in response to stress while two others, one reportedly a pheromone, are enriched in male versus female urine. TAARs are evolutionarily conserved from fish to humans and are found in both fish and mouse OE, suggesting that they serve as olfactory receptors in diverse organisms and that their function is distinct from that of ORs. The ligands identified for TAARs thus far suggest that these receptors may be involved in the detection of social cues, such as pheromones.
Determinants of Aging and Life Span
Several years ago, we embarked on a second line of research that is focused on mechanisms underlying aging and life span. We are particularly intrigued by the possibility that there is a central control of life span in which a subset of cells influences aging in cells throughout the body. We are also interested in whether a drug administered to an adult organism might slow its rate of aging and increase its life span. To explore these questions, we are conducting high-throughput screens for chemicals that extend life span in Caenorhabditis elegans. We anticipate that the identification of the targets of such chemicals will provide information about the mechanisms that underlie aging in nematodes and, by extension, in humans.
In initial studies, we have screened 88,000 small molecules for life span–enhancing effects in C. elegans and identified more than 100 compounds that appear to produce statistically significant increases in longevity. By testing individual compounds in combination with each other and on known aging mutants, it should now be possible to determine whether they act on the same, different, known, or unknown pathways that affect life span. Future goals include the identification of the endogenous targets of these compounds and investigation of their potential effects on the life spans of vertebrate organisms.
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 21, 2007
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