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The Physics and Biology of Olfaction

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If you've seen Living Waters, you were undoubtedly amazed at the complexity of operations going on inside a salmon's nose. Yet that animation vastly oversimplifies the olfactory sense. New findings continue to bring scientists closer to understanding how it works, adding to what we previously reported in September.

Last time we focused on the olfactory epithelium, the tissue that receives the odor molecules. We saw how it is organized into a hierarchical pattern that provides the best possible reception for different kinds of odorants. Each nostril's epithelium contains half a million olfactory sensory neurons (OSNs), long cells with cilia at one end and an axon at the other end. The cilia are where the odor molecules make contact with olfactory receptors (ORs). When a molecule "fits" just right, the receptor responds, triggering a cascade of activity. But what makes a good fit?

Vibrating Locks and Keys

There's been a lively debate about that. The leading view was that the molecule's shape fits the shape of the receptor like a "lock and key." In the 1990s, however, Luca Turin and others proposed a "vibrational" theory to account for shortcomings in the shape model. Why, for instance, do different shapes produce similar smell sensations in some cases, and similar shapes produce different sensations in others? Because the debate between the "shapists" and "vibrationists" has remained unsettled, the animators at Illustra alluded to both possibilities, showing the molecule fitting like a glove but also vibrating. (It's possible, too, that both theories are partly right.)

The vibration theory was thought to be down for the count last year when a team failed to find evidence for it in an experiment with mouse olfactory receptors in a petri dish. The receptors didn't react differently to two molecules with the same shape but different vibration frequencies. Now, though, the vibration theorists are back with a vengeance. John Hewitt tells about this at PhysOrg. A team from Italy, publishing in Scientific Reports, found evidence for discrimination between molecules with identical shapes but different vibrations. Four pairs of odorant molecules were carefully designed to be identical except that some hydrogen atoms were replaced with deuterium (heavy hydrogen, containing an extra neutron). The slight mass difference in these "isotopomers" ("same topology") alters the vibration frequency of the molecule. These same-shaped odorants were wafted into the noses of honeybees while the scientists monitored their brains in real time.

Sure enough, the bees appeared able to discriminate them, showing very different responses to the same-shaped pairs. "Considering the close structural correspondence between isotopomers," Hewitt writes, "the experimental truths observed here would be difficult for even the most ardent adherent to the shapist receptor philosophy to sweep under the rug." The implications are interesting for design theorists. Hewitt continues:

The authors observe that the shape-independent discrimination capabilities they found can not be dismissed as idiosyncratic to a few peculiar olfactory receptors, rather, they are a more general feature of ligand-receptor interaction. Much of the palpable in-house derision that members of the larger olfactory and neuroscience communities routine reserve for the vibrational theory might be traced to a deeper, more insidious fear: despite exhaustively focused efforts, they have no idea how receptors actually work. [Emphasis added.]

Hewitt sees a possible overarching principle at work in biological sensing. How did living things apply themselves to the task of "quickly (in evolutionary time) coming up with and artfully deploying 'universal detectors'" that are applied for diverse inputs, in everything from olfaction to vision to touch? Even the suntan response to UV light deploys this strategy. "Nature has unleashed her unbridled imagination," he quips -- and artfully so.

Score one for the vibrationists. The debate will continue, undoubtedly, but more to our interest, it illustrates the complexity of the olfactory sense and its extreme precision that has baffled scientists for decades. Imagine a honeybee, fruit fly, or salmon being able to discriminate twin molecules that differ only by one or two atomic mass units. Design doesn't get better than that.

Dynamic Switchboard

Meanwhile, a recent paper in Nature Communications takes us down the other end of the olfactory neuron to the tip of the axon. As shown in the Illustra animation, the nerve endings of a million OSNs converge on a remarkable organ, the olfactory bulb (OB), which is studded with connection points called glomeruli. In an amazing example of preprogrammed networking, these axons "know" during development somehow which glomerulus to attach to, depending on the type of odorant receptor they express (and there are hundreds of those). Axons for one receptor might grow toward a glomerulus on top of the bulb; axons for another to the backside. Between top-bottom, front-back, and left-right, the OB has three axes by which to discriminate connections coming from different classes of receptors. This is the first stage of sorting and classifying odorant types. (Note: it gets even more complicated from there.)

These scientists from the NIH and Carnegie Mellon University wanted to find out how malleable the olfactory inputs are. Once set up, is the olfactory tissue set for life? Can the olfactory bulb be rewired as conditions change or the fish grows older? When a new neuron replaces an old one, does it wire up the same way? The short answer is that rewiring is not only possible, but it occurs throughout adult life. Why might that be?

Incorporation of new neurons enables plasticity and repair of circuits in the adult brain. Adult neurogenesis is a key feature of the mammalian olfactory system, with new olfactory sensory neurons (OSNs) wiring into highly organized olfactory bulb (OB) circuits throughout life. However, neither when new postnatally generated OSNs first form synapses nor whether OSNs retain the capacity for synaptogenesis once mature, is known. Therefore, how integration of adult-born OSNs may contribute to lifelong OB plasticity is unclear. Here, we use a combination of electron microscopy, optogenetic activation and in vivo time-lapse imaging to show that newly generated OSNs form highly dynamic synapses and are capable of eliciting robust stimulus-locked firing of neurons in the mouse OB. Furthermore, we demonstrate that mature OSN axons undergo continuous activity-dependent synaptic remodelling that persists into adulthood. OSN synaptogenesis, therefore, provides a sustained potential for OB plasticity and repair that is much faster than OSN replacement alone.

Notice that reference to the "highly organized olfactory bulb circuits." Unlike Hewitt, who verged off into evolutionary speculations in his article after describing those "artfully deployed" sensors, these scientists didn't go the storytelling route. Their approach was to observe a phenomenon and find a purpose for it.

So what is the purpose of rapid structural remodelling of OSN synapses? Synapse turnover clearly plays an essential role during circuit formation (and in the case of the OB, incorporation of newborn neurons into existing circuits) by enabling selection, refinement and error correction. Hence, transient pre- or post-synaptic structures may represent those that fail to locate a synaptic partner, or form inappropriate connections that are rapidly eliminated. This may explain why immature OSN presynaptic terminals are formed and eliminated more rapidly than their mature counterparts (Figs 4, 5). Alternatively, these transient synaptic structures may represent short-lived synaptic contacts that temporarily contribute to network function, or play other roles such as promoting axon branch stabilization. Whatever the role of transient synaptic structures, ongoing synapse formation and elimination endows OB circuits with a plasticity potential that can be harnessed when needed, such as during learning or in response to altered experience.

That's the spirit. There must be a role, a purpose, a potential. At first, it would appear startling that so much rewiring takes place. What chip manufacturer would alter integrated circuits while they are in use? Maybe manufacturers could learn something from the way life does things.

Clearly a salmon is undergoing a lot of "learning" and "altered experience" as it grows from fingerling to adult, swimming downstream through a welter of new sensory experiences, memorizing hundreds of new odors and mapping them into its memory. It's possible that the brain and the olfactory bulb are triggering some of that rewiring in elaborate feedback loops, strengthening the connections to weak signals or reducing the connections to overpowering signals. It brings to mind a skilled technician on a sound board turning knobs and moving sliders to get the ideal overall experience in auditory space. In olfactory space, though, the salmon's sliders are automated. "Whatever the role" of these transient connections, we can infer from the results -- such as that a salmon can detect odorants at parts per trillion -- that they contribute to the spectacular performance of the olfactory system.

We've discussed "plasticity" before as a challenge to Darwinism. Why would a blind evolutionary process create "plasticity potential" that can be "harnessed when needed" in case of an altered experience? Darwinian evolution has no foresight. Plasticity makes perfect sense, though, from a design-based perspective on biology. There's no better example than right there in a salmon's nose, where the olfactory system will be encountering numerous new environments over a period of years. The scientists' expectations of roles for synaptic plasticity were confirmed in their conclusions (readers can find the details in the open-access paper).

One more thing. The scientists found that rewiring is "much faster" than replacement. While OSNs are replaced throughout life, the rewiring "plasticity potential" provides a more rapid response, giving the animal both high-speed (transient) and low-speed (permanent) fine tuning of its olfactory system. Since this is true of mice, it's undoubtedly true for us as well.

Now go out and smell the roses.

Image credit: © sumikophoto / Dollar Photo Club.