So what we know are that humans are sensitive to an enormous range of odorants. And odorants come in all kinds of molecular shapes and sizes. And these shapes and sizes interact with a large number of olfactory receptors. In fact the genes that encode olfactory receptors, are the among largest gene families that we know about. Within vertebrate and even invertebrate systems. So, there is tremendous conservation of these genes, but also tremendous diversity. In our case, we've got probably about 1200 olfactory receptor genes most of them are pseudo genes, that is, they don't express a competent protein, that functions as an olfactory receptor. The actual number of true genes, for olfactory receptors in us, is about 400 or so. Which is maybe about a 3rd the number that might be present in a typical canine. And perhaps this has a great deal to do with the relative sensitivity of olfactory discrimination and detection in canines versus humans. So humans can be sensitive to odorants down to a concentration range of nanomolar. So that's, really a remarkable amount of sensitivity, even though we don't typically think as humans as being the champions in the animal kingdom, in olfactory sense. yet, we're definitely holding our own. Relative to our mammalian kindred. And it's really fascinating to consider how these odorants interact with these receptors. So there can be very small and subtle changes in the molecular structure of an odorant that can give rise to very different percepts. So we want to understand some of the logic as to how that happens. For example, the d isoform of the odorant carvone for many of us smells like rye. Whereas the l isoform of carvone smells like spearmint. Very different perceptual qualities with a subtle rotation. Of a carbon bond in this molecule. another interesting aspect of olfaction is that the quality of the odor is sometimes modulated by the concentration of the odorant. So for example, low concentrations of the odorant indole smells like flowers, a floral bouquet. Whereas high concentrations of the very same odorant molecule can smell quite putrid. what we might think of as exactly the opposite end of this perceptual spectrum. And lastly I, I would make the point that most natural odors, they're really not a single odorant but they're quite complex. Much in the way we talked about human speech being spectrally complex, being composed of many fundamental frequencies. In an analogous way, most odorants are, are quite complex. There are many different odorant molecules that are present within that odor, and these molecules will interact with odorant receptors in various ways. And it's, to those interactions that I'd like to turn our attention now, using the slide that's before you. So what we have is an example of a combinatorial code. That relates odorants to olfactory receptors. And this code is based on the molecular shape of the odorant. Now, this figure provided by my colleague here at Duke, Hiro Matsunami, illustrates for us the relationship between molecular shape. And odorant receptor. For example, this odorant here at the top, it has sort of a triangular shape on the left hand side of this molecule, and a rectangular shape to the right. Well the rectangular part would appear to fit nicely into a receptor that has rectangular shaped receptor motif. Whereas the triangular piece would appear to fit quite nicely into a molecule that is configured in a way to interact with this triangular shape. Well, of course the molecules themselves aren't really rectangles or, or triangles, but rather there is a molecular shape that is interacting with a particular receptive motif that's present in the receptor protein itself. And the point here is that the same odorant molecule can interact with more than one receptor depending upon the geometrical configuration of odorant molecule. The receptor. In the case of this first odorant that is illustrated in this schematic here, we see that this one odorant can interact with at least two different olfactory receptors. For example, we see the complex shape of the odorant to the bottom has molecular form and structure to it that allows it to interact with three different odorant receptors. So, what we mean by combinatorial code, is a code based on the number and, as it turns out, the location, of odor receptors that interact with the same odorant molecule. So in this scheme, the first odorant would be indicated by the activation of these two odorant receptors. Here in the two left hand columns, whereas the odorant to the bottom would be indicated by activation of the three odorant receptors that are off to the right. Now this combinatorial code that we find in the relationship of odorants to olfactory receptors. Is converted into a spatial code that allows for the receptor neurons that express a given olfactory receptor allele to grow their axons and converge on the same pair of glomeruli in the olfactory bulb. So, let me explain this anatomy. And how this remarkable degree of convergence works. So, here's an illustration that shows us our olfactory epithelium, and we see a population of olfactory receptor neurons that grow their axons through the cribriform plate, and they reach the olfactory bulb. What we find in the olfactory bulb is a really particular compartment that is rich with receptors and synaptic connections between our sensory axons from our olfactory receptor neurons, and a variety of postsynaptic targets, including the principal neuron of the olfactory bulb called the mitral cell. So here we see a mitral cell that grows a dendrite into a spherical structure that we call the glomerulus. And it's within that glomerulus that the mitral cell receives synaptic input from an afferent axon. While there are a variety of other cell types that are present in the olfactory bulb, namely a small inter neuron called the periglomerulus neuron, there is also a small inter neuron called the granule cell. both of these neurons seem to mediate inhibitory interactions within and among glomeruli. There is also a cell called the tufted cell that contributes post synaptic targets for the afferent input that's arriving in the olfactory bulb. So, these spherical structures called glomeruli, are the first site of synaptic connection between the olfactory epithelium and the brain. Here's the challenge in setting up this circuitry between the olfactory epithelium, and the, olfactory bulb. Each glomerulus receives input from about 25,000 olfactory receptor neurons. But what's absolutely astounding about this convergence of information into a single glomerulus is that nearly all the olfactory receptor neurons. That provide input to that same glomerulus, will express the very same, alelle, for a particular olfactory receptor. That is, all of these 25,000 neurons, are expressing a receptor that will interact with the same set of odorants. This allows for convergence, of both anatomy, and function. Into each and every glomerulus that we find in the olfactory bulb. If we look across the entire olfactory epithelium, that's present on both sides of the midline, what we find is that, all of the olfactory receptor neurons, that express the same olfactory receptor, grow their axons and converge onto two bilaterally symmetrical glomeruli in the two olfactory bulbs. So this is an example of really a, a remarkable achievement in path finding, whereby axons from a broad epithelial surface, will grow and target, and ultimately establish sona, synaptic connectivity with a very limited spatial target. In this case, a spatial target of probably less than 100 microns or so, of typical dimension. That would be about the diameter of a typical olfactory glomerulus. Now, as I mention there are other cells that contribute to the circuitry of the glomerulus. I won't really say anything more about that except to suggest that the granule cells are a particularly interesting population of neurons. They seem to set up inhibitory networks across the olfactory bulb. They appear to have a role to play in. Synaptic plasticity that occurs within circuits of the olfactory bulb, and for many mammals, although it's not so clear that it happens in humans, the granule cell population is one set of neurons that is repopulated in life. That is, there is a set of stem cells, that produce new neurons that migrate along what's called the rostral migratory stream to enter the olfactory bulb, and contribute new neurons to the granule cell layer of the olfactory bulb. Again we're not so sure whether that really exists in our brains, as well as many mammals. But it is curious that of all the populations of neurons in the brain to be supplied throughout adult life, it's the granule cell population of the olfactory bulb in many mammals that, benefits from this neurogenesis that occurs even into adult life. We'll say more about development when we come to unit five, but just hang onto that thought now. That the olfactory bulb is a recipient of the production of new neurons in many mammals. One last thing about the olfactory bulb, before we move on to talk about the olfactory cortex in the brain, is that the olfactory bulb seems to solve some of the challenge of having complex odors that contain many different odorants. if we go back for just a moment to the previous slide, where we saw something about the logic of the relationship between odorants to receptors, and we discuss this notion of a combinatorial code. I think its perhaps apparent to you that the same complex odor might activate quite a large number of olfactory receptor neurons that express, each their own allele. but the protein that's produced by that allele, the olfactory receptor, potentially can interact with more than one odor molecule. And so as a result of this system of combinatorial coding in the olfactory epithelium and the convergence of the sensory neurons to individual glomeruli in the bulb, you might imagine that a complex odor ought to give rise to the activation of, of tens perhaps even hundreds of glomeruli. In the olfactory bulb, but that often does not seem to be the case. It seems to be that a much more sparse coding mechanism exists in the olfactory bulb for complex odors. Which is to say that there seem to be certain glomeruli that might dominate the representation of a complex odor. Not all glomeruli that may be receiving afferent information may be equally activated. And perhaps this is where these additional neurons come into play. With lateral inhibitory networks. much remains to be discovered about how representation in the bulb was actually achieved. But I do think it's notable that there is a sparse coding of complex odors in the activation of only a limited subset of glomeruli. And now the next challenge is to understand how does that information get transferred back into the rest of the ventromedial fore brain. And then how is that information coded and processed and then ultimately how do these olfactory signals impact behavior. So let's turn now from the bulb. We'll travel down the lateral factory tract and consider some of the central processing mechanisms that we find in the olfactory cortex.
