The olfactory system: It smells good to be alive (2023)

Professor Richard Axel won the Nobel Prize in Physiology or Medicine in 2004 together with Professor Linda B. Buck for their discoveries in olfactory receptors and the organization of the olfactory system.

How do we smell things?

When you see a beautiful bouquet of flowers or pass a perfume shop, you often lean in to smell them. Have you ever wondered what exactly it is that you smell? And how do you recognize the smell? When you smell a flower, you inhale molecules released by the flower and then create an internal representation of the flower's scent through electrical activity in the brain (figure 1).

Before we dive into the sense of smell, let's see howolfactory systemprojects. Odors consist of molecules released by the object you are smelling (such as an orange or a rose). The odor molecules, which are calledaromater, travel through the air and into your nose. Inside the nose, in the upper part of the back calledepithelium of the nose, there are cells that have special molecules calledreceptors. Each receptor has a unique shape so that it 'likes' certain aromatics more than others and is activated more by their presence (Figure 2). These receptors are present on nerve cells calledolfactory sensory neurons (OSNs). The interaction between odorant molecules and OSNs is translated by OSNs into electrical signals, which then travel to the brain. Thanks to this extraordinary design, each aromatic (such as beta-ionone when you smell a rose, limonene when you smell a lemon, or benzyl acetate when you smell a strawberry) activates aunique combinationby OSN [1] of more than a thousand types of OSNs you have, and this in turn causes a unique pattern of electrical activity that enables your perception of a particular smell. In summary, the encoding of odors in the brain relies on the activation of a unique subset of OSNs. Each OSN is electrically activated when its receptors interact with specific odorant molecules but not with other molecules. This electrical activity then travels to different areas of the brain that process and represent odor information.

Identification of olfactory receptor genes

When I started studying the olfactory system, it was known that animals can distinguish an extremely wide variety of odors, but it was not clear how. Whatit wasit was clearly understood that there must be a brain mechanism that enables an animal to recognize this enormous variety of odor molecules. This led to the idea that there must be a very large number of genes encoding olfactory receptors. Also, OSNs that translate odorant receptors must have a way to convert the odorant-receptor interaction into electrical signals.

In our research, we wanted to find the genes that code for (or dictate the nature of) odor receptors. To do this, we made three assumptions that simplified our search: (1) there should be a large family of genes encoding olfactory receptors; (2) olfactory receptors have a mechanism to convert interactions with odorant molecules into electrical signals. and (3) genes encoding olfactory receptors are expressedwhenin OSNs in the nasal epithelium. Using these hypotheses, we were able to efficiently search for a gene family encoding olfactory receptors in mice. We isolated their OSNs and found a new gene family in mouse DNA consisting of approximately 1,000 different receptor genes [2]. This was very exciting as it was the first time that olfactory receptor genes had been identified. Some 23 years later, in 2004, this discovery won me and my colleague Professor Linda Buck a Nobel Prize in Physiology or Medicine [3].

After identifying olfactory receptor genes, we could then use sophisticated techniques (including molecular genetics and neuroimaging) to ask more complex questions about the organization and activity of OSNs in the nose and brain. For example, how many of the receptor genes does each OSN express? Each OSN contains only one type of olfactory receptor ormanyreceptor types? These two possibilities imply two completely different structures and functional mechanisms in the olfactory system. As it turned out, the first possibility was correct: each OSN expresses only 1 of about 1,000 possible receptor genes.

Organization of olfactory sensory neurons

Now let's look at how OSNs are organized in the nose and brain, where odor recognition takes place. In mice, there are 10 million OSNs in the nose and 1,000 different olfactory receptors. Since each OSN expresses only one type of receptor, this means that each type of receptor is expressed in 10,000neurons(10 million/1,000 = 10,000). But how are the 10,000 neurons expressing the same olfactory receptor organized in the nasal epithelium? Are they spread out over a large area or clustered close together? And what happens to the electrical information they generate when they interact with their favorite perfume? Does information about a particular odorant converge (or combine) in a particular brain region?

We found the answer to these questions using an advanced technique that selectively stains neurons that express the same receptor gene. In the nasal epithelium, OSNs are randomly distributed over a large area (Figure 3). The OSNs then send their extensions (fibers calledaxis) to the first relay station in the brain that processes smell, calledolfactory bulb. All 10,000 OSNs expressing a specific receptor converge on a specific region of the olfactory bulb calledglomerulus(Figure 3, correct). In total, there are 1,000 separate glomeruli in the olfactory bulb, and each receives information from all (10,000) OSNs that express a particular receptor gene [4].

Activity of olfactory sensory neurons

What happens when an animal is exposed to a certain smell (Boks 1)? Odors consist of many molecules (e.g. more than 400 in the case of a rose [6]). As we have seen, each odor molecule activates a specific group of OSNs (10,000 of them), which converge and activate a specific glomerulus in the olfactory bulb. The smell of a rose activates a different group of glomeruli than the smell of chocolate, so specific smells create specific patterns (or "maps") of glomerular activity in the brain.

Today we can look down at the rodent's olfactory bulb using neuroimaging techniques and "read" the spatially organized patterns ("the map") of neural activity and from that activity decipher what odor we encountered. This is a great new method for scientists to identify smells, but it's clearly not how the animal identifies smells, since it doesn't have an imaging microscope in its olfactory bulb and can't look at its own neural activity from the outside like we do scientists.

Although the brain's fascinating ability to recognize odors is not yet fully understood, we know that neurons in the olfactory bulb project their axons to several brain regions (Figure 4). Some of these areas are responsible for automatic behavior in response to smells. For example, when an animal encounters a particular odor that indicates the presence of danger, such as when a mouse encounters the scent of a cat, an automatic "run!" response is enabled. Other axons travel from the olfactory bulb to areas of the brain where learning takes place. An animal learns specific behavioral responses based on the odors it encounters [3].

The vast majority of people's reactions to smells are of the second type, they are learned and not automatic. People attach learned meanings to specific odors, and these personal meanings influence their responses to odors. For example, a person who has a romantic first date involving wine may learn to associate the smell of that wine with the feeling of love. Then, when they smell wine, they feel "butterflies of excitement" and want to approach their beloved.

This means that individuals may have unique behavioral responses to a particular odor, depending on their previous experiences with that odor (Boks 2). For some of us, the scent of a rose is associated with a beautiful emotional experience (like love), while for others a rose may be associated with the color red, which may be associated with blood and fear. But if our brains respond differently to the same odor molecule, do we really smell the same when we smell a particular odor?

Does my orange smell like your orange?

Imagine that someone who has never seen or smelled an orange asks you to describe what an orange smells like. Could you put it into words? Probably not – an orange smells like an orange and you get to know and recognize that smell by association. When you see an orange, you smell it at the same time. then, even if you smell it in the dark, you know it's orange by associating the scent with the image of an orange or the name 'orange'. In this sense, the sense of smell is fundamentally different from sight. If someone has never seen an orange before and asks you what an orange looks like, you can say that it is round, orange in color, about the size of a baseball, smooth, etc. You can create an internal image of an object in your brain, but you can't really create an internal image of a smell in your brain.

If we can't describe smells using language, and we can't even create an internal image of smells, how do we know that you and I smell the same smell when we smell an orange? The answer is we don't know! As we mentioned, it's quite possible that when you and I smell an orange for the first time, we activate different patterns of neural activity in our individual brains—but we both associate that smell with the same fruit because we both see an orange . Besides associating the smell with the object 'orange', do we have a similar experience of that smell? Maybe, but the smells we perceive could becompared to everything elsewe have smelled in our lives. For example, an orange smells more like lemon than coffee, and that applies to all of us. This means that the similarities between how people perceive smells can be obviousrelative— simply that we all agree that a certain item smells better with some items than with others. This is a good reminder that our perception of smells is not absolute - unlike our perception of the color red, for example, which is based on the invariable frequency of light.

The enigma of perception - an open question for future scientists

There is a very important and complex question about perception that science has yet to answer. This question applies to olfaction and all other senses and is therefore very basic - to ask howinterpretationof sensory information occurs.

As we discussed, when the brain processes information from the senses, a specific pattern of electrical activity is generated in a specific set of neurons in the brain, which represent the physical world in the brain through patterns of neural activity. These activity patterns can vary in time (when they occur) and space (where in the brain they occur). Thus, the richness and variety of the entire natural world is somehow represented by the firing of specific groups of neurons at specific times and places in the brain.

For scientists, this implies two things: first, that physical reality is;absentfrom the brain and secondly that the brain mustinterpretthis abstract information to give it meaning. For example, an object in the outside world, such as an orange, is translated into a specific pattern of electrical activity that represents it in the brain, and then the brain "discovers" the meaning of the electrical activity (that there is an orange out there in the world) by interpreting and imposing meaning on this activity. But the brain must somehow associate this pattern of activity with a concept like "this is the smell of an orange. it makes me feel good because it reminds me of the orchard I visited a few years ago ...". At the moment, this amazing "leap" from electrical activity in the brain to interpretation and meaning is a real mystery – we don't yet understand how it happens. I believe that this "magical" step is the next great puzzle that future neuroscientists must face. Maybe you are one of them?

Recommendations for young minds

In my opinion, there is a very simple way to choose what you want to do in life. It doesn't matter what you choose – be it science or engineering. But whatever it is, make sure you choose a field you love, commit to it, and work at it with intensity and passion. That is all! You have to be passionate about what you do. This passion, fueled by skills and knowledge, will lead you to excellence. So you need to discover your field of interest and then learn as much as possible about that field. When passion and knowledge come together, it often leads to creativity and happiness.

Additional materials

1.Ted-Ed: What do we smell like?

Dictionary

Odor system:↑The sensory system responsible for smell.

Smelly:↑Odor molecules released from objects travel through the air and enter your nose.

Epithelium of the nose:↑A tissue at the top of the nose involved in smelling.

Sensory nerve:↑A molecule in a cell that interacts very specifically with another molecule, like a lock and a key, and translates the interaction into a signal inside the cell.

Olfactory Sensory Neurons (OSNs):↑Nerve cells containing olfactory receptors that translate interaction with odors into electrical signals that travel to the brain.

Neuron:↑A nerve cell; the most important cell type in the brain. Neurons produce electrical signals and send them to other nerve cells.

Axes:↑Nerve fibers that carry electrical signals from one neuron to another.

olfactory bulb:↑The first relay station in the brain involved in smells. It receives information from OSNs and sends information about odors to other areas of the brain.

Spheroid:↑An area in the olfactory bulb where all OSNs expressing a particular receptor converge.

Conflicts of interest

The author declares that the study was conducted in the absence of commercial or financial relationships that could be interpreted as a potential conflict of interest.

So

I would like to thankNoah Segevfor conducting the interview that served as the basis for this paper and for co-authoring the paper, Sharon Amlani for providing the illustrations and Susan Debad for writing the manuscript. Special thanks to Haran Shani-Narkiss for his valuable comments on the manuscript.