Case Study
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Case study of the day: Daniel, he was a healthy 35-year-old man. Until one winter day,
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when he slipped on some ice, fell forward, and hit his head hard. The doctors cleaned the cut,
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ran a CT scan – no bleeds, no major fractures – and sent him home.
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But after a couple of days, he noticed something strange was happening. Or rather, something wasn’t
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happening, he could no longer smell. Not his morning coffee, not his wife’s perfume,
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not even the food cooking in the kitchen. In the weeks that followed, he burned dinner
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because he couldn’t smell it starting to burn. He couldn’t smell the rain when he stepped outside,
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or the gasoline when he filled up his car. He drank expired milk because he couldn’t
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taste that it had gone sour. The world got a lot less interesting: eating wasn’t very exciting,
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and Daniel started getting depressed. Life felt sterile and unfamiliar.
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Daniel had anosmia, a partial or complete loss of the sense of smell, and with it,
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most of his ability to taste. This unfortunate condition can be caused by things like head
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trauma, respiratory infections, or even plain old aging. And I say “unfortunate”
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because what we sense informs who we are. The sense of smell is one of our five major
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special senses. And in this video, we’re going to break down how the system of smell works,
Content
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And we’re going to do that by first look at the Anatomy of the Olfactory System, the nasal cavity,
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the olfactory epithelium, and the specialized neurons that make smell detection possible.
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Then we’ll dive into the Microanatomy of Olfactory Neurons, we’ll zoom into this area, and see the
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structure of these unique sensory cells, and the supporting cells that stabilize this system.
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While we’re there, we’ll understand The Molecular Mechanism of Smell Detection,
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how odorant molecules bind to receptors, and generate electrical signals.
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And then go through the Olfactory Pathway to the Brain, take you through the pathway from
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the olfactory bulb, all the way to the primary olfactory cortex. And also talk about Why
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Smell is Uniquely Tied to Memory and Emotion, the direct connection to the limbic system,
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the amygdala, and the hippocampus, and why certain smells can instantly
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transport you back in time full of emotions. We’ll also mention quickly how Smell and Taste
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Work Together, and add some clinical correlation along the way, things like
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olfactory adaptation, anosmia and hyposmia. What’s up everyone, my name is Taim. I’m a
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medical doctor, and I make animated medical lectures to make different topics in medicine
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visually easier to understand. If you’d like a PDF version or a quiz of this presentation, you can
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find it on my website, along with organized video lectures to help with your studies.
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Alright, let’s get started. Let’s start by understanding where smell actually
Anatomy of the Olfactory System
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happens. When you breathe in, air enters through your nostrils and flows into the nasal cavity.
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Inside the nasal cavity, we can see these shelf-like structures called the nasal conchae,
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sometimes called turbinates. There are three on each side: the superior, middle, and inferior
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nasal conchae, and they increase the surface area of the nasal cavity to warm and filter
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the inhaled air. Surrounding the nasal cavity are the paranasal sinuses, which are air-filled
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spaces in the skull bones that drain into it. Here’s the thing. Most of the nasal cavity is
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lined with what we call respiratory epithelium, this tissue warms, humidifies, and filters the
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air you breathe. But there’s a very specific region, located high up in the roof of the
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nasal cavity. This is where you detect smell. This small yellowish region is the olfactory
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region. It’s located specifically on the roof of the nasal cavity. This
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specialized area is only about 2 to 5 square centimeters on each side, roughly the size
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of a typical key on a computer keyboard. The reason this region is located up so
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high is actually important because during normal, quiet breathing, some air does reach this area,
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but the airflow is relatively smooth and laminar. When you want to smell something more carefully,
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you sniff, right? And sniffing creates turbulent airflow that actively pulls more odorant molecules
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upward into this olfactory zone. This increases the concentration of smell molecules reaching
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your receptors, which is why you instinctively sniff when you’re trying to identify a smell.
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Now, you see the bone that forms the roof of the nasal cavity? This thin, horizontal bone
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is called the cribriform plate. It’s part of the ethmoid bone. And the cribriform plate is
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special because it’s actually perforated with tiny holes, about 20 to 30 small openings on each side.
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These holes allow nerve fibers from the olfactory region below to pass upward through the bone and
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enter the space inside the skull. This is the only place in the body where nervous tissue
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essentially comes into direct contact with the outside environment through such a thin barrier.
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Remember Daniel from our case? When he fell and hit his head, the sudden impact caused
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his brain to shift inside the skull. The nerve fibers passing through these tiny holes in the
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cribriform plate can get stretched, or torn by this sudden brain movement. This type of
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nerve fiber injury is one of the most common causes of smell loss after a head trauma.
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Studies show that 25-30% of patients with severe head injuries experience some degree of smell
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loss — and often, there’s no skull fracture at all. The stretching force alone is enough to
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damage these delicate fibers. And, because this bone is thin and perforated, fractures here can
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create a pathway for cerebrospinal fluid to leak into the nasal cavity, or for infections
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to spread from the nose into the brain. That’s why trauma to this region is taken seriously.
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Now, once those nerve fibers pass through the cribriform plate, where do they go? They
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enter a structure called the olfactory bulb. The olfactory bulb is an oval-shaped structure
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that sits directly above the cribriform plate, resting on the floor of the anterior
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cranial fossa at the base of the frontal lobe. So now we’ve seen the anatomical landscape of
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everything related to smell. But what are the cells responsible for detecting smell?
Olfactory Epithelium
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let’s zoom into the olfactory epithelium and see what’s actually happening at the cellular level.
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What’s really important to know about this first is that the actual olfactory epithelium is a type
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of pseudostratified columnar epithelium. This means the cells are arranged in what looks like
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multiple layers, but all of them actually touch the basement membrane at the bottom,
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they’re just at different heights, which gives it a layered appearance. That’s why
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we say ‘’psuedo’’, which means false. The olfactory epithelium is one of the
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two main parts of the olfactory mucosa. The other part is the lamina propria,
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the connective tissue layer underneath it. If we focus just on the epithelial layer itself,
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it’s made up of three main cell types, each with a specific role.
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First, we have the olfactory receptor neurons, which are the actual sensory cells that detect
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smell. Second, we have sustentacular cells, also called supporting cells,
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which provide structural and metabolic support. And third, at the base, we have basal cells,
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which act as stem cells and continuously regenerate new olfactory neurons throughout life.
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Deeper in the tissue, located in the underlying lamina propria beneath the epithelium,
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we have Bowman’s glands. These are specialized glands that produce the mucus layer covering the
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epithelial surface. Their secretory ducts extend up through the epithelium to deliver this mucus.
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Alright, olfactory receptor neurons. These are the cells that actually detect smell. And
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they’re unique because they’re bipolar neurons, meaning they have two projections extending from
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the cell body. One dendrite that goes toward the surface, and one axon towards the Olfactory bulb.
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The dendrite that extends toward the surface of the epithelium,
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at the very tip of this dendrite, there’s a small bulb-like swelling called the olfactory knob,
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sometimes called the dendritic knob. From this olfactory knob, 10 to 30 thin,
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hair-like projections radiate outward. These are called olfactory cilia, and they’re absolutely
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critical for smell detection. These cilia are non-motile, meaning they don’t move or
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beat like the cilia in your respiratory tract. Instead, they just extend outward into the mucus
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layer that covers the epithelial surface. And it’s on these cilia where the actual smell receptors
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are located. We’ll talk about this in detail in a few minutes. But an interesting thing with these
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olfactory receptor neurons is that they’re one of the only types of neurons in your body that
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regularly regenerate. Most neurons, once they die, are gone forever. But olfactory receptor neurons
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have a lifespan of only about 30 to 60 days. After that, they die and are replaced by new neurons.
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This constant turnover is essential because these cells are directly exposed to the environment,
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to pollution, toxins, viruses, bacteria, and they take a beating. So the ability to
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replace them is crucial for maintaining your sense of smell throughout life.
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Now, surrounding and supporting these olfactory receptor neurons are sustentacular cells,
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also called supporting cells. These are tall, columnar cells that extend from the basement
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membrane all the way up to the surface of the epithelium. They’re wider at the top,
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and their nuclei sit higher up in the epithelium compared to the olfactory neurons.
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These cells they not only provide structural support, but they also help maintain the proper
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ionic environment for the neurons to function and they metabolize. In addition to this, they clear
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away odorant molecules after they’ve been detected so the receptors don’t become overwhelmed. Without
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these supporting cells, the olfactory neurons couldn’t function properly. You’ve probably
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felt it during the COVID-19 pandemic where many suddenly lost their sense of smell. Initially,
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scientists thought the virus was directly attacking the olfactory receptor neurons. But
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research in 2020 and 2021 showed that SARS-CoV-2 actually infects the sustentacular cells,
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not the neurons themselves. The virus binds to ACE2 receptors, which are highly expressed
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on supporting cells. When these cells become inflamed and dysfunctional, they can’t maintain
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the proper environment for the olfactory neurons, and smell detection fails even though the neurons
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are technically intact. In most cases, once the infection resolves and the sustentacular
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cells recover, smell returns — though this can take weeks to months, and in some cases,
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the recovery is unfortunately incomplete. At the very base of the epithelium,
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we have basal cells. These are small, rounded stem cells that sit right on the basement
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membrane. And these are the cells responsible for that regeneration we just talked about.
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Basal cells continuously divide and differentiate into new olfactory receptor neurons to replace the
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old ones that die off every 30 to 60 days. This regenerative capacity is remarkable,
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and it means that even after certain types of damage — like a viral infection — the olfactory
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system has the potential to recover, as long as the basal cells themselves aren’t destroyed.
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Now, remember we mentioned the olfactory glands? These are specialized serous glands,
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and their job is to produce the mucus that covers the entire surface of the olfactory epithelium.
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This mucus layer is absolutely essential for smell. Because odorant molecules floating in
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the air are hydrophobic — they don’t dissolve easily in water. But for these molecules to
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reach the receptors on the olfactory cilia, they need to dissolve in something. That’s where the
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mucus comes in. The mucus produced by Bowman’s glands contains special odorant-binding proteins.
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These proteins capture hydrophobic odorant molecules from the air and transport them through
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the mucus to the olfactory receptors on the cilia. The mucus also serves other functions. It provides
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a protective barrier for the delicate olfactory cilia, it keeps the epithelial surface moist,
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and it helps wash away odorants after they’ve been detected so the receptors can reset and detect new
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smells. If your nose is dry, you literally cannot smell. This is true in the opposite
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way as well when you’re congested and your nasal passages are blocked with thick mucus, your sense
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of smell decreases dramatically — the odorant molecules just can’t reach the receptors properly.
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So that was basically all the cells at the olfactory region.
Odorant Molecules
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So how does an olfactory receptor neuron actually detect a smell? Let’s start with
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the odorant molecules themselves. These are small, volatile chemical compounds that evaporate from
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substances and float through the air. For a molecule to be smelled, it generally needs
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to be small enough to become airborne, and it needs to have the right chemical properties
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to interact with our receptors. We’re talking about molecules from anything, things like food,
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coffee, flowers, gasoline — anything with a scent releases these odorant molecules into the air.
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When you inhale, these odorant molecules enter the nasal cavity and dissolve in that mucus
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layer we just talked about. The odorant-binding proteins in the mucus capture these molecules and
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transport them to the olfactory cilia, where the actual detection happens.
Molecular Mechanism of Smell
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Now, the actual detection happens through odorant receptors, which are specialized proteins embedded
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in the membrane of those olfactory cilia. These receptors belong to a family called G-protein
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coupled receptors. And the discovery of these odorant receptors is actually one
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of the landmark achievements in neuroscience. In 1991, two scientists named Richard Axel and
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Linda Buck identified the genes encoding these olfactory receptors, and they were awarded the
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Nobel Prize in 2004 for this work. What they found was that humans have approximately 400 different
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functional odorant receptor genes. This makes it the largest gene family in the human genome.
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Interestingly, we actually have about 1,000 odorant receptor-related genes total,
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but around 60% of them are pseudogenes — non-functional remnants from evolution.
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Other mammals, especially dogs, have many more functional receptors, which is why their sense
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of smell is far more sensitive than ours. Now, each olfactory receptor neuron expresses
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only ONE type of odorant receptor. This is called the ‘one neuron, one receptor’ rule.
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So out of the 400 possible receptor types, each individual neuron picks just one and sticks
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with it for its entire 30 to 60 day lifespan. But, here’s the clever part: a single odorant
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molecule can activate multiple different receptor types. The brain interprets smell
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not from one receptor firing, but from the pattern of which combination of receptors are
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firing. This is called the combinatorial code. With 400 receptor types, the number of possible
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combinations is astronomical. In fact, a study published in 2014 estimated that humans can
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distinguish over one trillion different odors, far more than the old estimate of 10,000. So
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even though we only have 400 receptor types, the combinatorial nature of the system allows us to
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detect an almost unlimited variety of smells. Let’s say you just walked past a bakery, and
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a molecule from freshly baked bread enters your nose, dissolves in the mucus, and drifts over to
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the cilia of an olfactory receptor neuron that has a receptor that is responsive to that molecule.
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Step 1: The odorant molecule binds to the odorant receptor on the ciliary membrane.
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The receptor is a G-protein coupled receptor with seven transmembrane domains forming a
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pocket where the odorant docks. Step 2: When the odorant binds,
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it activates G-protein on the intracellular side. This specific G-protein is called Golf,
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the olfactory G-protein. It’s a variant of the stimulatory G-protein family.
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Step 3: Once activated, Golf exchanges GDP for GTP and dissociates. The active subunit then
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activates an enzyme called adenylyl cyclase type III, which is highly expressed in olfactory cilia.
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Step 4: Adenylyl cyclase III converts ATP into cyclic AMP. And cAMP levels
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inside the cilium rapidly increase. Step 5: The rising cAMP directly binds to
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and opens cyclic nucleotide-gated ion channels in the ciliary membrane. These channels are
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non-selective cation channels, meaning they allow both sodium and calcium ions to flow into the cell
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Step 6: The influx of sodium and calcium depolarizes the membrane slightly, and the
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calcium that enters the cell then activates calcium-activated chloride channels. Now,
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here’s the interesting part in olfactory cilia, the intracellular chloride concentration is
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unusually high, so when these chloride channels open, chloride actually flows OUT of the cell,
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which further depolarizes the membrane. Step 7: If the depolarization reaches threshold,
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an action potential is generated. This electrical signal then travels
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up the axon toward the olfactory bulb. The entire cascade, from odorant binding
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to action potential, happens in milliseconds. And this system is extraordinarily sensitive.
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Studies have shown that olfactory neurons can respond to just a few odorant molecules.
Smell Adaptation
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One unique feature of the olfactory system is how rapidly it adapts to continuous stimuli. You’ve
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probably noticed that when you first enter a room and you smell some food cooking, but after a few
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minutes, you stop smelling it. This isn’t because the smell went away; your olfactory system has
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adapted. The adaptation happens through multiple mechanisms, one of which is because the calcium
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that enters, binds to calmodulin, which together reduces the sensitivity of cyclic nucleotide–gated
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ion channels. This negative feedback quickly desensitizes the receptors,
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allowing you to detect new smells rather than being overwhelmed by constant background odors.
Olfactory Bulb
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So, an action potential has been fired. That signal now needs to get to the brain
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and be processed. Let’s follow that pathway. The axons from these olfactory receptor neurons
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are thin and unmyelinated, and they bundle together in small groups of 10 to 100 fibers.
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These bundles are called olfactory filaments, and they pass upward through those tiny holes
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in the cribriform plate, to the olfactory bulb. Inside the bulb, the incoming axons
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synapse with second-order neurons in structures called glomeruli. All olfactory receptor neurons
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that express the same odorant receptor type converge onto the same glomerulus.
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So if you have, say, Type 1 neurons that all express the same receptor,
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every single one of their axons will target the exact same glomeruli. Another type of
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neurons that express the same receptors will target another same glomeruli, and so on.
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Within each glomerulus, the axons synapse onto two types of projection neurons: mitral cells
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and tufted cells. These are the neurons that will carry the signal out of the olfactory
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bulb toward the brain. Each mitral cell sends a single primary dendrite into one glomerulus,
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where it receives input from thousands of olfactory receptor neurons. There are other
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accessory cells here in the olfactory bulb as well that regulate the signals and sharpen the
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timing of signals. We did cover them in the video about the actual olfactory nerve, but for now,
Olfactory Pathway to the Brain
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let’s follow the axons of the mitral and tufted cells as they leave the olfactory
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bulb and form the olfactory tract, which runs along the undersurface of the frontal lobe.
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As the tract extends backward, it reaches an area near the anterior perforated substance,
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where it widens into a triangular region called the olfactory trigone. And from this trigone,
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the tract splits into three separate pathways — the medial olfactory stria,
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the lateral olfactory stria, and sometimes an intermediate olfactory stria.
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The lateral stria is the largest and carries most of the olfactory information. It travels
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to several regions collectively known as the primary olfactory cortex. This includes the
Primary Olfactory Cortex
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piriform cortex, which is the largest component and sits in the temporal lobe. It also goes to
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parts of the amygdala, specifically the cortical nucleus, and to parts of the entorhinal cortex,
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which is the gateway to the hippocampus. And here’s where things get really interesting:
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these fibers project DIRECTLY to these cortical and limbic structures without passing through the
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thalamus. The thalamus sits deep in the brain that is basically responsible for taking in sensory
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information, and directs that sensory information to the cortex for conscious perception. This
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makes olfaction unique among all the sensory systems. Every other sense — vision, hearing,
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touch, taste — they all go through a thalamic relay before reaching the cortex. But smell,
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it bypasses the thalamus entirely and goes straight to the emotion and memory centers.
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Now, for conscious perception and identification of smells — when you can actually say ‘that’s
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coffee’ or ‘that smells like roses’ — the primary olfactory cortex actually sends
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projections through the mediodorsal nucleus of the thalamus to the orbitofrontal cortex. So
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there IS a thalamic pathway, but it’s secondary, not primary. The direct pathway to the limbic
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system happens first, and that’s what makes smell so uniquely tied to emotion and memory.
Smell and Memory (Proust Effect)
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So we’ve just seen that smell has direct connections to the amygdala and the
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hippocampus — your emotion and memory centers. You have probably experienced this: you smell
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something — maybe a particular perfume, the smell of rain, or the scent of old
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books — and suddenly you’re transported back to a very specific moment in your past. Maybe
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your grandmother’s house, your first day of school, or a summer vacation. And it’s
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not just a vague memory — it comes with the full emotional weight of that moment.
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This is called the Proust Effect, named after the French writer Marcel Proust,
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who famously wrote about how the smell and taste of a cookie dipped in tea brought back
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an intense flood of childhood memories. And this isn’t just poetic — it’s neuroscience.
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Research has consistently shown that olfactory memories are more emotional, more vivid,
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and more resistant to forgetting compared to memories triggered by other senses. Brain imaging
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studies show that when people recall memories triggered by smell, there’s greater activation
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in the amygdala compared to when the same memories are triggered by visual or verbal cues.
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Why is this? It comes back to that unique anatomical pathway. Visual, auditory, and tactile
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information all pass through the thalamus before reaching the cortex, and only then do they connect
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to the limbic system. But olfactory information goes directly to the amygdala and hippocampus with
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minimal synaptic delay. Smells get tagged with emotional significance immediately,
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at the earliest stages of processing, which is why they’re encoded so deeply.
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From an evolutionary standpoint, this makes perfect sense. Smell has been critical for
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survival for millions of years. You need to remember which foods made you sick,
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which plants are poisonous, which locations are dangerous. Attaching strong emotional weight to
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smells ensured that those memories stuck. Now, we need to address something that ties
Smell and Taste
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directly into Daniel’s experience: the relationship between smell and taste.
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Because when Daniel lost his sense of smell, he also lost most of his ability
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to taste. And that’s not a coincidence. Taste, or gustation, refers specifically
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to the five modalities detected by taste buds on your tongue: sour, salty, sweet, bitter,
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and umami. Those five sensations are the only things your tongue can actually taste. Everything
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else — all the complexity, the difference between a strawberry and a raspberry, between coffee
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and tea — that’s not taste. That’s smell. When you put food in your mouth and chew,
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you release volatile aroma compounds. These molecules travel from the back of your mouth up
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through the nasopharynx into the nasal cavity from behind. Studies estimate that about 80
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to 90 percent of what we perceive as ‘taste’ is actually smell. Your tongue can tell you ‘sweet,
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slightly sour, some saltiness,’ but your nose is telling you ‘this is a strawberry,
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it’s ripe, it’s fresh.’ The brain integrates these signals in the orbitofrontal cortex
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to create the unified perception of flavor. And this is exactly what happened to Daniel. After
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his head trauma, he had anosmia. In many cases, the taste buds themselves remain largely intact,
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but without smell, food had no complexity, no richness, no flavor. This is why patients with
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anosmia often report significant weight loss and depression. Eating becomes a purely functional
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act instead of a pleasurable experience. So when we talk about the sense of smell,
Smell’s significance
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we’re not just talking about detecting odors in the environment — we’re talking about a system
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that’s fundamental to how you experience flavor, how you form memories, and how you navigate the
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world around you. And with that, we’ve covered all the 5 basic special senses in the previous
Ending
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5 videos. I really hope you found that helpful. I’ve made free courses for other topics here on
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YouTube if you wanna keep learning, otherwise if you want a handmade PDF version of this
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lecture or take a quiz to test your knowledge, or access an organized list of all my videos,
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you can find everything on my website. Thanks for watching! See you in the next one.