Ben Marcus, PhD (University of Chicago)

Austin Lim, PhD (DePaul University) 

Canadian Edition Editor: Michael Gordon (University of British Columbia)

In the previous two chapters, we examined some of the ways we detect and perceive our physical environment, including through phenomena such as light, sound, and tactile sensations.

In this chapter, we will complete our tour of the senses by exploring how we sense and perceive chemical compounds. In particular, we will describe the neural processes underlying our senses of smell, taste, and the chemical status of our internal homeostatic state.

Our olfactory system (smell) is activated by compounds called odourants, while our gustatory system (taste) is activated by compounds called tastants. We use these words to distinguish between the chemicals themselves (odourants/tastants) and the sensations they evoke (odour/taste). Olfaction and gustation are closely intertwined; odourants, tastants, and other sensations in the mouth, including pain and texture, combine to produce the flavour of what we eat. Try eating a fancy meal with a stuffed-up nose, and you’ll quickly notice that you lose the subtle complexities (and most of the joy!) of those foods.

Chemicals in our body, such as the amount of carbon dioxide in the blood or the presence of toxins in our digestive tract, are detected with our internal chemosensory systems. Many of these sensory systems are intimately tied with our autonomic nervous system (Chapter 2). Changes in chemical balance here results in unconscious or involuntary physiological changes to restore homeostasis.

11.1 Olfactory System

Olfaction is the ability to sense and perceive volatile chemicals that are suspended in the air. Estimates vary widely, but a combination of experimentation and modeling suggests a typical human can distinguish at least 10,000 distinct odours (with one group suggesting the number is over 1 trillion!). Odours range from the sweet aroma of esters produced by apples and oranges, to the putrid smells of sulfurous compounds produced by skunks and rotten eggs. Because odourants can drift along in the air, some chemicals can be detected long before the source is within eyesight: think about smelling a burning bonfire from miles away.

Smells affect our conscious behaviour. They can motivate us to approach freshly-baked bread or avoid a rotting animal carcass. These chemicals serve as survival cues: bread gives us energy-rich carbohydrates while a decaying carcass can expose us to disease. Odourants can even affect our behaviours unconsciously: sleeping amidst the scent of a romantic partner increases the efficiency of our sleep, and subliminal exposure to citrus smells can lead people to clean their space more completely after eating a crumbly biscuit (an effect described in a study called “Smells Like Clean Spirit,” a nod to 90s punk band Nirvana).

Olfaction is one of the oldest functions we possess as animals, but as humans, our sense of smell may appear to have taken a back seat to other senses relative to other animals. The olfactory bulb, which is the first neural relay station in the olfactory system, takes up about 2% of the total mouse brain but only a scant 0.01% of the human brain. However, while the size of our olfactory bulbs is small relative to our total brain, the absolute size of the human olfactory bulb is quite large, and olfaction plays an important role in our everyday lives. Scientists now also appreciate that our olfactory system is capable of some remarkable feats. For example, humans use the smells of sweat to clue us into the emotional state of others, and we can even subconsciously detect sickness through body odour.

11.1.1  Organization of the Peripheral Olfactory System

Your sensation of smell begins when an odourant traverses your nostrils and passes into the nasal cavity, an empty, air-filled space just behind the front of the skull. The dorsal-most portion of the nasal cavity is covered in a mucus-covered patch of tissue called the olfactory epithelium.

Embedded within the olfactory epithelium are the olfactory sensory neurons (OSNs, also called olfactory receptor neurons, or ORNs), which directly detect odourants. OSNs are ciliated bipolar neurons, with long dendritic projections protruding into the epithelium. Here, the cilia form a meshwork embedded in mucus that absorbs chemicals in the air, bringing the chemicals into contact with receptors expressed on the OSN’s surface. One consequence of this structure is that OSNs are the only neurons that are directly exposed to the outside world. This, unfortunately, causes them to encounter all sorts of dangers such as toxins, particulates, and microbes. They are one of the few known populations of neurons where adult neurogenesis occurs, each having a lifespan in the range of 30 days to a year. The average human olfactory system has somewhere between 6-20 million OSNs.

On the dendrites of OSNs are odourant receptors (ORs). The OR family comprises about 1,000 different genes (about 3% of the total human genome), but many have evolved mutations that make them non-functional (pseudogenes). Still, the human olfactory system expresses roughly 400 different functional OR proteins. Each OSN expresses only one OR gene, and each receptor typically responds to a range of chemicals. Some ORs are “narrowly tuned” and respond to a small number of chemicals, while others are “broadly tuned” and respond to a wider array. For example, the receptor OR2W1 is activated by over 100 known food odours, while OR2M3, to our knowledge, only responds to one specific chemical that gives the characteristic smell of raw onions. Even though scientists have identified the odourants that activate some receptors, most of the olfactory receptors are still “orphaned,” and have not yet been matched with their corresponding odourants. The initial research into the genetics underlying these neurons earned Drs. Linda Buck and Richard Axel a Nobel prize in 2004, but there is still much work to be done.

ORs are transmembrane G protein-coupled receptors that signal downstream effectors using the intracellular transduction molecule G_αolf. This protein complex is 90% similar to the stimulatory G-protein G_s, and likewise triggers activation of adenylate cyclase, elevating the intracellular concentration of cyclic AMP (see section 5.3 for a refresher on this signalling pathway). Activation of G_αolf causes depolarization, causing the OSN to fire action potentials.

The axons of OSNs pass through the skull through a tiny series of holes at the cribriform plate, a sieve-like section of the ethmoid bone. These primary neurons form synaptic connections onto neurons in the olfactory bulb, the beginning of the olfactory nerve (CN I). Like the optic nerve, the olfactory nerve runs along the ventral surface of the brain.

The site of synaptic connectivity between the OSNs and the secondary neurons in the olfactory bulb is a highly specialized clump of tissue called a glomerulus. The typical human has a little under 2,000 glomeruli, and, importantly, each glomerulus only receives inputs from OSNs that express the same OR gene.

11.1.2 Coding and Information Flow in the Olfactory System

The anatomical and functional studies described above support three main principles that are critical to our understanding of how information is coded in the olfactory system:

• 1) Each OR responds to an array of odourants, and each odourant typically activates several to many ORs.
• 2) Each OSN expresses only one OR gene (and its associated protein), and the activity of an OSN reflects the tuning of its OR. Thus, OSNs also typically respond to many odourants, and each odourant typically activates many OSNs.
• 3) OSNs expressing the same OR gene converge onto a small number of glomeruli in the olfactory bulb; similarly, each glomerulus contains axons from only OSNs expressing the same OR gene.

What emerges from this picture is that different odourants will activate partially overlapping combinations of glomeruli in the olfactory bulb. This creates what neuroscientists refer to a combinatorial code, where the identity of an odourant is encoded by the combination of neurons (or glomeruli in this specific case) that respond to it. Thus, the activity of one particular glomerulus is typically not enough for us to identify an odourant, but the pattern of glomeruli activated across the entire olfactory bulb will be unique to that odourant and sufficient to reveal its identity.

Within each glomerulus are the dendrites of the secondary neurons, which exist in two types: The mitral cells and the tufted cells. These two cell populations project axons directly into the olfactory cortex. This makes the olfactory system the only sensory system that does not pass signals through the thalamus before cortical processing.

There are also two types of inhibitory neurons that regulate this pathway: granule cells found within glomeruli, and periglomerular cells, which send axonal projections into the glomeruli, both help refine the synaptic processing of scent information using lateral inhibition, a system similar to that found in the retina of the visual system (Chapter 9).

Collectively, the olfactory cortex is made up of several different regions.

Piriform cortex

The piriform cortex is the main cortical input site for axonal projections from the olfactory bulb and the primary cortical area associated with the sense of smell. In some species of mammals that rely very heavily on their sense of smell for survival, up to 10% of total cortical volume is piriform cortex. Like in the olfactory bulb, olfactory information is represented by a combinatorial code in the piriform cortex. The outputs of the piriform cortex project into other structures of the olfactory cortex, as well as the mediodorsal thalamus, a relay centre that contributes to learning and decision making.

Cortical amygdala

The amygdala is a part of the brain that helps mediate complex emotional states (Chapter 16). Generally, it is subdivided into a few different subnuclei. One of them in particular, the cortical amygdala, receives strong inputs from the olfactory nerve. The cortical amygdala sends projections into the hippocampus, a brain structure critically important for the formation of new memories.

The strong neural connections between the olfactory bulb and amygdala are believed to be the reason why smell and emotional memories are strongly linked. Think about a time when you caught a slightest whiff of a scent, and that scent mentally transported you to a distant place from a long time ago (this experience was also described by author Marcel Proust in his highly- regarded novel, In Search of Lost Time). We form associations between specific smells and emotionally salient memories. Some odourants, like the volatile Maillard reaction products that are made as a product of cooking, remind us of the “good ole days” watching a parent bake or grill. Many bakeries take advantage of these positive memories and point their exhaust out into the street to entice passersby.

Unfortunately, the memories associated with smells can also have negative valence. For example, the smell of petroleum and oil fumes can trigger a sickness-like conditioned response in Gulf War veterans.

Entorhinal cortex (EC)

The entorhinal cortex is a small section of the medial temporal lobe. As with the cortical amygdala, the EC sends strong connections into the hippocampus, indicating that olfactory signals contribute to the strong associations formed between smell and memory through EC, as well.

Other than receiving and processing olfactory signals, the entorhinal cortex is also involved in spatial navigational tasks.

Orbitofrontal cortex (OFC)

As the name implies, the orbitofrontal cortex (OFC) is found just behind the orbit, the bony socket of the skull where the eyes sit. OFC is found at the ventral surface of the frontal lobe. Circuits in this brain area function as an integration site for sensory inputs, since it also receives projections from visual, taste, and somatosensory cortices.

The full extent of the OFC is still under examination, but it is also implicated in decision making and social behaviours.

11.1.3 Disorders of the Olfactory System

Like other sensory systems, the structures involved in olfaction can be injured. An injury to the olfactory system can result in hyposmia, a reduced ability to smell, or anosmia, a complete loss of smell.

The most common insult to the olfactory system is simple nasal congestion, a temporary, physical blockage of the entry to the nasal cavity that decreases airflow and, therefore, the number of particles that reach the olfactory epithelium. Congestion can be caused by allergies, the common cold, upper respiratory bacterial or viral infections, or sinus infections. Hyposmia is also one of the main neurological symptoms of COVID-19.

Hyposmia is common among healthy, older adults, affecting about half of the population between 65 and 80 years old. As a person ages, spontaneous calcification causes the holes in the cribriform plate to shrink, which can impinge on and damage OSN axons.

Hyposmia can also be caused by abrupt head injuries. The OSN axons that project through the holes of the cribriform plate are particularly sensitive to blows to the head.

Neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease, also contribute to smell deficiency. Usually, hyposmia precedes the major clinically observed symptoms of these disorders, hinting that smell deficiency may serve as an early diagnostic biomarker.

Another olfactory deficit, phantosmia, is when a person perceives “phantom” scents, or in other words, experiences an olfactory hallucination. Phantosmia may be triggered by a temporal lobe seizure or a stroke. It can also be caused by a brain tumor affecting the olfactory nerve (CN I), or the subsequent surgical removal of the tumor, leading to injury. Schizophrenia, a psychiatric condition characterized by auditory hallucinations, may also cause phantosmia.

11.2  Gustatory System

Your gustatory system, which mediates your sense of taste, helps you walk the line between health and illness. It guides you towards foods that are energy rich, and keeps you away from food that could make you sick. The five primary taste modalities – salt, sweet, sour, bitter, and umami – all support this balance. In contrast to the olfactory system, which has evolved a remarkable ability to distinguish between chemicals, the gustatory system is in the business of categorizing tastants and reacting appropriately. Sweetness is most often a signal of energy-rich carbohydrates (e.g. sugars) and, therefore, promotes ingestion. In contrast, toxic compounds are often bitter, causing you to respond with feelings of disgust. Salt presents a particularly interesting case because it is essential to survival, yet harmful at high levels. Thus, it is perhaps unsurprising that the valence (positive versus negative) of salt is concentration dependent. Low concentrations sprinkled on french fries are delicious, but sea water evokes disgust.

All these reactions are adaptations animals have evolved to promote survival and maintain homeostasis in the body.

11.2.1  Organization of the Peripheral Gustatory System

Lingual papillae (singular; papilla) are the large anatomical structures that give the tongue its characteristic rough surface. These structures can be seen with the unaided eye. Each papilla contains up to a hundred taste buds, which are onion-shaped and harbour taste receptors. Taste buds can also be found on the palate and in the throat. In total, a person has about 10,000 taste buds but the number varies by age: Taste bud concentration in the mouth peaks in childhood and decreases throughout adulthood. No wonder you can now devour those brussel sprouts you hated as a child.

Within each taste bud are approximately 100 taste receptor cells. These cells are not neurons, but are instead derived from specialized epithelial cells. These cells reach toward the apical tip of the taste bud and sprout thin projections called taste hairs, which extend into taste pores. These tiny pockets at the apical tip of the taste bud are where taste hairs meet saliva. Taste buds also contain basal cells, which reproduce to form supporting cells, and over time, these mature further into taste receptor cells. Taste receptor cells turnover every 8–22 days.

Taste receptors cells (TRCs) communicate with afferent gustatory neurons. These gustatory nerve fibres originate from three of the twelve cranial nerves.

• The nerve fibres from the anterior two- thirds of the tongue are part of the facial nerve (CN VII).
• The posterior third of the tongue sends information through the glossopharyngeal nerve (CN IX).
• The back of the palate and the throat can send taste-related signals through the vagus nerve (CN X).

11.2.2 Coding and Information Flow in the Gustatory System

TRCs are responsible for sensing and conveying information about taste in accordance with the primary taste modalities (salty, sweet, sour, bitter, umami). TRCs are thought to express receptors for only one taste modality – a salty TRC expresses only salt receptors, and a sweet TRC responds only to sugars and other sweet substances. This peripheral organization in the taste system stands in contrast to what we discussed above for the olfactory system. Most importantly, while OSNs typically respond to many different odourants, TRCs are, in most cases, specific for an individual taste modality. This has led to the proposal that taste information follows a labeled line coding model, where each taste modality is encoded by a dedicated population of neurons at each level of the taste pathway. This model fits with behavioural evidence that animals have specific reactions to different taste modalities but cannot distinguish different tastants within a modality. However, while the bulk of evidence supports this model in TRCs, it remains heavily debated at higher levels of taste processing where responses appear less specific and may follow a model closer to the combinatorial coding scheme discussed in the olfactory system.

Afferent gustatory neurons, which have cell bodies in the geniculate ganglia, project to and form synapses on second-order neurons in the rostral medulla in an area called the solitary nucleus (or gustatory nucleus) in the medulla oblongata. Unlike most other sensorimotor systems, the gustatory system sends ipsilateral projections into the CNS; that is to say, taste information from the left half of the tongue gets represented in the left hemisphere of the brain, and vice versa.

From the medulla, neurons carrying taste information send axonal projections onto third-order taste neurons in the ventral posteromedial (VPM) nucleus of the thalamus. These neurons send projections widely across several areas of the cortex.

The gustatory cortex is made up of two different parts: the anterior end of the insular cortex and the frontal operculum of the frontal lobe. These neurons convey information such as the taste identity (modality) and its intensity.

Taste processing outside of the cortex is also critical for our reaction to foods on our tongues. Notably, some neurons in the gustatory cortex project to the amygdala, which was discussed above as a site for the emotional processing of odours. Different areas of the amygdala process positive (e.g. sweet) and negative (e.g. bitter) tastes and are necessary for the valence (pleasure versus disgust) of the response. However, the amygdala appears dispensable for perception of taste identity. Thus, mice lacking function in the amygdala can tell when they taste something bitter, but it no longer disgusts them!

11.2.3  Taste modalities of the gustatory system

Currently, it is believed that humans sense five basic tastes: Salty, sour, sweet, bitter, and umami. Salty and sour taste are both mediated by ionotropic taste receptors, while sweet, bitter, and umami taste are mediated by metabotropic taste receptors. Besides varying by type, these receptors are also not distributed evenly across the surface of the tongue. For example, the tip of the tongue is most sensitive to sugars, while the back of the tongue is most sensitive to bitter compounds.

Salt

Sensation of salt taste is primarily driven by Na⁺ ions. When you sprinkle a little table salt (NaCl) onto your tongue, it dissolves in saliva and the free sodium ions can passively influx into salt taste receptor cells through epithelial sodium channels (ENaCs). This movement of positively charged Na⁺ ions causes depolarization of the taste receptor cell, just like in neurons. This depolarization activates voltage-gated calcium channels, prompting neurotransmitter release that, in turn, activates the afferent gustatory nerve fibers.

Salty foods elicit a biphasic response depending on concentration. Foods cooked with a low concentration of salt taste bland and are not very appetizing; however, high salt concentrations elicit a strong aversive reaction – imagine how disgusted you were when you first tried to cook and were overly generous with the salt! This is because concentrations of salt above about 100 mM begin to activate TRCs for the two aversive taste modalities – bitter and sour. The mechanism(s) by which high salt concentrations activate bitter and sour TRCs are currently unknown; however, unlike appetitive salt taste, it does not involve ENaCs. This distinction is underscored by the observation that attractive salt taste is mostly specific to sodium, while aversive high salt taste occurs in response to any salt species.

Additionally, the appeal of salt at a given moment depends on our body’s need for salt at the time. Several hormones such as the appetite-stimulating hormone ghrelin contribute to regulating the concentration of salt in the body by mediating Na⁺ absorption. Current salt levels can also impact salt appetite. For example, high salt solutions are highly rewarding in chronically-sodium deprived animals.

Why are we so sensitive to the taste of salt? As it turns out, both Na⁺ and Cl⁻ are essential nutrients. They are critical for maintaining blood volume and pressure, for regulating body water, for maintaining muscle contractions, and mediating action potentials. Cl^– also helps maintain a healthy pH balance. But for these functions to be performed optimally, salt must be present at a specific range of concentrations in the body.

Sour

Sour taste is the sensation of acid, which is mediated by a proton-selective channel called Otopetrin 1 (Otop1). Influx of these positively-charged ions influences the permeability of other ion channels, ultimately leading to neurotransmitter release from the sour TRC and signalling to gustatory afferent neurons. Animals, including mice, which are the subject of most mammalian taste research, typically find sour tastants to be aversive. It is thought that this reflects an evolved aversion to the acidity produced in over-ripe or rotting foods. However, sour taste is not the only reason that animals don’t like acidic foods. Low pH also triggers responses in pain fibers of the somatosensory system in the mouth, a phenomenon we will discuss in the context of spiciness below.

Human sour taste is a bit more ambiguous than what we observe in rodents, with people enjoying low levels of acidity in some foods. It is unclear what selective pressure produced humans’ relative enjoyment of sourness, but one theory is that it supports consumption of Vitamin C. Humans and other higher primates cannot synthesize Vitamin C on their own, so it is possible that we evolved to find a combination of sourness and sweetness attractive enough to consistently consume Vitamin C-rich fruits. However, sour can be aversive to humans, motivating us to avoid spoiled or unripe foods that might contain pathogens, just like our more distant evolutionary relatives.

Umami

Umami is the taste of savory deliciousness, such as the taste of rich chicken broth, a perfect medium-rare steak, or aged cheese. The word is derived from the Japanese word umai, which means “delicious.” Like sweet flavour, umami taste is mediated by a heterodimeric metabotropic receptor from the T1R family and actually shares one of the subunits from the sweet receptor. Umami is signalled when amino acids, particularly glutamate (chemically the same as the neurotransmitter!) bind to T1R1/T1R3 receptors. This is why monosodium glutamate (MSG) is added to many savory foods to enhance their appeal.

Bitter

Bitter taste is sensed via a family of about 25 receptors from the taste receptor type 2 (TAS2R or T2R) gene family. Various T2Rs are co-expressed in each bitter TRC, making those cells broadly responsive to bitter chemicals. The ligands for most T2Rs have not yet been identified, but one receptor – T2R38 – has been intensively studied because it presents an excellent example of genotypic variation leading to phenotypic variation in humans. There are two common variants of the T2R38 gene in humans, referred to as the PAV and AVI haplotypes (named based on the amino acids at three polymorphic positions in the protein). People carrying two AVI alleles cannot taste certain bitter compounds including phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP), while people carrying one AVI and one PAV allele perceive moderate bitterness and two PAV alleles confers “supertasting” of these bitter substances. It is thought that T2R38 also may confer some sensitivity to glucosinolates found in vegetables like broccoli. So those of us who can’t stand eating vegetables may be able to blame our genetics!

Bitter taste likely evolved to drive animals away from consuming compounds that may be toxic. For example, alkaloids like strychnine are both extremely bitter and highly toxic, as are compounds found in deadly plants like poison hemlock and nightshade. Another, less deadly, example is cucurbitacins, a group of bitter-tasting compounds found naturally in gourds, including cucumbers and pumpkins, which are believed to have evolved as a defense mechanism by the plant to avoid predation.

Like sweet taste receptors, bitter receptors are also found in non-taste tissues such as the gut and lungs. Particular attention has been paid to the lungs, where it is thought that T2Rs help mediate an immune response against bacteria. Interestingly, people carrying the non-taster mutations in T2R38 are actually more sensitive to chronic rhinosinusitis (inflammation of the nasal passages) and are more likely to develop sinus infections and require surgery to address this condition. Thus, aside from being a fun experiment you can try at home, testing your sensitivity to PTC and PROP could reveal your predisposition to specific airway conditions.

Signalling downstream of sweet, umami, and bitter taste receptors

The intracellular signalling transduction process is similar for sweet, bitter, and umami sensation. Tastants of these modalities all activate GPCRs that use the G protein α-gustducin. This activation increases the activity of phospholipase C-β2 (PLC-β2), which, in turn, activates the inositol 1,4,5-triphosphate (IP3) receptor, causing the release of calcium into the cytoplasm. The calcium opens the transient receptor potential cation channel subfamily M member 5 (TRPMP5), which causes the taste cell membrane to depolarize, generating an action potential. This causes the release of ATP into the synapse, which activates afferent nerve fibres to signal the presence of these tastants.

11.2.3 Other oral sensations from food

Fat

Triglycerides are chemicals made up of three fatty acids bonded to a glycerol molecule. They are a large part of our diet and are commonly found in animal fat and butter. Triglycerides contribute to the “mouthfeel” of foods, giving foods a creamy, rich quality. However, triglycerides themselves don’t have a taste.

In 2015, researchers found that humans might be able to sense fatty acid chain molecules in the mouth. It turns out that in their study participants could distinguish between a control drink, a bitter drink, a sour drink, and drinks containing fat. Participants initially grouped the fatty drinks with the bitter and sour tastes, suggesting that fat by itself is an aversive taste, despite being high in energy content.

The research on this fat taste, called oleogustus, is still in its infancy compared to that of the other taste modalities. Researchers have not elucidated the mechanisms underlying this pathway.

Spicy

It’s no accident that the word “hot” is used to describe both the temperature and the spiciness of a food. After eating that delicious plate of curry, your body may exhibit a strong somatic response: intense salvation, a flushing of the skin, sweating, and sometimes even crying. As it turns out, the pain of eating a hot pepper is similar to experiencing other forms of physical injury. Spiciness activates C fibers on the tongue and other areas of the mouth, the same type of fibers that carries afferent painful information across the body (Chapter 10). These fibers travel via the trigeminal nerve, distinct from taste information. Thus, while you may be used to thinking of spice as a type of taste, strictly speaking it activates the somatosensory system, not the gustatory system.

Our ability to detect spicy flavours originates at the TRPV1 receptor, a nonselective cation channel. Upon activation, these receptors cause depolarization of the nerve fibre. Peppers contain the compound capsaicin, a potent activator of the TRPV1 receptor. These TRPV1 receptors are also temperature sensitive, opening at around 43C. Because these receptors can be activated by either chemical ligands or high temperatures, biting into a ghost pepper causes a similar sensation as if your tongue was literally being burned – the “heat” of spicy foods is more than just a colloquialism.

TRPV1 receptors are not only activated by capsaicin. Ethanol, for example, can also activate these receptors, which is why a shot of hard liquor causes a painful, burning sensation. Since low pH potentiates TRPV1 receptors, acid can also contribute to how “hot” a food is perceived.

11.3 Internal Chemosensory Systems

In addition to detecting chemicals with our noses or mouths, we also host a variety of chemosensory systems that sense various conditions about our internal environment. These systems contribute to homeostasis. Whenever the body is pushed out of it’s ideal operating range, these chemosensory systems respond by reflexively adjusting chemical absorption or behaviour.

11.3.1 Respiration

Neural control of the respiratory system originates in several circuits within the hindbrain. Of particular relevance is the medulla, the inferior- most segment of the brain stem. These complex circuits communicate with descending motor signals that are critically important for respiration through the action of two main nerves. The main driver of respiration is the phrenic nerve, which is the only nerve that innervates the diaphragm. The other drivers of respiration are the intercostal nerves, which innervate the intercostal muscles, the set of accessory respiratory muscles found between the ribs that expand the chest cavity during inhalation. People with spinal cord injury at the level of C5 or higher, which results in damage to the phrenic nerve, may need to be put on a ventilator. These circuits express opioid receptors, which is why opioid overdose can lead to fatal respiratory depression.

Regular respiration is an autonomic function. When CO₂ levels rise (a condition called hypercapnia), these hindbrain neurons drive increased respiratory rate, which helps the body expel excess CO₂.

Respiratory patterns are also regulated homeostatically to restore a healthy level of pH in the blood. The pH of CSF is essentially a proxy measure for CO₂ in the blood: CO₂ diffuses easily across the blood brain barrier into the CSF. Once there, CO₂ quickly reacts with H₂O to form carbonic acid, which then dissociates into a bicarbonate ion and an H⁺ ion. Because of this chemical reaction, when blood CO₂ is elevated, so is the concentration of H⁺ (low pH) in CSF.

Central chemoreceptors detect changes in the pH level of the CSF by sensing H⁺ ions, which enter the cells through acid-sensing ion channels (ASICs). When ASIC-expressing neurons detect pH levels less than 7, they send signals to the nerves that mediate diaphragm and intercostal muscle activity to increase respiration. This increases the exchange of CO₂ out of the lungs, shifting the pH of the blood back towards more physiological levels of 7.4.

11.3.2. Vomiting

Vomiting (or emesis) is a rapid contraction of respiratory and abdominal muscles, compressing the stomach, thereby expelling stomach contents through the esophagus. Vomiting is often preceded by nausea, the unpleasant sensation of stomach discomfort.

Although aversive and painful, vomiting can be a natural and healthy protective response. For example, when toxins are produced during bacterial gastroenteritis (food poisoning), it is beneficial to expel the spoiled or rotten food from the stomach to minimize further exposure to bacterial toxins.

The neural signals that lead to vomiting originate at the afferent inputs of the vagus nerve (Cranial Nerve X), found in the intestinal tract. These ascending inputs form connections within the dorsal vagal complex (DVC), a series of nuclei found in the medulla of the brain stem. A region within the DVC that mediates the vomiting response is area postrema (AP), which is found on the floor of the fourth ventricle. Within AP is the chemosensory trigger zone, which is dense with neurons that sense the presence of various chemicals. The AP is considered to be a circumventricular organ, meaning that it is not isolated from the blood by a blood brain barrier. Instead, toxins and other large molecules in the blood are able to influence AP neurons directly. Additionally, because they are bathed by CSF, they can also sense the presence of toxins in CSF.

Image Credits

Cover: https://pixabay.com/photos/pork-ribs-dinner-pork-food-meat-2157179/
11.1 https://commons.wikimedia.org/wiki/File:Southern_spotted_skunk.jpg
11.2 https://commons.wikimedia.org/wiki/File:1543,Vesalius%27OlfactoryBulbs.jpg https://commons.wikimedia.org/wiki/File:Anatomy_of_the_woodchuck_(Marmota_monax)_(2005)_(18007398570).jpg olfactory structures outlined by Austin Lim
11.3 https://commons.wikimedia.org/wiki/File:Head_olfactory_nerve.jpg
11.4 https://commons.wikimedia.org/wiki/File:Location_of_olfactory_ensheathing_cells_(OECs)_within_the_olfactory_system.png modified by Austin Lim
11.5 https://commons.wikimedia.org/wiki/File:Cribriform_plate_Close-up_view.png
11.6 https://commons.wikimedia.org/wiki/File:Olfactory_Sensory_Neurons_innervating_Olfactory_Glomeruli.jpg modified by Austin Lim
11.7 https://pixabay.com/photos/grain-bread-bread-rye-bread-cut-3135224/
11.8 https://commons.wikimedia.org/wiki/File:Entorhinal_-_DK_ATLAS.png
11.9 https://commons.wikimedia.org/wiki/File:MRI_of_orbitofrontal_cortex.jpg
11.10 https://commons.wikimedia.org/wiki/File:Anatomy_and_physiology_of_animals_Taste_buds_on_the_tongue.jpg modified by Austin Lim
11.11 https://commons.wikimedia.org/wiki/File:1402_The_Tongue.jpg modified by Austin Lim
11.12 https://openbooks.lib.msu.edu/neuroscience/chapter/taste-central-processing/ modified by Austin Lim
11.14 ttps://commons.wikimedia.org/wiki/File:EMA401_Mechanism_of_Action.jpg
11.15 https://commons.wikimedia.org/wiki/File:Gray806.png phrenic nerve highlighted by Austin Lim
11.15 ttps://commons.wikimedia.org/wiki/File:Buffer_Part_1.png modified by Austin Lim
11.17 https://commons.wikimedia.org/wiki/File:Human_caudal_brainstem_posterior_view_description.JPG modified by Austin Lim

The Open Neuroscience Initiative is funded by a grant from the Vincentian Endowment Fund of DePaul University.

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.