Positive expectations facilitate reward processing and negative expectations prime pain processing
Photo by Ryan Quintal on Unsplash
The expectations humans have of a pleasurable sensation asymmetrically shape neuronal responses and subjective experiences to hot sauce, according to a study published October 8th, in the open-access journal PLOS Biologyby Yi Luo from East China Normal University, Kenneth Kishida from Wake Forest School of Medicine, US, and colleagues.
Expectations shape our perception, profoundly influencing how we interpret the world. Positive expectations about sensory stimuli can alleviate distress and reduce pain through what’s known as the placebo effect, while negative expectations may heighten anxiety and exacerbate pain. In the new study, Luo, Kishida, and colleagues investigated the impact of the hedonic aspect of expectations on subjective experiences.
Specifically, the researchers measured neurobehavioral responses to the taste of hot sauce among individuals with a wide range of taste preferences. In total, 47 participants completed the tasks while undergoing functional magnetic resonance imaging scanning. The researchers identified participants who liked versus those who strongly disliked spicy flavors and provided contextual cues about the spiciness of the sauce to be tasted. That way, they were able to dissociate the effects of positive and negative expectations from sensory stimuli (i.e., visual and taste stimuli), which were the same across all participants.
The results showed that positive expectations lead to modulations in the intensity of subjective experience. These modulations were accompanied by increased activity in brain regions previously linked to pleasure, information integration, and the placebo effect, including the anterior insula, dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex. By contrast, negative expectations decreased hedonic experience and increased neural activity in the Neurological Pain Signature network.
Taken together, these findings demonstrate that hedonic aspects of one’s expectations asymmetrically shape how the brain processes sensory input and associated behavioral reports of one’s subjective experiences of intensity, pleasure, and pain. The results suggest a dissociable impact of hedonic information. While positive expectations facilitate higher-level information integration and reward processing, negative expectations prime lower-level processes related to pain and emotions. According to the authors, this study demonstrates the powerful role of hedonic expectations in shaping subjective reality and suggests potential avenues for consumer and therapeutic interventions targeting expectation-driven neural processes.
The authors add, “Our study highlights how hedonic expectations shape subjective experiences and neural responses, offering new insights into the mechanisms behind pain perception.”
In the early 1900s, Japanese scientist Kikunae Ikeda first proposed umami as a basic taste in addition to sweet, sour, salty and bitter. About eight decades later, the scientific community officially agreed with him. Now, scientists led by researchers at the USC Dornsife College of Letters, Arts and Sciences have evidence of a sixth basic taste, which fans of salt licorice will recognise.
In research published in Nature Communications, USC Dornsife neuroscientist Emily Liman and her team found that the tongue responds to ammonium chloride through the same protein receptor that signals sour taste.
Salt licorice has been a popular sweet in northern European countries since at least since the early 20th century, and also appears on South African shelves. The treat counts among its ingredients salmiak salt, or ammonium chloride.
Scientists have for decades recognised that the tongue responds strongly to ammonium chloride. However, despite extensive research, the specific tongue receptors that react to it remained elusive.
Liman and the research team thought they might have an answer. In recent years, they uncovered the protein responsible for detecting sour taste. That protein, called OTOP1, sits within cell membranes and forms a channel for hydrogen ions moving into the cell.
Hydrogen ions are the key component of acids, and as foodies everywhere know, the tongue senses acid as sour, such as the citric acid in lemon juice. Hydrogen ions from these acidic substances move into taste receptor cells through the OTOP1 channel.
Because ammonium chloride can affect the concentration of acid – that is, hydrogen ions – within a cell, the team wondered if it could somehow trigger OTOP1.
To answer this question, they introduced the Otop1 gene into lab-grown human cells so the cells produce the OTOP1 receptor protein. They then exposed the cells to acid or to ammonium chloride and measured the responses.
“We saw that ammonium chloride is a really strong activator of the OTOP1 channel,” Liman said. “It activates as well or better than acids.”
Ammonium chloride gives off small amounts of ammonia, which moves inside the cell and raises the pH, meaning fewer hydrogen ions.
“This pH difference drives a proton influx through the OTOP1 channel,” explained Ziyu Liang, a PhD student in Liman’s lab and first author on the study.
To confirm that their result was more than a laboratory artifact, they turned to a technique that measures electrical conductivity, simulating how nerves conduct a signal. Using taste bud cells from normal mice and from mice the lab previously genetically engineered to not produce OTOP1, they measured how well the taste cells generated electrical responses called action potentials when ammonium chloride is introduced.
Taste bud cells from wildtype mice showed a sharp increase in action potentials after ammonium chloride was added while taste bud cells from the mice lacking OTOP1 failed to respond to the salt. This confirmed their hypothesis that OTOP1 responds to the salt, generating an electrical signal in taste bud cells.
The same was true when another member of the research team, Courtney Wilson, recorded signals from the nerves that innervate the taste cells. She saw the nerves respond to addition of ammonium chloride in normal mice but not in mice lacking OTOP1.
Then the team went one step further and examined how mice react when given a choice to drink either plain water or water laced with ammonium chloride. For these experiments, they disabled the bitter cells that also contribute to the taste of ammonium chloride. Mice with a functional OTOP1 protein found the taste of ammonium chloride unappealing and did not drink the solution, while mice lacking the OTOP1 protein did not mind the alkaline salt, even at very high concentrations.
“This was really the clincher,” Liman said. “It shows that the OTOP1 channel is essential for the behavioral response to ammonium.”
But the scientists weren’t done. They wondered if other animals would also be sensitive to and use their OTOP1 channels to detect ammonium. They found that the OTOP1 channel in some species seems to be more sensitive to ammonium chloride than in other species. And human OTOP1 channels were also sensitive to ammonium chloride.
So, what is the advantage in tasting ammonium chloride and why is it evolutionarily so conserved?
Liman speculates that the ability to taste ammonium chloride might have evolved to help organisms avoid eating harmful biological substances that have high concentrations of ammonium.
“Ammonium is found in waste products – think of fertiliser – and is somewhat toxic,” she explained, “so it makes sense we evolved taste mechanisms to detect it. Chicken OTOP1 is much more sensitive to ammonium than zebra fish.” Liman speculates that these variations may reflect differences in the ecological niches of different animals. “Fish may simply not encounter much ammonium in the water, while chicken coops are filled with ammonium that needs to be avoided and not eaten.”
But she cautions that this is very early research and further study is needed to understand species differences in sensitivity to ammonium and what makes OTOP1 channels from some species sensitive and some less sensitive to ammonium.
Towards this end, they have made a start. “We identified a particular part of the OTOP1 channel – a specific amino acid – that’s necessary for it to respond to ammonium,” Liman said. “If we mutate this one residue, the channel is not nearly as sensitive to ammonium, but it still responds to acid.”
Moreover, because this one amino acid is conserved across different species, there must have been selective pressure to maintain it, she says. In other words, the OTOP1 channel’s ability to respond to ammonium must have been important to the animals’ survival.
In the future, the researchers plan to extend these studies to understand whether sensitivity to ammonium is conserved among other members of the OTOP proton family, which are expressed in other parts of the body, including in the digestive tract.
And who knows? Perhaps ammonium chloride will join the other five basic tastes to bring the official count to six.
Paediatric medicines often come in a sweetened liquid form for compliance in ingesting it, but if it’s too palatable, a child may empty an entire bottle and poison themselves. But children can perceive taste in different ways. A new study published in the International Journal of Molecular Sciences uncovers genetic variations in how sweetness of medicine is perceived, with adult participants of African descent finding it than those of European descent.
A multidisciplinary research group specialising in paediatrics, genetics, and psychophysics, co-led by Julie A. Mennella, PhD, Principal Investigator at the Monell Chemical Senses Center, has identified wide variation in the sensory perception of a paediatric formulation of ibuprofen. Some were tied to genetic ancestry, and some were not. These findings indicate that a range of factors come into play in determining how a medicine tastes to an individual. Their work is the first in a series of studies funded by the National Institutes of Health to look at variation in the taste of medicines.
“Taste is personal and determining how individuals differ and why is critical to understanding medication adherence and personal risks,” said Mennella. Bitter taste and irritating sensations in the throat are the top reasons for non-compliance, as a child (or adult) is less likely to ingest a medicine that is unpleasant (or tastes bad). However, if a child finds the medicine bottle uncapped and finds it tastes sweet like candy, they may ingest too much. Discovering how individuals differ in sensory perception is especially key when it comes to liquid ibuprofen, which accounts for many unintentional poison exposures among children younger than six years old in the US, according to the US Poison Centers.
“Sweetening medicines like ibuprofen is a delicate balance between having it taste good enough that kids take it, but bitter enough that, should they get unguarded access to it, it’s irritating enough that they stop drinking it and don’t poison themselves,” said Mennella. “We found genetic markers, both ancestry-related and independent of it, that could predict if someone would find a medication irritating or pleasantly sweet. If we get to the point of tailor-making medications in the future, knowing these associations could help us design taste specifically for each child in the not-so-distant future.”
The study included 154 adult panellists from Philadelphia, who represented the diversity of their city. According to a genome-wide association study, 63 had African ancestry, 51 European, 13 South Asian, seven East Asian, and seven American. They underwent training in sensory methods and then rated the sweetness, irritation, bitterness, and palatability of a paediatric formulation of a berry-flavoured ibuprofen after swallowing, and also after just tasting it without swallowing.
Researchers found that panellists of African genetic ancestry had fewer chemaesthetic sensations such as tingling or an urge to cough, rated the medicine as tasting sweeter and more palatable than those of European genetic ancestry. Researchers also found a novel association between the TRPA1rs1198875 genetic variation and tingling sensations, independent of ancestry. This is significant as TRPA1 is a family of neuron receptors that are involved in sensory neural response to a variety of chemical irritants found in foodstuff and other medicines.
Discovering both an ancestry-related link and non-ancestry-related genetic variation to taste and irritation perception shows that who perceives a medicine as palatable or not is a complicated picture and must consider a variety of factors.
This first study was conducted with adults because the sensory measures were complex and included several hour-long test sessions. That does not mean future tests should not include children, Mennella said, adding that this is just the first in a line of studies on the taste of paediatric medicines and methods need to be developed to measure sensory irritation in children. “This is a small study, but it is the first step in showing how research on diverse populations is needed to be able to unravel the genetic, cultural, dietary, and developmental paths that underlie medicine adherence and also risk for poisoning,” said Mennella. “It’s looking at both sides of the same, very important coin.”
Findings from this research will affect how sensory tests can be designed in the future. Since participants did both swallow and sip-and-spit tests, the team was able to determine that just tasting medicine allowed predictions and perceptions after swallowing, which could simplify future studies in different age groups. Other studies as part of this National Institutes of Health grant are ongoing, including determining the variation and acceptance of medicines in children.
A surprising fact is that bitter taste receptors are found not just in the mouth, but elsewhere including the airways. Activating those receptors dilates up lung passageways, making them a potential target for treating asthma or chronic obstructive pulmonary disease (COPD). Now, researchers report in the Journal of Medicinal Chemistry that they have designed a potent and selective compound that could lead the way to such therapies.
Among the 25 different types of bitter taste receptors, the TAS2R14 subtype is one of the most widely distributed in tissues outside the mouth. Scientists are uncertain about the structure of the receptor, and they haven’t identified the particular compound or “ligand” in the body that activates it. However, a few synthetic compounds, such as the nonsteroidal anti-inflammatory drug (NSAID) flufenamic acid, are known to bind to and activate TAS2R14s. But these compounds aren’t very potent, and they don’t have similar structural features. These difficulties make it challenging to create a better ligand. Nevertheless, Masha Niv, Peter Gmeiner and colleagues used flufenamic acid as a starting point to design and synthesise analogues with improved properties. Next, the team wanted to extend that work to develop a set of even better TAS2R14 ligands.
Building on these earlier findings, the researchers made several new variations. They tested these compounds in a cell-based assay that measures receptor activation. This approach revealed that replacing a phenyl ring with a 2-aminopyrimidine and substituting a tetrazole for a carboxylic acid group was a promising strategy. One of the new ligands was six times more potent than flufenamic acid, meaning less of the compound was needed to produce a similar response as the NSAID. This ligand was also highly selective for TAS2R14 compared to non-bitter taste receptors, which could potentially minimise side effects. The researchers speculate that new compounds will help shed light on the structure, mechanism and physiological function of bitter taste receptors and guide development of drug candidates to target them.
