(Image caption: This ribbon diagram shows three ankyrin repeats, a common structure found in receptor proteins that sense either cold or hot temperatures. A Duke team has identified three single-point mutations that can invert temperature-sensitivity, turning a cold-sensor into a heat-sensor. All three of these mutations are located in on a single ankyrin repeat. Credit: Grandl Lab, Duke University)

Small Mutation Changes Brain Freeze to Hot Foot

Ice cream lovers and hot tea drinkers with sensitive teeth could one day have a reason to celebrate a new finding from Duke University researchers. The scientists have found a very small change in a single protein that turns a cold-sensitive receptor into one that senses heat.

Understanding sensation and pain at this level could lead to more specific pain relievers that wouldn’t affect the central nervous system, likely producing less severe side effects than existing medications, said Jorg Grandl, Ph.D., an assistant professor of neurobiology in Duke’s School of Medicine who led the research team.

Temperature-induced pain, also called thermal pain, occurs when the body’s sensory neurons come in contact with temperatures above or below a certain threshold, such as plunging a limb into freezing water.

"We want to understand how either hot or cold temperatures can activate the sensors of hot and cold temperatures in the body," Grandl said.

Previous research has identified transient receptor potential (TRP) ion channels as being highly sensitive to either cold or hot temperatures. TRP ion channels are porous proteins that play a role in initiating electrical signals by controlling the flow of charged ions across the cell membrane.

It’s still unclear how temperatures make this happen, but the Grandl team’s research reveals that single-letter changes in DNA, called point mutations, are sufficient to make cold-sensitive TRP ion channels become sensitive to hot temperatures instead.

"There is strong interest in understanding temperature-sensitive molecules from a functional perspective because they are promising targets for developing analgesic compounds to treat chronic pain," said Grandl, who is also a member of the Duke Institute for Brain Sciences. "It is something we currently do not treat well. So, one promising strategy is to stop pain where it is initially sensed — at that first molecule that functions as a sensor of pain."

In a study appearing online early May 8 in the journal Neuron, Grandl’s team focused on TRPA1, an ion channel best known as a sensor for pain caused by environmental irritants and pungent chemicals, such as mustard oil, the active compound found in wasabi.

Grandl’s colleagues, postdoctoral fellow Sairam Jabba and research technician Raman Goyal, investigated whether single-point mutations could change cold-activated mouse TRPA1 into heat-activated. They formed this hypothesis because, in some other animals, including Drosophila fruit-flies and rattlesnakes, TRPA1 is naturally heat-activated.

To identify these structures, the team created a library of 12,000 mutant clones of the cold-activated mouse TRPA1 ion channel and randomly inserted one or two point mutations into each clone. After placing single clones into the individual slots of a 384-well plate and heating it from 25 degrees Celsius to 45 C in a matter of seconds, they were able to measure the thermal sensitivity of each mutant protein.

This screening pinpointed seven clones that showed strong activation when exposed to heat. Gene sequencing of these clones revealed 12 mutations that could potentially be responsible for changing the mouse TRPA1 from cold-activated to heat-activated. Out of these 12 mutations, Jabba and Goyal identified three mutations powerful enough to individually make that switch in TRPA1.

The mutations all turned out to be located within a single small domain of the ion channel protein known as ankyrin repeat six, indicating this domain plays a role in determining cold or heat activation. Ankyrin repeats are often responsible for managing protein-to-protein interactions, but their precise function in TRPA1 had not been previously known.

Interestingly, these single-point mutations didn’t change the ion channels’ responses to chemicals, such as mustard oil.

"This was very surprising and it demonstrates that making a single-point mutation produced a profound change in the temperature sensitivity of the protein, but it did not affect the chemical sensitivity," Grandl said. "It shows these mechanisms are to some degree distinct."

Grandl said that taken together, the findings also suggest that the effectiveness of such a small mutation might have been key to a single ancestral ion channel evolving into the wide diversity of temperature-activated ion channels we see today.

Brrrrrrrrr! It’s Brain Freeze Season

Brain freeze is practically a rite of summer.

It happens when you eat ice cream or gulp something ice cold too quickly. The scientific term is sphenopalatine ganglioneuralgia, but that’s a mouthful. Brain freeze is your body’s way of putting on the brakes, telling you to slow down and take it easy. Wake Forest Baptist Medical Center neuroscientist Dwayne Godwin, Ph.D., explains how it works.

"Brain freeze is really a type of headache that is rapid in onset, but rapidly resolved as well," he said. "Our mouths are highly vascularized, including the tongue - that’s why we take our temperatures there. But drinking a cold beverage fast doesn’t give the mouth time to absorb the cold very well."

Here’s how it happens: When you slurp a really cold drink or eat ice cream too fast you are rapidly changing the temperature in the back of the throat at the juncture of the internal carotoid artery, which feeds blood to the brain, and the anterior cerebral artery, which is where brain tissue starts.

"One thing the brain doesn’t like is for things to change, and brain freeze is a mechanism to prevent you from doing that," Godwin said.

The brain can’t actually feel pain despite its billions of neurons, Godwin said, but the pain associated with brain freeze is sensed by receptors in the outer covering of the brain called the meninges, where the two arteries meet. When the cold hits, it causes a dilation and contraction of these arteries and that’s the sensation that the brain is interpreting as pain.

Analyzing brain freeze may seem like silly science to some, but “it’s helpful in understanding other types of headaches,” Godwin said.

"We can’t easily give people migraines or a cluster headache, but we can easily induce brain freeze without any long-term problems," he said. "We can learn something about headache mechanisms and extend that to our understanding to develop better treatments for patients."

Is there a cure for brain freeze? Yes - stop drinking the icy cold beverage. You can also jam your tongue up to the roof of your mouth because it’s warm or drink something tepid to normalize the temperature in your mouth.

(Image: Erik S. Peterson/ Wikimedia Commons)

Study finds that hot and cold senses interact

A study from the University of North Carolina School of Medicine offers new insights into how the nervous system processes hot and cold temperatures. The research led by neuroscientist Mark J. Zylka, PhD, associate professor of cell biology and physiology, found an interaction between the neural circuits that detect hot and cold stimuli: cold perception is enhanced when nerve circuitry for heat is inactivated.

“This discovery has implications for how we perceive hot and cold temperatures and for why people with certain forms of chronic pain, such as neuropathic pain, or pain arising as  direct consequence of a nervous system injury or disease, experience heightened responses to cold temperatures,” says Zylka, a member of the UNC Neuroscience Center.

The study also has implications for why a promising new class of pain relief drugs known as TRPV1 antagonists (they block a neuron receptor protein) cause many patients to shiver and “feel cold” prior to the onset of hyperthermia, an abnormally elevated body temperature. Enhanced cold followed by hyperthermia is a major side effect that has limited the use of these drugs in patients with chronic pain associated with multiple sclerosis, cancer, and osteoarthritis.

Zylka’s research sheds new light on how the neural circuits that regulate temperature sensation bring about these responses, and could suggest ways of reducing such side-effects associated with TRPV1 antagonists and related drugs.

The research was selected by the journal Neuron as cover story for the April 10, 2013 print edition and was available in the April 4, 2013 advanced online edition.

This new study used cutting edge cell ablation technology to delete the nerve circuit that encodes heat and some forms of itch while preserving the circuitry that sense cold temperatures. This manipulation results in animals  that were practically “blind” to heat, meaning they could no longer detect hot temperatures, Zylka explains. “Just like removing heat from a room makes us feel cold (such as with an air conditioner), removing the circuit that animals use to sense heat made them hypersensitive to cold. Physiological studies indicated that these distinct circuits regulate one another in the spinal cord.”

TRPV1 is a receptor for heat and is found in the primary sensory nerve circuit that Zylka studied. TRPV1 antagonists make patients temporarily blind to heat, which Zylka speculates is analogous to what happened when his lab deleted the animals’ circuit that detects heat: cold hypersensitivity.

Zylka emphasizes that future studies will be needed to confirm that TRPV1 antagonists affect cold responses in a manner similar to what his lab found with nerve circuit deletion.

Research Institute Study Shows How Brain Cells Shape Temperature Preferences

While the wooly musk ox may like it cold, fruit flies definitely do not. They like it hot, or at least warm. In fact, their preferred optimum temperature is very similar to that of humans—76 degrees F.

Scientists have known that a type of brain cell circuit helps regulate a variety of innate and learned behavior in animals, including their temperature preferences. What has been a mystery is whether or not this behavior stems from a specific set of neurons (brain cells) or overlapping sets.

Now, a new study from The Scripps Research Institute (TSRI) shows that a complex set of overlapping neuronal circuits work in concert to drive temperature preferences in the fruit fly Drosophila by affecting a single target, a heavy bundle of neurons within the fly brain known as the mushroom body. These nerve bundles, which get their name from their bulbous shape, play critical roles in learning and memory.

The study, published in the January 30, 2013 edition of the Journal of Neuroscience, shows that dopaminergic circuits—brain cells that synthesize dopamine, a common neurotransmitter—within the mushroom body do not encode a single signal, but rather perform a more complex computation of environmental conditions.

“We found that dopamine neurons process multiple inputs to generate multiple outputs—the same set of nerves process sensory information and reward-avoidance learning,” said TSRI Assistant Professor Seth Tomchik. “This discovery helps lay the groundwork to better understand how information is processed in the brain. A similar set of neurons is involved in behavior preferences in humans—from basic rewards to more complex learning and memory.”

Using imaging techniques that allow scientists to visualize neuron activity in real time, the study illuminated the response of dopaminergic neurons to changes in temperature. The behavioral roles were then examined by silencing various subsets of these neurons. Flies were tested using a temperature gradient plate; the flies moved from one place to another to express their temperature preferences.

As it turns out, genetic silencing of dopaminergic neurons innervating the mushroom body substantially reduces cold avoidance behavior. “If you give the fly a choice, it will pick San Diego weather every time,” Tomchik said, “but if you shut down those nerves, they suddenly don’t mind being in Minnesota.”

The study also showed dopaminergic neurons respond to cooling with sudden a burst of activity at the onset of a drop in temperature, before settling down to a lower steady-state level. This initial burst of dopamine could function to increase neuronal plasticity—the ability to adapt—during periods of environmental change when the organism needs to acquire new associative memories or update previous associations with temperature changes.

(Image: ALAMY)

Yawning may cool brain when needed

Yawning isn’t triggered because you’re bored, tired or need oxygen. Rather, yawning helps regulate the brain’s temperature, according to Gary Hack, of the University of Maryland School of Dentistry, and Andrew Gallup, of Princeton University.

"The brain is exquisitely sensitive to temperature changes and therefore must be protected from overheating," they said in a University of Maryland news release. "Brains, like computers, operate best when they are cool."

During yawning, the walls of the maxillary sinuses (located in the cheeks on each side of the nose) flex like bellows and help with brain cooling, according to the researchers.

They noted that the actual function of sinuses is still the subject of debate, and this theory may help clarify their purpose.

"Very little is understood about them, and little is agreed upon even by those who investigate them. Some scientists believe that they have no function at all," Hack said in the news release.

The researchers said their theory that yawning helps cool the brain has medical implications. For example, excessive yawning often precedes seizures in people with epilepsy and pain in people with migraine headaches.

Doctors may be able to use excessive yawning as a way to identify patients with conditions that affect temperature regulation.

"Excessive yawning appears to be symptomatic of conditions that increase brain and/or core temperature, such as central nervous system damage and sleep deprivation," Gallup said in the news release.