Discover how groundbreaking research has solved one of sensory biology's most stubborn mysteries
Imagine stepping from a sweltering summer day into an air-conditioned room. That wave of relief isn't just psychological—it's the result of an intricate neural circuitry in your body that detects and responds to cool temperatures. For decades, neuroscientists have understood a great deal about how we sense heat, but the biological mechanisms behind our perception of persistent cold remained one of sensory biology's most stubborn mysteries. While researchers had identified proteins that sense hot, warm, and even cool temperatures over 20 years ago, the sensor for temperatures below about 60 degrees Fahrenheit had eluded confirmation until very recently 5 .
The sensor for temperatures below 60°F remained unidentified for decades despite advances in understanding heat detection.
This gap affected real patients, including cancer patients undergoing chemotherapy who experience painful reactions to cold 5 .
Before delving into the cold sensation breakthrough, it's helpful to understand some basics of how sensory systems work. Our sensory neurons are specialized cells that detect specific types of stimuli—like light, sound, or temperature—and convert them into electrical signals that travel to the brain. For temperature sensing, this process begins with protein receptors on sensory neurons that act as molecular thermometers, changing their shape when temperatures shift 9 .
These temperature sensors are tuned to specific ranges, much like different strings on a piano produce different notes. Some receptors respond to painfully hot temperatures, others to pleasant warmth, and still others to cool and cold temperatures. This specialization allows our nervous system to distinguish between the refreshing coolness of a breeze and the dangerous cold of freezing temperatures 5 . What makes "absolute cold" particularly interesting is that it requires detecting persistent cold temperatures rather than just temperature changes—a crucial ability for animals preparing for seasonal shifts 1 .
| Temperature Range | Sensor Type | Biological Role |
|---|---|---|
| Extreme heat (>45°C) | TRPV1 | Detects painful, dangerous heat |
| Warmth (30-45°C) | TRPV3/TRPV4 | Detects pleasant warmth |
| Cool (25-30°C) | TRPM8 | Detects mild cooling |
| Cold (<25°C) | GluK2 | Detects sustained cold |
In 2020, a landmark study in fruit flies (Drosophila melanogaster) provided the first complete map of a neural pathway dedicated to sensing absolute cold 1 4 . Why study temperature sensing in fruit flies? These tiny insects are especially sensitive to persistent cold due to their small body size and status as ectotherms (cold-blooded animals), making them ideal subjects for understanding how organisms detect seasonal cold to survive winter conditions 1 .
Thermosensory receptor neurons (TRNs) in the antenna detect persistent cold
TPN-II neurons relay signals without adaptation
DN1a neurons translate cold signals into sleep regulation
| Circuit Component | Location | Function |
|---|---|---|
| Sacculus TRNs | Antenna | Detect persistent cold temperatures |
| TPN-II neurons | Posterior antennal lobe | Relay and amplify cold signals without adaptation |
| DN1a neurons | Brain circadian network | Translate cold signals into sleep regulation |
The implications of this circuit are fascinating—it directly links temperature sensing with sleep regulation. When researchers exposed flies to cold temperatures, they observed increased morning sleep and restructuring of afternoon and evening sleep patterns.
This circuit also integrates with other sensory information. DN1a neurons can be activated by light through input from other neurons, allowing light to compensate for cold inhibition. This explains why flies (and perhaps humans) can still wake up with morning light even in colder temperatures 1 .
While the fruit fly research revealed how cold information is processed in a neural circuit, the fundamental question remained: what is the actual molecular sensor that detects cold in mammals? This mystery was solved in March 2024 when University of Michigan researchers identified the GluK2 protein as the long-sought cold sensor in mammals 5 .
The research team, led by neuroscientist Shawn Xu, started with an unexpected subject: Caenorhabditis elegans, a species of millimeter-long worms. In 2019, they discovered a cold-sensing receptor protein in these worms.
Because the gene encoding this protein is evolutionarily conserved across species, including mice and humans, it provided a starting point for identifying the mammalian counterpart: GluK2 (Glutamate ionotropic receptor kainate type subunit 2) 5 .
To confirm GluK2's role, researchers tested mice that were genetically engineered to lack the GluK2 gene. Through a series of experiments measuring behavioral responses to temperature and other stimuli, they found that these mice responded normally to hot, warm, and cool temperatures—but showed no response to noxious cold 5 .
What makes this discovery particularly intriguing is GluK2's dual role. It's primarily found in the brain, where it receives chemical signals to facilitate communication between neurons. But it's also expressed in sensory neurons in the peripheral nervous system, where it processes temperature cues instead of chemical signals 5 .
"This discovery of GluK2 as a cold sensor in mammals opens new paths to better understand why humans experience painful reactions to cold, and even perhaps offers a potential therapeutic target for treating that pain in patients whose cold sensation is overstimulated," says Shawn Xu 5 .
Beyond immediate sensation, research reveals that our brains form memories of cold experiences that influence future metabolic responses. In a fascinating study led by Prof. Tomás Ryan from Trinity College Dublin, scientists discovered that mice form lasting memories of cold that alter their metabolism 7 .
Researchers trained mice to associate visual cues with cold environments of 4°C. After several days, when presented with the same visual cues at room temperature, the mice would increase their metabolism in anticipation of cold—a phenomenon called predictive thermogenesis.
This response was driven by specific memory-encoding neurons, or "engrams," in the hippocampus. When these cold engram cells were artificially stimulated, mice increased their metabolism to generate heat even without actual cold exposure 7 .
Conversely, when these engrams were inhibited, mice could no longer express cold memories in response to the conditioned visual cues. This shows that the brain doesn't just sense temperature—it stores thermal experiences and uses them to prepare for future conditions 7 .
Understanding cold sensation requires sophisticated tools and methods. Here are some key approaches mentioned in the research:
| Tool/Method | Function | Application in Cold Research |
|---|---|---|
| Genetic engineering | Creates organisms lacking specific genes | Testing mice without GluK2 gene to confirm its role 5 |
| Dipole analysis (EEG) | Locates sources of electrical signals in the brain | Identifying brain regions activated by temperature stimuli 2 |
| Event-related spectral perturbation (ERSP) | Measures power changes in brain frequency bands | Distinguishing hot vs. cold processing patterns 2 |
| Optogenetics | Uses light to control specific neurons | Artificially activating cold engram cells 7 |
| Functional MRI | Detects brain activity through blood flow | Locating regions activated by temperature experiences 2 |
| Calcium imaging | Visualizes neural activity in real time | Observing cold responses in sensory neurons 1 |
Enable precise manipulation of specific genes to understand their function
Allow visualization of neural activity in response to temperature stimuli
Enable controlled activation of specific neurons to test their functions
The discovery of cold-sensing mechanisms has significant practical implications. As Dr. Hironori Watanabe notes, "The practical applications include the development of automatic climate control systems that balance energy efficiency and comfort, as well as more accurate methods for evaluating comfort in clothing design" 2 .
In medicine, understanding cold sensation could lead to new treatments for conditions where temperature processing goes awry. "This discovery of GluK2 as a cold sensor in mammals opens new paths to better understand why humans experience painful reactions to cold, and even perhaps offers a potential therapeutic target for treating that pain in patients whose cold sensation is overstimulated," says Shawn Xu 5 .
This is particularly relevant for cancer patients receiving chemotherapy, who often experience painful reactions to cold 5 .
Future research will likely explore how the brain processes these various skin signals and how we've evolved not only to differentiate between them, but also connect emotions with them for self-protection 9 .
As Bo Duan wonders, "In summer, I love walking along Lake Michigan and having a gentle breeze hit my face. I feel very cool, very comfortable. But the winter is really terrible for me" 9 . This intersection of sensory biology and subjective experience remains a rich area for exploration.
The journey to understand cold sensation—from the initial detection by GluK2 proteins in the skin, through the amplified signal in the spinal cord, to the processing in brain regions that connect temperature with memory and behavior—reveals the remarkable complexity of our sensory systems. This multi-level understanding transforms something as simple as feeling cool air on a summer day into a masterpiece of biological engineering.
These discoveries remind us that our everyday sensory experiences, which we often take for granted, are the result of exquisitely evolved mechanisms that enable us to navigate and survive in a changing world. The next time you feel a refreshing cool breeze or bundle up against winter's chill, remember the sophisticated neural circuitry working behind the scenes to make those experiences possible—circuitry that we're only now beginning to understand.