A plummeting body temperature usually means an accident. It conjures dire images of people falling into a frozen pond or wandering about in a blizzard. But for some mice—or rather the scientists who study them—a sudden chill recently proved to be a good thing. Neuroscientist Jan Siemens at Heidelberg University in Germany and colleagues engineered mice with deficient thermoregulation systems in order to investigate how the body maintains a particular internal temperature. In each mouse they implanted a molecular switch that allowed them to control its body temperature. By giving the mice a certain drug, the researchers could flip the switch on; it activated a particular set of neurons in the hypothalamus and the mouse’s core temperature plunged about 7 degrees Celsius. “It was quite frightening to see a mouse’s body temperature drop like that,” says Siemens, lead author on the paper published this week in Science. But the fact that he and his co-workers could cause such a dramatic change meant that they had homed in on a central piece of the thermoregulation puzzle. Comparatively little is known about human thermoregulation, which is a crucial aspect of our health. Rises or falls in body temperature often signify serious problems such as systemic infections or inflammation, and drastic changes in temperature can prove fatal. The hypothalamus is widely considered to be an important part of how our bodies maintain a set body temperature but little was known about how much control it exerts or by what mechanisms. Earlier research singled out a subset of cells in the hypothalamus that respond to increases in body temperature. These so-called warm-sensitive neurons lie within a region called the preoptic area and clearly play a key role, Seimens says, but we do not know how other parts of the body’s thermostat are involved. The new research suggests one way that warm-sensitive neurons could monitor and influence body temperature—via a temperature-sensitive protein called TRPM2. The findings make a strong case that it is part of the reason that warm-sensitive neurons respond to their surrounding temperature, explains neuroscientist Shaun Morrison at Oregon Health & Science University, who was not involved in the research. “This is a major discovery in the field of thermoregulation.” Moreover, the ability to control a mouse’s body temperature as Siemens and his team did represents a significant addition to the repertoire of methods available to study thermoregulation and its related systems. “This is really science fiction, and it’s beautiful,” says neuroscientist Andrej Romanovsky of the Barrow Neurological Institute in Phoenix. “It’s really changing our understanding and giving us these fantastic tools.” To control the mouse’s neuronal activity, the researchers used a complex combination of molecular devices. A protein called Cre recombinase allows the expression of a set of protein receptors called DREADDs (for designer receptors exclusively activated by designer drugs), which increase the activity of the neurons in which they are inserted. By inserting this Cre–DREADD system into cells with TRPM2, Siemens and colleagues were able to selectively activate only TRPM2-expressing neurons. They also used another type of DREADD that blocks neuronal activity to show that turning off TRPM2-containing neurons causes body temperature to rise. Thermoregulation has proved difficult to study—in part because the system behind it is ill-defined, with many different parts that interact within the body, Romanovsky explains. He and many other researchers believe that thermoregulation does not occur via one centralized system but rather “works as a federation of control systems.” Siemens and colleagues have not yet suggested a mechanism to explain how TRPM2 trips the loss of body heat in mice. Morrison notes that this will be a key step in elucidating the role TRPM2 plays in thermoregulation. Scientists will also have to validate the findings in other animals before they can begin to determine whether the protein functions in a similar way in humans, Morrison adds. There are many examples of thermoregulation mechanisms that exist in mice but not rats. Because Siemens and his colleagues observed that TRPM2 was activated only at high body temperatures, they suspect that it may serve as a kind of emergency brake to stop fevers from rising too high. But that physiology has yet to be fully fleshed out, and Romanovsky expressed some skepticism that the reported data fully support such a role. If it does turn out to be true, however, Morrison notes it would be interesting to see whether uncontrollable fevers might be driven in part by changes in TRPM2 function. The technology used here to change body temperature on command could ultimately help scientists studying and treating human diseases. Regulating body temperature is closely tied to metabolism, which means these new findings could have implications for controlling body weight and increasing longevity, according to Morrison. Siemens says he is particularly excited about the possibility of cooling the human body for therapeutic purposes. For example, lowering a patient’s body temperature can mitigate tissue damage from heart attacks. Doctors currently use cold liquids, ice baths and specific drugs to prevent the nervous system from its desperate attempt to restore the body’s core temperature. But using molecular tools would effectively set a patient’s internal thermostat a little lower, convincing his or her body that it didn’t need to fight the change. It is still far too early to know how this technology could be applied to humans, but the tools are immediately useful in mouse models of thermoregulation and other physiology. “Thermoregulation has been uncharted territory for many decades,” Siemens says. “This is the tip of the iceberg.”
Neuroscientist Jan Siemens at Heidelberg University in Germany and colleagues engineered mice with deficient thermoregulation systems in order to investigate how the body maintains a particular internal temperature. In each mouse they implanted a molecular switch that allowed them to control its body temperature. By giving the mice a certain drug, the researchers could flip the switch on; it activated a particular set of neurons in the hypothalamus and the mouse’s core temperature plunged about 7 degrees Celsius.
“It was quite frightening to see a mouse’s body temperature drop like that,” says Siemens, lead author on the paper published this week in Science. But the fact that he and his co-workers could cause such a dramatic change meant that they had homed in on a central piece of the thermoregulation puzzle. Comparatively little is known about human thermoregulation, which is a crucial aspect of our health. Rises or falls in body temperature often signify serious problems such as systemic infections or inflammation, and drastic changes in temperature can prove fatal.
The hypothalamus is widely considered to be an important part of how our bodies maintain a set body temperature but little was known about how much control it exerts or by what mechanisms. Earlier research singled out a subset of cells in the hypothalamus that respond to increases in body temperature. These so-called warm-sensitive neurons lie within a region called the preoptic area and clearly play a key role, Seimens says, but we do not know how other parts of the body’s thermostat are involved.
The new research suggests one way that warm-sensitive neurons could monitor and influence body temperature—via a temperature-sensitive protein called TRPM2. The findings make a strong case that it is part of the reason that warm-sensitive neurons respond to their surrounding temperature, explains neuroscientist Shaun Morrison at Oregon Health & Science University, who was not involved in the research. “This is a major discovery in the field of thermoregulation.”
Moreover, the ability to control a mouse’s body temperature as Siemens and his team did represents a significant addition to the repertoire of methods available to study thermoregulation and its related systems. “This is really science fiction, and it’s beautiful,” says neuroscientist Andrej Romanovsky of the Barrow Neurological Institute in Phoenix. “It’s really changing our understanding and giving us these fantastic tools.”
To control the mouse’s neuronal activity, the researchers used a complex combination of molecular devices. A protein called Cre recombinase allows the expression of a set of protein receptors called DREADDs (for designer receptors exclusively activated by designer drugs), which increase the activity of the neurons in which they are inserted. By inserting this Cre–DREADD system into cells with TRPM2, Siemens and colleagues were able to selectively activate only TRPM2-expressing neurons. They also used another type of DREADD that blocks neuronal activity to show that turning off TRPM2-containing neurons causes body temperature to rise.
Thermoregulation has proved difficult to study—in part because the system behind it is ill-defined, with many different parts that interact within the body, Romanovsky explains. He and many other researchers believe that thermoregulation does not occur via one centralized system but rather “works as a federation of control systems.”
Siemens and colleagues have not yet suggested a mechanism to explain how TRPM2 trips the loss of body heat in mice. Morrison notes that this will be a key step in elucidating the role TRPM2 plays in thermoregulation. Scientists will also have to validate the findings in other animals before they can begin to determine whether the protein functions in a similar way in humans, Morrison adds. There are many examples of thermoregulation mechanisms that exist in mice but not rats.
Because Siemens and his colleagues observed that TRPM2 was activated only at high body temperatures, they suspect that it may serve as a kind of emergency brake to stop fevers from rising too high. But that physiology has yet to be fully fleshed out, and Romanovsky expressed some skepticism that the reported data fully support such a role. If it does turn out to be true, however, Morrison notes it would be interesting to see whether uncontrollable fevers might be driven in part by changes in TRPM2 function.
The technology used here to change body temperature on command could ultimately help scientists studying and treating human diseases. Regulating body temperature is closely tied to metabolism, which means these new findings could have implications for controlling body weight and increasing longevity, according to Morrison.
Siemens says he is particularly excited about the possibility of cooling the human body for therapeutic purposes. For example, lowering a patient’s body temperature can mitigate tissue damage from heart attacks. Doctors currently use cold liquids, ice baths and specific drugs to prevent the nervous system from its desperate attempt to restore the body’s core temperature. But using molecular tools would effectively set a patient’s internal thermostat a little lower, convincing his or her body that it didn’t need to fight the change.
It is still far too early to know how this technology could be applied to humans, but the tools are immediately useful in mouse models of thermoregulation and other physiology. “Thermoregulation has been uncharted territory for many decades,” Siemens says. “This is the tip of the iceberg.”
