Heat Stroke

Temperature-Regulating Neurons Identified, Hint at Treatment Strategies for Heat Stroke, Obesity

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The results of a study in rodents carried out by scientists at Nagoya University suggest that a group of neurons, called EP3 neurons, in the preoptic area (POA) of the brain play a key role in regulating body temperature in mammals. The discovery could pave the way for the development of technology that artificially adjusts body temperature, as a way of helping to treat conditions such as heat stroke, or hypothermia, and potentially obesity.

“On top of that, this technology could lead to new strategies for survival of people in hotter global environments, which are becoming a serious worldwide problem,” said research lead Kazuhiro Nakamura, PhD. The scientists reported on their study in Science Advances, in a paper titled, “Prostaglandin EP3 receptor–expressing preoptic neurons bidirectionally control body temperature via tonic GABAergic signaling.”

Thermoregulation is a physiological function that is fundamental to homeostasis in mammals, the authors noted. “Body core temperature is maintained within a control range by autonomous regulation of the balance between heat production within the body and heat loss to the environment.” In humans and many other mammals, body temperature is regulated at around 37°C (98.6°F), which optimizes all regulatory functions. But when body temperature noticeably deviates from the normal range, these functions can be impaired, potentially leading to heat stroke, hypothermia, and, in the worst case, death. These conditions might possibly be treated if body temperature could be artificially adjusted to remain within the normal range.

The brain’s temperature regulation center resides in the preoptic area, a part of the hypothalamus that controls the body’s vital functions. For example, when the preoptic area receives signals from a mediator called prostaglandin E (PGE2) that is produced in response to infections, this area releases a command to raise body temperature to fight against viruses, bacteria, and other disease-causing organisms. “The POA receives and integrates thermosensory (cool- and warm-sensory) neural signals from skin thermoreceptors and a pyrogenic humoral signal mediated by prostaglandin E2 (PGE2), which is produced in response to infections,” the team noted.

However, it is still unclear exactly which neurons in the preoptic area release commands to increase or decrease body temperature. To identify such neurons, Nakamura, together with Yoshiko Nakamura, PhD, and colleagues at Nagoya University, in collaboration with Hiroyuki Hioki, PhD, at Juntendo University, designed a study in rodents. They focused on how EP3 neurons in the preoptic area that express the EP3 subtype of PGE2 receptor may be involved in regulating body temperature. “… we investigated the physiological role of POAEP3R neurons in the central circuit mechanisms of thermoregulation and fever,” the team explained.

Nakamura and colleagues started by looking at how the activity of EP3 neurons in the preoptic area varied in response to changes in ambient temperature. “We first examined activation of POAEP3R neurons in response to ambient thermal challenges and then histochemically and physiologically determined the neurotransmitter phenotype of POAEP3R neurons,” they noted. A comfortable environmental temperature for rats is around 28°C. For two hours, the researchers exposed the rats to cold (4°C), room (24°C), and hot (36°C) temperatures. Results showed that exposure to 36°C activated EP3 neurons, while exposure to 4°C and 24°C did not. “These observations indicate that the POAEP3R neuronal group includes a substantial subpopulation of warming-activated neurons but not cooling-activated neurons,” the investigators suggested.

The group then observed nerve fibers of EP3 neurons in the preoptic area to identify where the signals from EP3 neurons are transmitted. Their observations revealed that nerve fibers are distributed to various brain regions, particularly to the dorsomedial hypothalamus (DMH), which activates the sympathetic nervous system. Their analysis also showed that the substance that EP3 neurons use for signal transmission to DMH is gamma-aminobutyric acid (GABA), a major inhibitor of neuronal excitation. “Although many POAEP3R neuronal cell bodies express a glutamatergic messenger RNA marker, their axons in the DMH predominantly release γ-aminobutyric acid (GABA), and their GABAergic terminals are increased by chronic heat exposure,” they stated. The combined results, the team further wrote, “… demonstrate that POAEP3R neuron–derived axons predominantly form GABAergic synapses onto DMH neurons.”

To further investigate the role of EP3 neurons in temperature regulation, researchers artificially manipulated their activity using a chemogenetic approach. They found that activating the neurons led to a decrease in body temperature, whereas suppressing their activity led to their increase. “Chemogenetic stimulation of POAEP3R neurons at room temperature reduces body temperature by enhancing heat dissipation, whereas inhibition of them elicits hyperthermia involving brown fat thermogenesis, mimicking fever,” they noted.

Rodent experiments to investigate neuronal control of body temperature
In hot environments, EP3 neurons in the preoptic area continually send inhibitory signals with GABA to suppress sympathetic outflows to defend body temperature from ambient heat. In cold environments or during infections, EP3 neurons are inhibited and therefore, sympathetic pathways are activated to increase heat production and inhibit heat loss to prevent hypothermia or to develop fever. The activity level of EP3 neurons is a critical determinant of body temperature. [© 2022 Yoshiko Nakamura]

The combined study results demonstrated that EP3 neurons in the preoptic area play a key role in regulating body temperature by releasing GABA to send inhibitory signals to DMH neurons to control sympathetic responses. “The present study demonstrates that POAEP3R neurons, a target of PGE2 for its pyrogenic action, play a pivotal role in the preoptic efferent control of central sympathetic outflow for basal thermoregulation,” the team wrote. “Our study shows strong evidence that POAEP3R neurons provide tonic GABAergic inhibitory signaling to sympathoexcitatory efferent pathways as a fundamental determinant of body temperature for thermal homeostasis and fever.”

Lead author Nakamura further suggested, “Probably, EP3 neurons in the preoptic area can precisely regulate the signal strength to fine-tune body temperature. For example, in a hot environment, signals are augmented to suppress sympathetic outputs, resulting in increased blood flow in the skin to facilitate the radiation of the body’s heat to prevent heat stroke. However, in a cold environment, signals are reduced to activate sympathetic outputs, which promote heat production in brown adipose tissue and other organs to prevent hypothermia. Furthermore, at the time of infection, PGE2 acts on EP3 neurons to suppress their activity, resulting in activation of sympathetic outputs to develop fever.”

This study’s findings could pave the way for the development of a technology that artificially adjusts body temperature, which might then be applied to a wide range of medical fields. Interestingly, this technology may also be helpful in the treatment of obesity, by keeping body temperature slightly higher than normal to promote fat burning.

“On top of that, this technology could lead to new strategies for survival of people in hotter global environments, which are becoming a serious worldwide problem,” said Nakamura.

Hospital admissions for heat stroke declining in the U.S.

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Heat waves are becoming more common, but the number of hospital admissions for heat stroke has declined significantly in the United States in recent years, according to a new study from Harvard T.H. Chan School of Public Health published in the journal Environmental Health. In one of the largest studies of its kind, researchers examined data from more than 23 million Medicare beneficiaries in 1,916 U.S. counties between 1999-2010.

Heat stroke is a serious and life-threatening illness that often occurs when patients have a core body temperature over 104 degrees Fahrenheit. In the study, researchers calculated the relative risk of heat stroke among older adults during heat wave days (defined as at least two consecutive days with daily mean temperature greater than the 97th percentile of temperatures in that county) compared to non-heat wave days.

Researchers found that over time, the risk of heat stroke declined, with notable geographic differences. The risk was highest in the Northeast, while it was lower in the South and Southwest. They also found that heat waves early in the summer were more likely to result in heat stroke admissions than those later in the season.

According to Francesca Dominici, professor of biostatistics and senior associate dean for information technology at Harvard Chan School, and senior author of the study, there could be several reasons for the decline, including greater awareness of the risk of heat stroke, expanded use of air conditioning, and the potential that climate change is making people acclimate more easily to higher temperatures.

Despite the decline in heat stroke admissions, Dominici says the increasing frequency of heat waves underscores the importance of public health messaging urging people to seek cool places during hot temperatures.

“I think there is the need to—especially for the elderly population, for physicians and the public to be more aware that heatwaves are coming, are going to come more often, and whenever they happen, they should be indoors,” said Dominici.

Cold Packs on Extremities Aid in Heat Stroke

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Symptoms of heat stroke may be eased by applying cold packs to the cheeks, hands and feet, a study suggests, potentially offering a new way to help lower body temperatures in overheated athletes.

“The cheeks, palms, and soles of the feet are special areas,” with blood vessels that don’t contract when cold packs are applied, helping to remove heat from the skin surface and cool body temperatures, said study co-author Dr. Grant Lipman, a researcher in emergency medicine at Stanford University in California.

Lipman and colleagues tested a new method for applying cold packs to overheated athletes to see if their alternative might be more effective than the traditional placement of cold packs on the skin over large blood vessels in the neck, groin and armpits.

They dressed ten healthy men in insulated military clothes designed to trap body heat, then asked the men to walk on a treadmill for 30 to 40 minutes in a room heated to about 40 C (104 F).

Each man did the treadmill test three times, with at least one day between trials to allow for rest and recovery. First, they finished with no treatment to help lower their body temperature. Then they got cold packs the traditional way, applied at the neck, groin and armpits. Last, they received cold packs using the new method, placed on the cheeks, hands and feet.

The average body temperature after the treadmill test was 39.2 C (102.6 F), the authors report in an article online now in the journal Wilderness and Environmental Medicine.

Without any treatment, the men cooled by an average of 0.3 degrees Celsius after five minutes and by a total of 0.42 degrees (to 101.8 F) after 10 minutes.

Ice packs on the usual spots cooled the men by an average of 0.4 degrees after five minutes and 0.57 degrees after 10 minutes (to 101.5 F). With ice packs on the hands, feet and cheeks, the decline in body temperature was steeper: 0.6 degrees after five minutes and 0.9 degrees after 10 minutes (to 100.9 F).

One limitation of the study is related to ethics — the researchers couldn’t induce heat stroke so they instead tested the new cooling method by giving the men hyperthermia (heat exhaustion), which isn’t as dangerous and is easier to reverse.

The experiments also relied on young, healthy volunteers, even though the majority of heat stroke deaths occur in the elderly.

Even so, the findings suggest that the new method could be used to help cool down overheated athletes, particularly as a treatment started in the field and continued by paramedics on the way to the hospital, Lipman said by email.

Because the temperature-lowering effect was only about one degree after 30 minutes, though, the cold packs regardless of placement may not work fast enough help a heat stroke victim, said Dr. Edward Otten, a professor of emergency medicine at the University of Cincinnati. “That would be too slow and too little to make a difference.”

The new placement method for cold packs might be useful for less severe heat illness, and work well at rehab stations for firefighters or soldiers, or for cooling tents at marathons and other athletic events, said Otten, who wasn’t involved in the study.

“Intuitively it makes sense to place cold packs on large blood vessels because most of the blood volume is going through them,” Otten said in an email. “However, microcirculation in the palms, soles and cheeks is such that heat transfer works more efficiently through them.”