Have We Solved Hibernation? (A Perspective on Recent Advances in Understanding of Hibernation Induction)
Infrared thermal imaging of the surface body temperature of mice from Takahashi et al. 2020
Despite many attempts over the years, the mystery of what sends animals into hibernation - a state of extended hypometabolism - has never been solved. Two research studies may just bring us closer to finally solving (some of) the mystery. These studies were published last week in Nature from different labs - one at Harvard (Hrvatin et al.) and one at the University of Tsukuba in Japan (Takahashi et al.); each claiming to have identified key neurons in the hypothalamus (a part of the brain responsible for many essential body functions such as temperature control, circadian rhythm, appetite control and others) that appear to regulate hibernation or torpor in mice and rats.
avMLPA - region of the hypothalamus (Hrvatin et al. 2020)
These papers approached the problem in different ways. The Harvard group used a clever labeling strategy to identify and genetically tag neurons that are active as mice naturally enter torpor when deprived of food. These neurons are located in the anterior and ventral portions of the medial and lateral preoptic area (avMLPA). The researchers were then able to re-activate these neurons and cause the mice to enter torpor. They next performed single-cell RNA-seq on these populations of neurons that trigger torpor and identified specific genetic signatures, including expression of the genes Adcyap1 and Vglut2.
A few questions naturally arise from the work in this first paper. The first is whether these findings hold true outside of mice. Mice have a different kind of torpor behavior - which only lasts for hours - than true hibernators (like the 13-lined ground squirrel) that spend most of their time in a pre-programmed metabolically depressed state for six to nine months out of the year. Intriguingly, similar to this study, activation of neurons in the ventral part of the medial preoptic area (MPA) has been observed in 13-lined ground squirrels during torpor (ref 1). The MPA is a major thermoregulatory center of the hypothalamus, so it’s possible that the neurons identified in this study are responsible for controlling the drop in body temperature and/or suppression of metabolism in both true hibernators and animals only capable of shallow torpor like mice. This leads into the next question: if these neurons are indeed responsible for some or part of the induction of true hibernation - what is the natural trigger that sets them off? Knowing a genetic signature allows us to start to explore what genes are upstream and what could be the inducing event that triggers this cascade resulting in an animal entering a hibernation-like state.
Expression of QRFP mRNA in different regions of the brain in mice, humans and pigs (human protein atlas).
Meanwhile, the group out of Tsukuba University started out exploring a group of neurons expressing the gene QRFP (“Q-neurons”). They found that activation of QRFP expressing neurons caused a multi-day hibernation-like state (“Q-induced hibernation (QIH)”). Activation of these Q-neurons was accompanied by a new lowered body temperature set-point, which is similar to hibernation, where animals will actively defend body temperature from going any lower than their new set-point (ref2). Similar to the first study, the authors also found that the Q-neurons were located in the MPA, as well as the anteroventral periventricular nucleus (AVPe) Given the proximity, it is likely that Q-neurons are at least talking to, if not partially the same, torpor-inducing neurons identified in the Harvard study. The authors noted that while the Q-neurons were necessary to lower body temperature during natural (fasting-induced) torpor in the mouse, the QRFP gene itself had no effect on regulating torpor, as mice that did not express this gene were still capable of entering torpor. Remarkably, the authors of this second paper extended their findings to rats, a species that does not naturally enter torpor, although the drop in body temperature and metabolic rate was not as pronounced as in mice.
Getting a non-hibernating mammal to enter a torpor-like state is quite a feat - and a naturally burning follow-up question is can we make other non-hibernating mammals, such as humans, enter a hibernation-like state by activating these neurons? Examining datasets from true hibernators, we noted that QFRP does not seem to be expressed in the hypothalamus. Even in the human protein atlas, the expression of QRFP in humans and pigs does not at all resemble that in rodents, with 40% of 121 human hypothalamic samples not even expressing QRFP and the remaining samples expressing levels close to zero. Given that the QRFP gene has no effect on torpor, it could be that these Q-neurons do not express this gene in other mammals, or alternatively, these neurons simply do not exist beyond mice and rats. Clearly, further study is needed.
A defining characteristic of hibernation is the ability to actively suppress metabolic rate in order to conserve energy. In many hibernators, the drop in metabolic rate precedes any drop in body temperature (ref 2). In hibernating bears, metabolic rate actually becomes uncoupled from body temperature, with bears suppressing metabolism while increasing body temperature as they emerge from hibernation in the spring (ref 3). In the second study, while activating the Q-neurons caused metabolic rate to decrease, we noted that this decrease appeared to be tightly coupled to the decrease in body temperature. When extended to rats, metabolic rate only slightly decreased from baseline, yet the drop in body temperature was more pronounced. Thus, while the precise physiological role of the Q-neurons still needs resolving, we could hypothesize that these neurons play a role in lowering the set-point of body temperature but not the initial shut down of metabolic rate that is characteristic of hibernation.
So have we solved the mystery of hibernation? Like most of science, these studies fit a nice piece into a very complex puzzle. By identifying specific neurons that control the thermoregulatory dynamics of torpor, we can begin to tease out the genetic networks and physiological factors that activate these neurons. And this indeed may bring us one step closer to solving the mystery.
Ref 1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2774134/
Ref 2: https://journals.physiology.org/doi/full/10.1152/ajpregu.2000.278.3.R698