Chilling time with synthetic torpor

Lead Research Organisation: University of Bristol
Department Name: Physiology and Pharmacology


Torpor can be thought of as a short term hibernation. It is a protective physiological strategy adopted by many different species (including mice) to conserve energy during environmental challenges, such as exposure to low ambient temperature and/or food shortage and/or illness.

Torpid animals actively and profoundly decrease their metabolic rate (by up to 90%) and temperature (to just above ambient temperature). Remarkably, animals emerge uneventfully from this state without incurring harm to themselves or their organ systems. In addition to creating resilience to decreased tissue delivery of oxygen and nutrients, torpor also modulates the immune system, enables tolerance of infection, promotes resistance to radiation and halts tumour growth. Because of these extraordinary characteristics, torpor has been studied for several decades, and even though some progress has been made in its understanding, the complex physiology triggering and regulating this state has been largely unknown.

Since natural torpor is widespread across mammalian species (including some primates), it is reasonable to hypothesize that there are common brain circuits, present in all animals but active only in few of them. This suggests that the same neural circuit might be artificially activated in animals that do not show torpor (like rats or humans), allowing them to be induced to decrease their body temperature below the normal tightly regulated 37 degrees C.

Recent advances have begun to identify the brain circuit responsible for torpor in the mouse hypothalamus in an area that is known to be involved in temperature regulation. Activation of particular neurons in this region can trigger Torpor without the need for an external motivation (like food shortage or cold ambient temperature). These neurons can be selectively targeted using genetic strategies to express engineered receptors for specific drugs or light sensitive proteins allowing 'synthetic torpor' to be switched on in mice at will, allowing us to undertake a detailed analysis of its physiology and neuronal circuit organisation.

Almost all animals have day-night rhythms in their cellular and physiological processes whose synchronised co-ordination by molecular oscillators is important for health. There is evidence in hamsters that hibernation can cause these clocks to pause. It is not clear whether a similar phenomenon happens with torpor in mice - if it does happen then this could lead to de-synchronisation of the brain master clock and the body's local clocks (like happens with jet lag) which would be detrimental to the animal. We will test whether these clocks remain in synchrony during and after torpor (controlling for temperature) and how this is achieved.

We will take a similar circuit dissection approach in rats to see whether we can produce 'synthetic torpor' in a non-hibernator species. This will start to define whether the same regulatory circuits are present in the rat hypothalamus and what prevents them from triggering torpor. In so doing we will learn about regulation and triggering of torpor and further identify whether this remarkable set of cellular and physiological adaptations which serve to protect the organism could one day be used in humans which could have a broad range of applications from space travel to healthcare.

Technical Summary

Torpor is a protective, allostatic mechanism adopted by some mammals to conserve energy during environmental challenges. Torpid animals profoundly reduce their metabolic rate, body temperature, cardiac output, and minute ventilation without harm.

The neural mechanisms controlling torpor are still poorly defined. Recent studies show neurons in the preoptic area (POA) of the mouse hypothalamus are active during torpor, and their reactivation induces a state of hypothermia and inactivity 'synthetic torpor'. It is not known whether these POA neurons generate the full ensemble of physiological adaptations seen with torpor.

We will address this question in mice using a genetic activity dependent TRAP2 strategy to express DREADDs/opsins in the neurons active during torpor and assess in vivo and in the working heart brainstem preparation whether this POA ensemble generates the characteristic profile of cardiorespiratory, thermal and metabolic depression. We will also use a Cre-mouse to determine whether the POA-PACAP neurons are mediating this effect.

True hibernation pauses the circadian clock. It is not known what effect torpor in mice has on these rhythms. We will examine the effect of torpor on the synchronization of peripheral and central circadian clocks using genetic, hormonal and behavioral measures. We will examine the influence of natural and synthetic torpor bouts and control for the effects of temperature.

Rats do not enter torpor, however our pilot data shows activating excitatory neurons in the POA of the rat induces a hypothermic, inactive state like torpor. We will investigate whether this synthetic torpor is driven by activation of a glutamatergic projection from the POA to the DMH and if activating these neurons induces the full spectrum of torpor physiology.

This work will define how the components of torpor are coordinated, determine how torpor influences circadian rhythms and test whether analogous circuits are present in rats.


10 25 50
Description MRC GW4 DTP
Amount £100,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2023 
End 09/2027
Description Collaboration with the University of Bologna 
Organisation University of Bologna
Country Italy 
Sector Academic/University 
PI Contribution We have developed methiods of torpor induction and manipulation of the neural circuits that are novel
Collaborator Contribution They have expertise in the analysis of torpor, circadian and cardiovascular / metabolic physiology and so we are benefitting from their expertise and support. We will make bilateral reserach visits over the coming years.
Impact The collaboration is still developing but the postdoctoral fellow who was originally named on the grant (Timna Hitrec) has been appointed to a lectureship at Bologna and so we anticipate that this will enhance our collaborations and we now have shared publications.
Start Year 2022
Description Interview for national newspaper 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact inteview by jounralist writing a piece on human hibernation for a national newspaper.
Year(s) Of Engagement Activity 2023
Description Participation in an activity, workshop or similar - Bristol Neuroscience festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Regional neuroscience festivval - 3 day festival hosted by the univrsity of bristol showcasing neuroscience resrearch at the university. Visited by primary schools, secondary schools, and the general public. We had a stall withposter and videos of mice entering torpor. Discussed inducing synthetic torpor-like states in species that do not naturally enter torpor.
Year(s) Of Engagement Activity 2023
Description lecture to undergraduate biology society at University of Warwick 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact invited talk about torpor and synthetic torpor-like states at University of Warwick Biology Society
Year(s) Of Engagement Activity 2023