Targeting torpor circuits across species: towards translation

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 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, or illness. Torpid animals actively and profoundly decrease their oxygen consumption (by up to 90%) and body 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 is of interest both for clinical applications and for possible long-distance space travel in the future. Recently significant progress has been made so that are beginning to identify the key regions of the brain that trigger torpor in mice. We and others have independently converged on the same region of the hypothalamus, in an area that is known to be involved in temperature regulation. We know that this region of the brain is active during torpor, and using genetic strategies to express engineered receptors, or light sensitive proteins, in this region allows us to switch the neurons on and observe how this affects the behaviour of mice. When we switch this part of the mouse brain on, we see a drop in temperature and other groups have observed reduced heart rate, but we do not know whether this region alone controls all aspects of torpor.

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. Indeed, we have recently found that activating the corresponding region of the rat brain makes the rat cool down, reduce its oxygen consumption, and slows down the heart. These are cardinal features of torpor, and this finding is striking because rats do not naturally enter torpor. Hence, we have activated a synthetic torpor-like state in a species for which it is not a natural behaviour.

The project will develop on this work. We will explore in more detail the brain circuits responsible for triggering torpor in the mouse. We are keen to know exactly what type of neuron is responsible, and where they send their signals to generate all the changes that we see in torpor. We will also compare the characteristics of torpor in the mouse with the synthetic torpor state we have generated in the rat in order to understand the degree of similarity. We will also explore in more detail the circuits within the brain that generate synthetic torpor in the rat, comparing them with the mouse, and identifying what is their normal role in the rat. Finally, we will test whether the synthetic torpor state in the rat is protective in a model of acute lung injury. During acute lung injury there is a reduction in the ability of the lungs to absorb oxygen. We already know that oxygen consumption in the rat is reduced by approximately 40% during synthetic torpor. Hence, synthetic torpor might allow the rat to better tolerate impaired lung function, as less oxygen is required by the body.

This project will further our understanding of the neural control of torpor, begin to explore the translational potential of synthetic torpor, and provide proof of concept evidence for whether reducing the metabolic demand in intensive care patients might allow them to better tolerate illness and protect against organ damage.

Technical Summary

We are interested in torpor as a model of resilience that might be mimicked in an ICU setting. Several lines of evidence recently identified neurons in the preoptic area (POA) of the mouse hypothalamus that are active during torpor, and whose reactivation induces hypothermia and inactivity. This evidence suggests a role for a glutamatergic Adcyap1-expressing projection from the POA to the dorsomedial hypothalamus (DMH).

It is not clear whether POA-Adcyap1 neurons generate all the physiological adaptations associated with torpor. We will address this question in mice using a genetic activity dependent TRAP2 strategy to express DREADDs or opsins in POA neurons that are active during torpor (i.e., TRAPed). We will assess in vivo and in the working heart brainstem preparation whether this POA ensemble generates a typical profile of cardiorespiratory, thermal, and metabolic depression. We will compare activating all POA neurons that were TRAPed during torpor with the effects of activating a specific subset of POA Adcyap1-expressing neurons using an Adcyap1-Cre mouse line. Both these will be compared with natural torpor in wild type mice.

Rats do not enter torpor, however chemo-activating excitatory neurons in the POA of the rat induces a hypothermic state with reduced oxygen consumption and bradycardia ('synthetic torpor'). We will investigate the degree to which synthetic torpor in the rat recapitulates natural torpor in the mouse, whether synthetic torpor is driven by a glutamatergic projection from the POA to the DMH, and explore the natural drivers for this population of neurons in the rat.

We will test whether synthetic torpor is protective in a lung-injury model in the rat, with a 2x2 factorial design with measures of physiological parameters (e.g. SpO2, respiratory rate), lung histology/weights, inflammatory markers, and lactate.

This work will inform the approach to be taken towards developing synthetic torpor as a possible therapeutic strategy.


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