Chilling time with synthetic torpor

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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.