Exploiting natural and synthetic torpor for therapeutic hypothermia in humans - A study on central neural control of arousal and pathophysiological and genetic aspects

Torpor is a hypometabolic state characterised by reduced metabolic rate and body temperature, that enables some species to survive harsh environmental conditions. The occurrence, in some species, of a sequence of several long torpor bouts is called hibernation. Torpor expression involves extreme physiological adaptations, such as tolerance to hypoxia and metabolic depression. In particular, the heart of hibernators is a model of resilience to such extreme conditions, maintaining functionality despite prolonged periods of hypothermia and bradycardia. Humans cannot hibernate, but synthetic torpor – a state resembling natural torpor, artificially induced in non-hibernators like rats - offers translational potential for medical applications (ischaemia protection) or space travel. The capacity of a non-hibernator to survive a synthetic torpor procedure suggests shared genetic mechanisms between natural and synthetic torpor, allowing to speculate that hypometabolism may be accessible across species, with even some reports of human survival in extreme hypothermia. This thesis aimed to: (1) assess cardioprotection against ischemia-reperfusion injury in synthetic torpor (rats); (2) identify cardiac gene expression overlaps between animals in hibernation (bears, squirrels) and animals in synthetic torpor (rats); and (3) map neuronal networks driving arousal from torpor (mice). For aim 1, isolated Langendorff hearts from synthetic torpor and euthermic rats underwent a ischemia-reperfusion protocol. Torpid hearts exhibited smaller infarct sizes, indicating cardioprotection. For aim 2, RNAseq analysis revealed nine cardiac genes differentially expressed in both synthetic torpor and natural hibernation compared to euthermia, suggesting shared adaptive pathways. For aim 3, cFos mapping and retrograde tracing from Raphe Pallidus in mice showed that arousal involves coordinated activity in medial preoptic and dorsomedial hypothalamic regions, with sustained brain activity during torpor implying active regulatory control. These findings advance the understanding of torpor's regulatory mechanisms, providing a translational foundation for precision medicine approaches aimed at harnessing torpor-induced adaptations to improve human clinical outcomes.