DESCRIPTION (provided by applicant): Thermosensitivity and thermotolerance are fundamental processes that affect virtually all aspects of human physiology. Human sensation of cold - ranging from refreshingly cool to unpleasant and frigid - relies on the ability of primar sensory afferents to transduce these stimuli into electrical signaling, thereby triggering adaptive biological response. Dysregulation of thermosensation underlie cold allodynia - a common hallmark of chemotherapy-, nerve injury- and post-stroke-induced neuropathic pain, in which even mild cooling can be perceived as excruciatingly painful. Despite significant medical relevance, the molecular aspects of cold sensation under normal, adaptive and pathological conditions, and the sequence of events that underlies this process still remain enigmatic and controversial. Animals that tune temperature sensitivity to the extreme provide ideal model to delineate cellular and molecular aspects of thermotolerance and temperature perception in general. We are using mammalian hibernation as a naturally-reversible model to understand these processes. Unlike the standard laboratory rodents, hibernating animals do not perceive cold temperature as uncomfortable until -2°C. This remarkable ability contributes to their unusual resistance to cold during hibernation, when the animals drop their core body temperature to 2-4°C. In this proposal, we are aiming to examine contribution of TRPM8 and Nav1.8 ion channels into cold adaptations in hibernating squirrels at the level of somatosensory system using multi-disciplinary approach, including physiology, imaging, behavioral paradigms, cell biology, differential transcriptomics, genomics and bioinformatics.