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 -2C. This remarkable ability contributes to their unusual resistance to cold during hibernation, when the animals drop their core body temperature to 2-4C. 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.

Public Health Relevance

Molecular mechanisms that contribute to the modulation of temperature sensitivity under acute, pathological, or adaptive conditions remain to be fully elucidated. The objective of this proposal is to use mammalian hibernation as a model for analyzing adaptive regulatory mechanisms that underlie temperature perception. Insights gleaned from these studies could have profound outcomes for human health in regard to treatment of nerve injury-induced neuropathic pain, cold allodynia and development of novel analgesic therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS091300-06
Application #
10238591
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Mohapatra, Durga Prasanna
Project Start
2015-09-15
Project End
2021-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Yale University
Department
Physiology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Hoffstaetter, Lydia J; Mastrotto, Marco; Merriman, Dana K et al. (2018) Somatosensory Neurons Enter a State of Altered Excitability during Hibernation. Curr Biol 28:2998-3004.e3
Anderson, Evan O; Schneider, Eve R; Matson, Jon D et al. (2018) TMEM150C/Tentonin3 Is a Regulator of Mechano-gated Ion Channels. Cell Rep 23:701-708
Hoffstaetter, Lydia J; Bagriantsev, Sviatoslav N; Gracheva, Elena O (2018) TRPs et al.: a molecular toolkit for thermosensory adaptations. Pflugers Arch 470:745-759
Schneider, Eve R; Anderson, Evan O; Mastrotto, Marco et al. (2017) Molecular basis of tactile specialization in the duck bill. Proc Natl Acad Sci U S A 114:13036-13041
Matos-Cruz, Vanessa; Schneider, Eve R; Mastrotto, Marco et al. (2017) Molecular Prerequisites for Diminished Cold Sensitivity in Ground Squirrels and Hamsters. Cell Rep 21:3329-3337
Laursen, Willem J; Schneider, Eve R; Merriman, Dana K et al. (2016) Low-cost functional plasticity of TRPV1 supports heat tolerance in squirrels and camels. Proc Natl Acad Sci U S A 113:11342-11347
Schneider, Eve R; Gracheva, Elena O; Bagriantsev, Slav N (2016) Evolutionary Specialization of Tactile Perception in Vertebrates. Physiology (Bethesda) 31:193-200