Molecular and Genetic Mechanisms of Abnormal Cold Sensing – Implication for Thermoregulation, Obesity and Pain Research

• Applicant: Professorin Dr. Katharina Zimmermann
• Subject Area: Anaesthesiology ; Anatomy and Physiology ; Molecular Biology and Physiology of Neurons and Glial Cells ; Pharmacology
• Term: from 2013 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 241650140

Cold nociceptors and thermoreceptors in the skin are dedicated to detect cold and noxious cold temperatures. Their function is tightly connected to body temperature homeostasis. Although the molecular specialization of the cold sensitive cutaneous nerve endings has been recognized, with the cold transducer Transient Receptor Potential M8 and A1 channels, we still have little knowledge about more complex physiological functions, for example the genetic and sex-specific mechanisms that lead to cold hypo- and hypersensitivity. Using a large screening study based on a custom-designed thermal gradient assay, we identified, among 25 inbred mouse strains, cold hypo- and cold hypersensitive strains and strains with and without sex difference in comfort temperature selection. Genetic mapping analysis of the strain and sex differences in the cold avoidance trait led us to candidate genes expressed in four different systems that are involved in thermoregulation and metabolism: primary afferents, hypothalamus, muscle and brown adipose tissue. The latter one, due to its critical role in body energy balance regulation, is becoming of increasing interest in obesity research. In addition to basic differences in comfort temperature selection and cold avoidance, mammals react to environmental cold by various means of adjustment leading to extended cold tolerance, improved comfort and decreased energy expenditure. So far, the molecular nature of these cold acclimation mechanism has not been revealed, but our preliminary data show that the TRPC5 receptor could be a promising candidate to mediate cold acclimation that leads, in presence of TRPC5, to improved cold comfort or, without TRPC5, to increased cold avoidance via adjustments of primary afferent cold sensitivity. TRPC5 has also a role in the trigeminal sensory system where our electrophysiological data imply a function as cold transducer in teeth together with TRPM8 and TRPA1. Transgenic mouse lines that lack combinations of the three cold transducers together with a recently developed technique that allows us to record propagated action potentials from tooth pulp nociceptors via mouse alveolar nerve-jaw preparations will provide us insight into how cold transduction works in teeth. Additionally, two new mouse lines with fluorescent TRPA1 and TRPC5 in combination with retrograde labeling from molar teeth will allow us to resolve the overlap of the three cold transducers in normal and inflamed nerves innervating molar teeth and in the trigeminal ganglia. When cold becomes painful, apart from core body temperature preservation, the physiological function is to protect from tissue damage and freeze injury, but in neuropathy or nerve injury, normal cold is perceived as burning pain. Using a genetic mapping approach based on a pharmacological model of cold allodynia, we identified a SNP in the Adra2b receptor as potential heritable factor that controls the severity of cold allodynia which will be validated.

• DFG Programme: Research Grants
• Major Instrumentation: Telemetriesystem, Klimakammer und Aktivitäsmessung (Kombinationsangebot)
• Instrumentation Group: 3850 Lerngeräte, Testgeräte, Konditionierungskammern