Molecular and Cellular Mechanisms of Cold Signalling in Somatosensory Neurons

Secondary Supervisor(s): Professor Mark Wall

University of Registration: University of Warwick

BBSRC Research Themes: Understanding the Rules of Life (Neuroscience and Behaviour)

Project Outline

Temperature influences almost every aspect of life in animals posing a huge impact on their quality of life. It is thus not surprising that detection of ambient temperature is one of the most fundamental aspects of physiology across the animal kingdom. Animals and humans critically rely on temperature sensing to select preferred environments and maintain body temperature while avoiding extreme hot/cold temperatures that cause tissue damage.

Temperature sensing is initiated by the activation of temperature receptors on sensory nerve endings where temperature information is transformed into nerve signals, which are then relayed to the spinal cord and brain, leading to the perception of different temperature modalities.

We aim to understand how warm and cold temperatures are differently encoded and represented in sensory and spinal cord neurons and what receptors and molecules are responsible for the coding of warm and cold temperatures. We will record and characterise nerve firing in response to different temperatures in sensory neurons and spinal cord neurons using electrophysiology and Ca²⁺ imaging. Temperature-responding neurons will then be categorised based on their responding profiles to temperatures and pharmacological agonists/antagonists. To determine the receptors responsible for temperature-evoked neuronal firing, we will use combined genetic and pharmacological approaches to investigate the effects of genetic deletion or pharmacological blockade of temperature receptors such as heat-activated TRPV1 and cold-activated TRPM8 channels on temperature-induced firing activities. Through these experiments, we aim to gain new understanding of unknown temperature receptors and transducers involved in temperature coding. To determine behavioural consequences, we will next examine the effect of different temperature receptors and transducers on temperature sensing using a novel temperature sensing rescue-assay developed in our lab.

Overall, our ambition is to gain novel and comprehensive understanding of the mechanisms of temperature sensing and coding through these molecular, cellular and behavioural studies. We will use electrophysiology (cell-attached, voltage and current patch-clamp), neuron culture, live cell imaging combined with animal behaviours.

References

1. Zhang, X. Molecular sensors and modulators of thermoreception. Channels (Austin. ) 9, 73-81 (2015).

2. Zhang, X. Direct Galphaq Gating Is the Sole Mechanism for TRPM8 Inhibition Caused by Bradykinin Receptor Activation. Cell Rep 27, 3672-3683.e3674 (2019).

3. Zhang, X., et al. Direct inhibition of the cold-activated TRPM8 ion channel by Galpha(q). Nat. Cell Biol 14, 851-858 (2012).