Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.784560
Title: Identification of a novel cold transduction mechanism in peripheral neurons
Author: Buijs, Tamara
ISNI:       0000 0004 7970 1095
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Abstract:
The main aim of this project was to identify the molecular basis of cold transduction in the somatosensory and sympathetic nervous systems. In sensory nerve endings, mechanisms for detecting temperature changes characterised to date depend on Transient Receptor Potential (TRP) ion channels. Temperature changes below 25-30℃ are detected by the menthol-sensitive TRPM8 ion channel, but it remains unclear how lower temperatures are detected. Furthermore, the cold-sensitivity of the mustard-sensitive TRPA1 ion channel is a matter of strong debate. The sympathetic nervous system is also directly cold-sensitive but does not express TRPM8 and only expresses TRPA1 in ~3% of neurons, while cold-sensitivity is observed in ~50% of neurons. Therefore, another cold-sensitive mechanism must be present. To identify this mechanism, we used a ratiometric calcium imaging system to measure the responses of acutely dissociated sensory and sympathetic neurons to cold stimuli in the presence of various ion channel antagonists. Results show that members of the store-operated calcium channel family mediate the observed cold-induced calcium entry. Heterologous overexpression of STIM1/Orai1 revealed that these two proteins are sufficient to induce cold-sensitivity. A second aim of this work was to determine the function of the cold-sensitivity of sympathetic neurons. The sympathetic nervous system is important in regulation of body temperature, and its ability to detect temperature directly may therefore play a role in thermoregulation. To achieve this aim, we used immunohistochemistry to identify expression of proteins associated with neurotransmitter pathways. Results show that nitric oxide synthase is expressed in these neurons. It is possible therefore that sympathetic nerves that innervate blood vessels may release nitric oxide after prolonged cold exposure to cause vasodilation and thus prevent frostbite. The third aim of this work was to develop a method for in vivo calcium imaging of sympathetic ganglia using mice that express genetically encoded calcium indicators to study the temperature sensitivity of sympathetic nerves in vivo. It was found that sympathetic ganglion neurons are spontaneously active and respond to body temperature changes. Overall, this thesis contributes to our understanding of cold transduction mechanisms for the purposes of both conscious temperature sensation and body temperature regulation.
Supervisor: McNaughton, Peter Anthony ; Malcangio, Marzia Anna Maria Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.784560  DOI: Not available
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