Mechanisms of cold sensitivity in mouse vagal and trigeminal ganglion neurons: functional and molecular characterization in healthy and neuropathic conditions

• Autores: Katharina Gers Barlag
• Directores de la Tesis: Félix Viana de la Iglesia (dir. tes.)
• Lectura: En la Universidad Miguel Hernández de Elche ( España ) en 2020
• Idioma: español
• Tribunal Calificador de la Tesis: Rosa María Señaris Rodríguez (presid.), Salvador Sala Pla (secret.), Carolina Laura Roza Fernández de Caleya (voc.)
• Programa de doctorado: Programa Oficial de Doctorado en Neurociencias
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• Resumen

  • The transient receptor potential (TRP) channels TRPM8 and TRPA1 are known to be crucial molecular sensors for cold temperatures. In addition, both channels are activated by a variety of natural and synthetic chemical agents. The channels are expressed in various tissues, including non-overlapping subpopulations of peripheral sensory neurons. In somatosensory neurons, they play important roles for detecting external temperatures and thermoregulatory behaviours. However, visceral sensory neurons, including vagal neurons, have also been found to respond to cold stimuli. These vagal neurons innervate a number of internal organs, where their function as cold sensors may not be as obvious as in somatosensory neurons.

    The first objective of this thesis was to compare the roles of TRPA1 and TRPM8 in the mechanisms of cold sensitivity in vagal and trigeminal ganglion neurons. For this, in vitro calcium imaging was performed on cultured neurons isolated from wild type or genetically modified mice. Cold ramps from 33 to ~11 °C and different combinations of TRP channel agonists and antagonists were applied. I showed that vagal cold responses are mainly mediated via TRPA1 activation, whereas both TRPA1 and TRPM8 contribute to cold sensing in trigeminal ganglion neurons. Using a side-by-side comparison approach, I further showed that vagal TRPA1-expressing neurons are more sensitive to cold and to the selective TRPA1 agonist allyl isothiocyanate (AITC) than their somatosensory trigeminal counterparts.

    Secondly, I investigated the cold sensitivity of airway-innervating vagal neurons. In order to identify these neurons, a retrograde tracer dye was administered to the lower airways of anesthetized mice via intubation. My data showed that cultured airway-specific vagal neurons are more sensitive to cold and TRPA1 agonists than vagal neurons innervating other tissues.

    The last objective of this thesis was to evaluate the functional and molecular changes in cold sensitivity in vagal and trigeminal neurons in a model of neuropathic pain. The chemotherapy agent oxaliplatin causes a peripheral neuropathy in patients with the dose-limiting factor being a hypersensitivity to cold temperatures in extremities as well as facial areas. To establish an experimental model of oxaliplatin-induced peripheral neuropathy, mice received three systemic injections of oxaliplatin. Performing in vitro calcium imaging on isolated neurons, I showed that oxaliplatin treatment increases the number of cold-sensitive neurons in both ganglia by increasing the sensitivity of TRPA1-expressing neurons to cold.

    Altogether, these findings highlight the marked differences in the mechanisms of cold sensitivity between visceral vagal and somatosensory trigeminal ganglion neurons. Furthermore, the results show that systemic oxaliplatin treatment recruits cold-sensitive vagal as well as trigeminal ganglion neurons.