Chemogenetic silencing of sensory neuron populations to uncover their role in touch and pain
<p>The ability of humans to experience touch and pain sensation is critical for our survival. The experience of pain is typically a protective mechanism, and ensures we avoid dangerous environmental cues. However, following incidences of genetic mutations, injury or disease of the somatosensor...
| প্রধান লেখক: | |
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| অন্যান্য লেখক: | |
| বিন্যাস: | গবেষণাপত্র |
| ভাষা: | English |
| প্রকাশিত: |
2020
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| বিষয়গুলি: |
| _version_ | 1826311672087707648 |
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| author | Middleton, SJ |
| author2 | Bennett, D |
| author_facet | Bennett, D Middleton, SJ |
| author_sort | Middleton, SJ |
| collection | OXFORD |
| description | <p>The ability of humans to experience touch and pain sensation is critical for our survival. The experience of pain is typically a protective mechanism, and ensures we avoid dangerous environmental cues. However, following incidences of genetic mutations, injury or disease of the somatosensory nervous system, protective pain can become pathological. Indeed, neuropathic pain affects seven to ten percent of the general population, and our current treatment strategies show poor efficacy and tolerability. </p>
<p>Currently, mechanisms surrounding neuropathic pain involve both peripheral and central sensitisation. However, there is an incomplete understanding of the functional roles of different sensory neuron populations, the sensory modalities they encode, and how they change under neuropathic conditions. Therefore, it is unclear which primary afferent subpopulations contribute to the induction and maintenance of neuropathic pain and which should be therapeutically targeted. This is largely due to the fact that peripheral sensory neurons within dorsal root ganglia (DRG) are highly heterogeneous and are thought to contain up to 17 different subpopulations.</p>
<p>A key aim of this work is to ascribe roles to primary afferent subpopulations in naïve rodents and those that have undergone traumatic nerve injury. Therefore, I have developed a novel chemogenetic toolbox to facilitate selective, reversible and repeatable neuronal silencing of defined sensory neuron populations. I have employed AAV9-GluClv2.0 to broadly silence all DRG neurons and observed functional recovery from neuropathic pain in vivo. Subsequently, I used AAV9-GluCl.Cre<sup>ON</sup> to target two populations of sensory neurons: the Nav1.8 positive (largely nociceptive) population, and the tyrosine hydroxylase positive C-low threshold mechanoreceptor (C-LTMR) population. Silencing each of these populations resulted in population-specific sensory phenotypes, with subtle or no changes in neuropathic mechanical hypersensitivity. Finally, using a molecule to man approach, the role of the voltage-gated sodium channel Nav1.7 was investigated in C-LTMRs and pleasant touch sensation. In humans and mice either genetic or pharmacological disruption of Nav1.7 resulted in deficits in C-LTMR function. This work challenges the current dogma that therapeutically targeting Nav1.7 will only effect the nociceptive system. Together, this work illustrates the need to better understand the roles of different primary afferent subpopulations and provides chemogenetic tools to achieve this. Ultimately, this work will facilitate the development of therapeutics which are better targeted towards the appropriate sensory neuron populations. </p> |
| first_indexed | 2024-03-07T08:14:41Z |
| format | Thesis |
| id | oxford-uuid:cdb2e05f-aad2-4448-b2ad-eab9be84bfd7 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:14:41Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | oxford-uuid:cdb2e05f-aad2-4448-b2ad-eab9be84bfd72023-12-13T12:41:59ZChemogenetic silencing of sensory neuron populations to uncover their role in touch and pain Thesishttp://purl.org/coar/resource_type/c_db06uuid:cdb2e05f-aad2-4448-b2ad-eab9be84bfd7TouchPainEnglishHyrax Deposit2020Middleton, SJBennett, D<p>The ability of humans to experience touch and pain sensation is critical for our survival. The experience of pain is typically a protective mechanism, and ensures we avoid dangerous environmental cues. However, following incidences of genetic mutations, injury or disease of the somatosensory nervous system, protective pain can become pathological. Indeed, neuropathic pain affects seven to ten percent of the general population, and our current treatment strategies show poor efficacy and tolerability. </p> <p>Currently, mechanisms surrounding neuropathic pain involve both peripheral and central sensitisation. However, there is an incomplete understanding of the functional roles of different sensory neuron populations, the sensory modalities they encode, and how they change under neuropathic conditions. Therefore, it is unclear which primary afferent subpopulations contribute to the induction and maintenance of neuropathic pain and which should be therapeutically targeted. This is largely due to the fact that peripheral sensory neurons within dorsal root ganglia (DRG) are highly heterogeneous and are thought to contain up to 17 different subpopulations.</p> <p>A key aim of this work is to ascribe roles to primary afferent subpopulations in naïve rodents and those that have undergone traumatic nerve injury. Therefore, I have developed a novel chemogenetic toolbox to facilitate selective, reversible and repeatable neuronal silencing of defined sensory neuron populations. I have employed AAV9-GluClv2.0 to broadly silence all DRG neurons and observed functional recovery from neuropathic pain in vivo. Subsequently, I used AAV9-GluCl.Cre<sup>ON</sup> to target two populations of sensory neurons: the Nav1.8 positive (largely nociceptive) population, and the tyrosine hydroxylase positive C-low threshold mechanoreceptor (C-LTMR) population. Silencing each of these populations resulted in population-specific sensory phenotypes, with subtle or no changes in neuropathic mechanical hypersensitivity. Finally, using a molecule to man approach, the role of the voltage-gated sodium channel Nav1.7 was investigated in C-LTMRs and pleasant touch sensation. In humans and mice either genetic or pharmacological disruption of Nav1.7 resulted in deficits in C-LTMR function. This work challenges the current dogma that therapeutically targeting Nav1.7 will only effect the nociceptive system. Together, this work illustrates the need to better understand the roles of different primary afferent subpopulations and provides chemogenetic tools to achieve this. Ultimately, this work will facilitate the development of therapeutics which are better targeted towards the appropriate sensory neuron populations. </p> |
| spellingShingle | Touch Pain Middleton, SJ Chemogenetic silencing of sensory neuron populations to uncover their role in touch and pain |
| title | Chemogenetic silencing of sensory neuron populations to uncover their role in touch and pain |
| title_full | Chemogenetic silencing of sensory neuron populations to uncover their role in touch and pain |
| title_fullStr | Chemogenetic silencing of sensory neuron populations to uncover their role in touch and pain |
| title_full_unstemmed | Chemogenetic silencing of sensory neuron populations to uncover their role in touch and pain |
| title_short | Chemogenetic silencing of sensory neuron populations to uncover their role in touch and pain |
| title_sort | chemogenetic silencing of sensory neuron populations to uncover their role in touch and pain |
| topic | Touch Pain |
| work_keys_str_mv | AT middletonsj chemogeneticsilencingofsensoryneuronpopulationstouncovertheirroleintouchandpain |