Author ORCID Identifier

0000-0003-3077-0615

Date of Award

12-13-2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience Institute

First Advisor

Daniel N. Cox

Second Advisor

Charles Derby

Third Advisor

Anne Z. Murphy

Fourth Advisor

Scott Nowak

Abstract

Thermosensory nociception alerts organisms to potential environmental dangers, thereby serving as a protective mechanism for driving adaptive behavioral responses to safeguard against incipient damage. Transient receptor potential (TRP) channels play a key role in thermosensation and some can be activated directly or indirectly by changes in temperature. Protostome, and many deuterostome, TRPA1s have been associated with high-temperature sensing. For example, Drosophila TRPA1 is known to function in Class IV (CIV) polymodal nociceptor neurons for high heat (as well as mechanical and chemical) nociception. Conversely, some deuterostome TRPA1s (including those of mice and humans) have been identified as noxious cold sensitive. However, little is known regarding how TRPs mechanistically function in regulating noxious cold detection and whether there is molecular conservation across phyla.

Our previous studies identified Class III (CIII) multidendritic (md) sensory neurons as cold nociceptors that are required for noxious cold-evoked contraction (CT) behavior in larvae. We further demonstrated via CIII-specific neurogenomic studies that TRPA1 is enriched in these neurons, suggesting it may contribute to noxious cold sensing. In this work, analyses of multiple TrpA1 whole-animal mutants revealed severe impairment of cold-evoked CT behavior, which we likewise observed with CIII-specific TrpA1 knockdown. Behavioral studies of TrpA1 mutations revealed isoform-specific requirements for noxious cold sensing that are distinct from isoforms linked to noxious heat sensing via CIV neurons. Electrophysiological recordings demonstrate that TRPA1 is required in CIII neurons for cold-evoked neural activity. TrpA1 appears to function in cold-evoked sensory transduction, and CIII-specific expression of TrpA1 rescued nocifensive behavior in whole animal TrpA1 mutants. Further, behavioral deficits were also rescued by ectopic expression of human TrpA1. Moreover, ectopic expression studies reveal TrpA1 is sufficient to confer cold sensitivity on otherwise non-cold-sensing neurons. Collectively, these findings shed new light on evolutionarily ancient properties of TRPA1 in thermal sensing and raise interesting questions regarding the molecular and mechanistic underpinnings of TRPA1 polymodality

File Upload Confirmation

1

Available for download on Thursday, December 08, 2022

Share

COinS