The class IV multidendritic neurons of Drosophila larvae are nociceptive. The nociception behavior of Drosophila melanagaster larvae includes an innately encoded directional preference. Nociception behavior is elicited by the ecologically relevant sensory stimulus of parasitoid wasp attack.

Summary Highly branched Class IV multidendritic sensory neurons of the Drosophila larva function as polymodal nociceptors that are necessary for behavioral responses to noxious heat (>39°C) or noxious mechanical (>30 mN) stimuli. However, the molecular mechanisms that allow these cells to detect both heat and force are unknown. Here, we report that the pickpocket(ppk) gene, which encodes a Degenerin/ Epithelial Sodium Channel (DEG/ENaC) subunit, is required for mechanical nociception but not thermal nociception in these sensory cells. Larvae mutant for pickpocket show greatly reduced nociception behaviors in response to harsh mechanical stimuli. However, pickpocket mutants display normal behavioral responses to gentle touch. Tissue specific knockdown of pickpocket in nociceptors phenocopies the mechanical nociception impairment without causing defects in thermal nociception behavior. Finally, optogenetically-triggered nociception behavior is unaffected by pickpocket RNAi which indicates that ppk is not generally required for the excitability of the nociceptors. Interestingly, DEG/ENaCs are known to play a critical role in detecting gentle touch stimuli in C. elegans and have also been implicated in some aspects of harsh touch sensation in mammals. Our results suggest that neurons which detect harsh touch in Drosophila utilize similar mechanosensory molecules.

SUMMARY Specialized somatosensory neurons detect temperatures ranging from pleasantly cool or warm to burning hot and painful (nociceptive). The precise temperature ranges sensed by thermally sensitive neurons is determined by tissue specific expression of ion channels of the Transient Receptor Potential (TRP) family. We show here, that in Drosophila, TRPA1 is required for sensing of nociceptive heat. We identify two new protein isoforms of dTRPA1named dTRPA1-C and dTRPA1-D that explain this requirement. A dTRPA1-C/D reporter was exclusively expressed in nociceptors and dTRPA1-C rescued thermal nociception phenotypes when restored to mutant nociceptors. However, surprisingly, we find that dTRPA1-C is not a direct heat sensor. Alternative splicing generates at least four isoforms of dTRPA1. Our analysis of these isoforms reveals a 37 amino acid intracellular region (encoded by a single exon) that is critical for dTRPA1 temperature responses. The identification of these amino acids opens the door to a biophysical understanding of a molecular thermosensor.

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Decision-making is defined as selection amongst options based on their utility, in a flexible and context-dependent manner. Oviposition site selection by the female fly, Drosophila melanogaster, has been suggested to be a simple and genetically tractable model for understanding the biological mechanisms that implement decisions [1]. Paradoxically, female Drosophila have been found to avoid oviposition on sugar which contrasts with known Drosophila feeding preferences [1]. Here we demonstrate that female Drosophila prefer egg laying on sugar, but this preference is sensitive to the size of the egg laying substrate. With larger experimental substrates, females preferred to lay eggs directly on sugar containing media over other (plain, bitter or salty) media. This was in contrast to smaller substrates with closely spaced choices where females preferred non-sweetened media. We show that in small egg laying chambers newly hatched first instar larvae are able to migrate along a diffusion gradient to the sugar side. In contrast, in contexts where females preferred egg laying directly on sugar, larvae were unable to migrate to find the sucrose if released on the sugar free side of the chamber. Thus, where larval foraging costs are high, female Drosophila choose to lay their eggs directly upon the nutritious sugar substrate. Our results offer a powerful model for female decision-making.

A107 RESULTS: Patients (n=660, 100% completion rate) completed the survey. All attributes were significant predictors of choice except sleepiness. Respondents were significantly more likely to choose a treatment that provided a 10% reduction in seizure frequency (Odds Ratio [OR]=1.75, 95% CI 1.68-1.82) or avoided weight gain (3lb) (OR=0.751, 95% CI=0.731-0.772). Respondents were willing to pay an additional £39 and £20 per month for AEDs with those attributes. Furthermore, respondents who become unresponsive during a seizure placed higher levels of preference on an AED that would reduce seizure frequency. Respondents who reported higher levels of adherence to their AEDs (MMAS-8) reported better quality of life (QoL) (QOLIE-31-P and EQ-5D-5L). CONCLUSIONS: Seizure reduction is the most important AED attribute to epilepsy patients, but lack of weight gain is also valued. Higher adherence to AEDs appears to be linked with improved QoL.

S29third-party payer's analysis. ReSultS: Incremental QALYs for Regorafenib compared to BSC was 0.12 (0.51 vs 0.39).