Genome-Wide Association Analyses Point to Candidate Genes for Electric Shock Avoidance in Drosophila melanogaster

Abstract

Electric shock is a common stimulus for nociception-research and the most widely used reinforcement in aversive associative learning experiments. Yet, nothing is known about the mechanisms it recruits at the periphery. To help fill this gap, we undertook a genome-wide association analysis using 38 inbred Drosophila melanogaster strains, which avoided shock to varying extents. We identified 514 genes whose expression levels and/ or sequences co-varied with shock avoidance scores. We independently scrutinized 14 of these genes using mutants, validating the effect of 7 of them on shock avoidance. This emphasizes the value of our candidate gene list as a guide for follow-up research. In addition, by integrating our association results with external protein-protein interaction data we obtained a shock avoidance-associated network of 38 genes. Both this network and the original candidate list contained a substantial number of genes that affect mechanosensory bristles, which are hair-like organs distributed across the fly’s body. These results may point to a potential role for mechanosensory bristles in shock sensation. Thus, we not only provide a first list of candidate genes for shock avoidance, but also point to an interesting new hypothesis on nociceptive mechanisms.

Analysis of genes within the schizophrenia-linked 22q11.2 deletion identifies interaction of night owl/LZTR1 and NF1 in GABAergic sleep control

“…Furthermore, we found strong enrichment of Nowl in Rdl-expressing MB neurons, consistent with Nowl's functioning in the regulation of sleep via wake-promoting neurons in the mushroom body. Interestingly, nowl was also identified in an olfactory-learning screen, in which it was found to inhibit electric-shockreinforced associative learning, consistent with a role for nowl in mushroom-body neuronal function [25]. Furthermore, we observed that Nf1 knockdown in Rdl-expressing neurons caused sleep reduction and fragmentation of night-time sleep similar to nowl knockdown, further supporting an interaction between Nf1 and nowl in the regulation of sleep.…”

“…On the other hand, night-time sleep dropped dramatically in both males and females. Loss of one copy of nowl (on the X chromosome) in females did not elicit a phenotype, suggesting that the nowl 1 mutation is a recessive loss-of-function allele, consistent with the transcript-level defect previously reported [25]. To further confirm these results, we generated a CRISPR/Cas9-mediated deletion of the nowl coding sequence.…”

“…2B-2D). Transcript levels of nowl have previously been shown to be drastically reduced in this mutant [25]. Like animals with neuronal knockdown, nowl 1 mutants exhibited decreased sleep, primarily during the second part of the night, compared with the genetic-background controls (w 1118 /Y and +/Y, where "+" denotes a wild-type X chromosome and "Y" a wild-type Y chromosome).…”

Multiple genetic loci affect place learning and memory performance in Drosophila melanogaster

“…This gene is primarily involved in the formation of hairs. 73 Appel et al 95 ). An RNAi screen specific to neurons identified ergic53 as a candidate gene involved in the perception of very high temperatures.…”

“…Both of these are significant only between the learning cohorts, with higher expression in the high learning cohort (Obp28a: Individual QTL BCI regions showing possible candidate genes. Appel et al95 also found evidence for a role of the genes influencing mechanosensory bristles and electric shock avoidance in a different D melanogaster mapping population, the DGRP. When a peak is shared between learning and memory, both BCIs are shown.…”