Chloride-dependent mechanisms of multimodal sensory discrimination and nociceptive sensitization in Drosophila
- Georgia State University, United States
Abstract
Individual sensory neurons can be tuned to many stimuli, each driving unique, stimulus-relevant behaviors, and the ability of multimodal nociceptor neurons to discriminate between potentially harmful and innocuous stimuli is broadly important for organismal survival. Moreover, disruptions in the capacity to differentiate between noxious and innocuous stimuli can result in neuropathic pain. Drosophila larval Class III (CIII) neurons are peripheral noxious cold nociceptors and innocuous touch mechanosensors; high levels of activation drive cold-evoked contraction (CT) behavior, while low levels of activation result in a suite of touch-associated behaviors. However, it is unknown what molecular factors underlie CIII multimodality. Here, we show that the TMEM16/anoctamins subdued and white walker (wwk; CG15270) are required for cold-evoked CT, but not for touch-associated behavior, indicating a conserved role for anoctamins in nociception. We also evidence that CIII neurons make use of atypical depolarizing chloride currents to encode cold, and that overexpression of ncc69-a fly homologue of NKCC1-results in phenotypes consistent with neuropathic sensitization, including behavioral sensitization and neuronal hyperexcitability, making Drosophila CIII neurons a candidate system for future studies of the basic mechanisms underlying neuropathic pain
Data availability
All data generated or analyzed during this study are included in the manuscript. We have plotted all data such that individual data points can be seen. Additionally, we have included heatmap representations of cold-evoked larval behavior for every single larva used in this study (see supplemental figures). Class III neuron-specific transcriptomic data has been deposited in GEO under accession number GSE69353. Accession numbers for sequences used in phylogenetic analysis are presented in the relevant figure. Raw data and sequence files are available in Dryad.
-
Choride-dependent mechanisms of multimodal sensory discrimination and nociceptive sensitization in DrosophilaDryad Digital Repository, doi:10.5061/dryad.dncjsxm3h.
Article and author information
Author details
Nathaniel J Himmel
Gennady S Cymbalyuk
Funding
National Institutes of Health (NS115209)
- Gennady S Cymbalyuk
- Daniel N Cox
National Institutes of Health (NS117087)
- Nathaniel J Himmel
Georgia State University (Honeycutt Fellowship)
- Nathaniel J Himmel
- Atit A Patel
Georgia State University (Brains & Behavior Fellowship)
- Nathaniel J Himmel
- Atit A Patel
- Jamin M Letcher
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Ishmail Abdus-Saboor, Columbia University, United States
Version history
- Preprint posted: December 11, 2021 (view preprint)
- Received: January 7, 2022
- Accepted: January 19, 2023
- Accepted Manuscript published: January 23, 2023 (version 1)
- Version of Record published: February 7, 2023 (version 2)
Copyright
© 2023, Himmel et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 905
- Page views
-
- 146
- Downloads
-
- 1
- Citations
Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Chloride-dependent mechanisms of multimodal sensory discrimination and nociceptive sensitization in Drosophila
eLife 12:e76863.
https://doi.org/10.7554/eLife.76863
Further reading
-
- Cell Biology
- Neuroscience
The amyloid beta (Aβ) plaques found in Alzheimer’s disease (AD) patients’ brains contain collagens and are embedded extracellularly. Several collagens have been proposed to influence Aβ aggregate formation, yet their role in clearance is unknown. To investigate the potential role of collagens in forming and clearance of extracellular aggregates in vivo, we created a transgenic Caenorhabditis elegans strain that expresses and secretes human Aβ1-42. This secreted Aβ forms aggregates in two distinct places within the extracellular matrix. In a screen for extracellular human Aβ aggregation regulators, we identified different collagens to ameliorate or potentiate Aβ aggregation. We show that a disintegrin and metalloprotease a disintegrin and metalloprotease 2 (ADM-2), an ortholog of ADAM9, reduces the load of extracellular Aβ aggregates. ADM-2 is required and sufficient to remove the extracellular Aβ aggregates. Thus, we provide in vivo evidence of collagens essential for aggregate formation and metalloprotease participating in extracellular Aβ aggregate removal.
-
- Computational and Systems Biology
- Neuroscience
The cerebellar granule cell layer has inspired numerous theoretical models of neural representations that support learned behaviors, beginning with the work of Marr and Albus. In these models, granule cells form a sparse, combinatorial encoding of diverse sensorimotor inputs. Such sparse representations are optimal for learning to discriminate random stimuli. However, recent observations of dense, low-dimensional activity across granule cells have called into question the role of sparse coding in these neurons. Here, we generalize theories of cerebellar learning to determine the optimal granule cell representation for tasks beyond random stimulus discrimination, including continuous input-output transformations as required for smooth motor control. We show that for such tasks, the optimal granule cell representation is substantially denser than predicted by classical theories. Our results provide a general theory of learning in cerebellum-like systems and suggest that optimal cerebellar representations are task-dependent.
