Cellular, circuit and transcriptional framework for modulation of itch in the central amygdala
- Washington University in St Louis, United States
- University of Washington, United States
Abstract
Itch is an unpleasant sensation that elicits robust scratching and aversive experience. However, the identity of the cells and neural circuits that organize this information remains elusive. Here we show the necessity and sufficiency of chloroquine-activated neurons in the central amygdala (CeA) for both itch sensation and associated aversion. Further, we show that chloroquine-activated CeA neurons play important roles in itch-related comorbidities, including anxiety-like behaviors, but not in some aversive and appetitive behaviors previously ascribed to CeA neurons. RNA-sequencing of chloroquine-activated CeA neurons identified several differentially expressed genes as well as potential key signaling pathways in regulating pruritis. Finally, viral tracing experiments demonstrate that these neurons send projections to the ventral periaqueductal gray that are critical in modulation of itch. These findings reveal a cellular and circuit signature of CeA neurons orchestrating behavioral and affective responses to pruritus in mice.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE130268
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Transcriptional Idenetity of Itch-activated Central Amygdala NeuronsNCBI Gene Expression Omnibus, GSE130268.
Article and author information
Author details
Eric Dameon Tycksen
Robert W Gereau IV
Funding
National Institute of Neurological Disorders and Stroke (R01NS106953)
- Robert W Gereau IV
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK116178)
- Robert W Gereau IV
National Institute of Diabetes and Digestive and Kidney Diseases (K01 DK115634)
- Vijay K Samineni
National Institute of Neurological Disorders and Stroke (5F31NS103472-02)
- Jose G Grajales-Reyes
National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK128475)
- Vijay K Samineni
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) of Washington University School of Medicine (approved protocol 20-0078).
Copyright
© 2021, Samineni 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.
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Cellular, circuit and transcriptional framework for modulation of itch in the central amygdala
eLife 10:e68130.
https://doi.org/10.7554/eLife.68130
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We present near-atomic-resolution cryoEM structures of the mammalian voltage-gated potassium channel Kv1.2 in open, C-type inactivated, toxin-blocked and sodium-bound states at 3.2 Å, 2.5 Å, 3.2 Å, and 2.9 Å. These structures, all obtained at nominally zero membrane potential in detergent micelles, reveal distinct ion-occupancy patterns in the selectivity filter. The first two structures are very similar to those reported in the related Shaker channel and the much-studied Kv1.2–2.1 chimeric channel. On the other hand, two new structures show unexpected patterns of ion occupancy. First, the toxin α-Dendrotoxin, like Charybdotoxin, is seen to attach to the negatively-charged channel outer mouth, and a lysine residue penetrates into the selectivity filter, with the terminal amine coordinated by carbonyls, partially disrupting the outermost ion-binding site. In the remainder of the filter two densities of bound ions are observed, rather than three as observed with other toxin-blocked Kv channels. Second, a structure of Kv1.2 in Na+ solution does not show collapse or destabilization of the selectivity filter, but instead shows an intact selectivity filter with ion density in each binding site. We also attempted to image the C-type inactivated Kv1.2 W366F channel in Na+ solution, but the protein conformation was seen to be highly variable and only a low-resolution structure could be obtained. These findings present new insights into the stability of the selectivity filter and the mechanism of toxin block of this intensively studied, voltage-gated potassium channel.
