apha.13543.pdf (2.81 MB)
The zebrafish histamine H3 receptor modulates aggression, neural activity and forebrain functional connectivity.
journal contributionposted on 2020-09-03, 08:55 authored by Florian Reichmann, Neal Rimmer, Ceinwen A Tilley, Elisa Dalla Vecchia, Joseph Pinion, Amir Al Oustah, Hector Carreño Gutiérrez, Andrew Mj Young, Jonathan R McDearmid, Matthew J Winter, William Hj Norton
AIM: Aggression is a behavioural trait characterized by the intention to harm others for offensive or defensive purposes. Neurotransmitters such as serotonin and dopamine are important mediators of aggression. However, the physiological role of the histaminergic system during this behaviour is currently unclear. Here, we aimed to better understand histaminergic signalling during aggression by characterizing the involvement of the histamine H3 receptor (Hrh3). METHODS: We have generated a novel zebrafish Hrh3 null mutant line using CRISPR-Cas9 genome engineering and investigated behavioural changes and alterations to neural activity using whole brain Ca2+ imaging in zebrafish larvae and ribosomal protein S6 (rpS6) immunohistochemistry in adults. RESULTS: We show that genetic inactivation of the histamine H3 receptor (Hrh3) reduces aggression in zebrafish, an effect that can be reproduced by pharmacological inhibition. In addition, hrh3-/- zebrafish show behavioural impairments consistent with heightened anxiety. Larval in vivo whole brain Ca2+ imaging reveals higher neuronal activity in the forebrain of mutants, but lower activity in specific hindbrain areas and changes in measures of functional connectivity between sub-regions. Adult hrh3-/- zebrafish display brain region-specific neural activity changes in response to aggression of both key regions of the social decision making network, and the areas containing histaminergic neurons in the zebrafish brain. CONCLUSION: These results highlight the importance of zebrafish Hrh3 signalling for aggression and anxiety and uncover the brain areas involved. Targeting this receptor might be a potential novel therapeutic route for human conditions characterized by heightened aggression.
National Centre for the Replacement Refinement and Reduction of Animals in Research. Grant Numbers: NC/M001881/1, NC/R001049/1
Seventh Framework Programme. Grant Number: 602805
Fondation pour la Recherche Médicale. Grant Number: SPE20150331881
Marie‐Curie ITN. Grant Number: 643051
Austrian Science Fund. Grant Number: J4090‐B29
CitationActa Physiologica. 2020;00:e13543.
Author affiliationDepartment of Neuroscience, Psychology and Behaviour, College of Life Sciences
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