PUBLICATION

The zebrafish histamine H3 receptor modulates aggression, neural activity and forebrain functional connectivity

Authors

Reichmann, F., Rimmer, N., Tilley, C.A., Dalla Vecchia, E., Pinion, J., Al Oustah, A., Carreño Gutiérrez, H., Young, A.M., McDearmid, J.R., Winter, M.J., Norton, W.H.

ID

ZDB-PUB-200804-2

Date

2020

Source

Acta physiologica (Oxford, England) 230(4): e13543 (Journal)

Registered Authors

Norton, Will, Tilley, Ceinwen

Keywords

aggression, anxiety, histamine H3 receptor, neural activity, whole brain calcium imaging, zebrafish

MeSH Terms

Humans
Brain/metabolism
Serotonin
Aggression
Prosencephalon/metabolism
Histamine
Receptors, Histamine H3*/metabolism
Animals
Zebrafish/metabolism

(all 9)

PubMed

32743878 Full text @ Acta Physiol. (Oxf).

Abstract

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.

Genes / Markers

Figures

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	stress	Adult	caudal periventricular hypothalamus rps6 expression increased amount, abnormal	Fig. 3
WT	stress	Adult	dorsal nucleus of ventral telencephalon rps6 expression increased amount, abnormal	Fig. 3
WT	stress	Adult	lateral zone of dorsal telencephalon rps6 expression increased amount, abnormal	Fig. 3
WT	stress	Adult	medial zone of dorsal telencephalon rps6 expression increased amount, abnormal	Fig. 3
WT	stress	Adult	posterior recess rps6 expression increased amount, abnormal	Fig. 3
WT	stress	Adult	ventral nucleus of ventral telencephalon rps6 expression increased amount, abnormal	Fig. 3
hrh3^uol1/uol1	standard conditions	Day 4	startle response disrupted, abnormal	Fig. 5
hrh3^uol1/uol1	standard conditions	Day 4	swimming decreased linear velocity, abnormal	Fig. 5
hrh3^uol1/uol1	standard conditions	Day 4	swimming decreased occurrence, abnormal	Fig. 5
hrh3^uol1/uol1	standard conditions	Adult	aggressive behavior decreased occurrence, abnormal	Fig. 2

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
a9		Complex	mpv17
jf4Tg	Tg(elavl3:GCaMP6s)	Transgenic Insertion
uol1		Insertion	hrh3
w2		Point Mutation	mitfa

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
hrh3	CRISPR2-hrh3	CRISPR

Fish

Fish
hrh3^uol1/uol1
hrh3^uol1/uol1; jf4Tg
WT

Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab4-rps6	polyclonal			Rabbit

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
GCaMP	EFG	GCaMP

Mapping

Reichmann et al., 2020 ZDB-PUB-200804-2 PMID:32743878

The zebrafish histamine H3 receptor modulates aggression, neural activity and forebrain functional connectivity

Reichmann et al., 2020

ZDB-PUB-200804-2
PMID:32743878