Egr1 is necessary for forebrain dopaminergic signaling during social behavior

Abstract

Finding the link between behaviors and their regulatory molecular pathways is a major obstacle in treating neuropsychiatric disorders. The immediate early gene EGR1 is implicated in the etiology of neuropsychiatric disorders, and is linked to gene pathways associated with social behavior. Despite extensive knowledge of EGR1 gene regulation at the molecular level, it remains unclear how EGR1 deficits might affect the social component of these disorders. Here we examined the social behavior of zebrafish with a mutation in the homologous gene egr1. Mutant fish exhibited reduced social approach and orienting, whereas other sensorimotor behaviors were unaffected. On a molecular level, expression of the dopaminergic biosynthetic enzyme, tyrosine hydroxylase (TH), was strongly decreased in TH-positive neurons of the anterior parvocellular preoptic nucleus. These neurons are connected with basal forebrain neurons associated with social behavior. Chemo-genetic ablation of around 30% of TH-positive neurons in this preoptic region reduced social attraction to a similar extent as the egr1 mutation. These results demonstrate the requirement of Egr1 and dopamine signaling during social interactions, and identify novel circuitry underlying this behavior.

SIGNIFICANCE STATEMENT

Egr1 is an immediate early gene linked to neuropsychiatric disorders, particularly those with social components. However, the role it plays in control of social behavior remains elusive. We found that zebrafish with a mutation in the egr1 gene present deficits in social approach and orienting behavior. Furthermore, egr1 mutants have reduced tyrosine hydroxylase expression, particularly in dopaminergic neurons of the preoptic area synaptically connected to neurons already identified within a social circuit. Our study provides evidence of a role for egr1 in establishing social behavior, and adds to our understanding of the underlying circuitry.