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Norton, W. H. J.

Publications and source records attributed to Norton, W. H. J..

2 recordsLinked to original sources

Environmental Enrichment Reduces adgrl3.1-Related Anxiety and Attention Deficits but Not Impulsivity

Environmental factors play a role in the development and severity of neuropsychiatric disorders. Externalizing disorders (EDs) are linked to genetic and environmental factors and frequently co-occur with internalizing disorders (ID), such as anxiety. Individuals experiencing both ED/ID are often among the most likely to seek healthcare services, as this co-occurrence is associated with more severe symptomatology and greater functional impairment. Here, we investigate the role of environmental enrichment (EE) on a gene associated with impulsivity and attention deficits in zebrafish, adgrl3.1. Zebrafish were reared in either standard or enriched environments (from 15 days-post fertilization), and attention, impulsivity, and anxiety-related phenotypes were assessed at adult stages (4 months-post fertilization) using the open field test and 5-choice serial reaction time task. EE mitigated anxiety-related behaviors in adgrl3.1 knockouts, normalizing locomotor patterns and decreasing thigmotaxis. Although attention deficits were reduced in adgrl3.1-/- fish reared in EE, impulsive behaviors were not. Together, these findings suggest that while EE can alleviate some externalizing and internalizing phenotypes in zebrafish, impulsivity remains resistant to environmental modification. This study suggests that impulsivity is a stable trait in adgrl3.1-/- fish, but highlights the importance of EE in mitigating some externalizing and internalizing symptoms. Summary statementEnvironmental enrichment reduces attention deficits and anxiety-like behavior, but not impulsivity in adgr3.1 knockout zebrafish, highlighting the interaction between genetic and environmental factors in shaping externalizing and internalizing phenotypes.

animal behavior and cognition↗

adgrl3.1-deficient zebrafish show noradrenaline-mediated externalizing behaviors, and altered expression of externalizing disorder-candidate genes, suggesting functional targets for treatment

Externalising disorders (ED) are a cause of concern for public health, and their high heritability make genetic risk factors a priority for research. Adhesion G Protein-Coupled Receptor L3 (ADGRL3) is strongly linked to several EDs, and loss-of-function models have shown impacts of this gene on several core ED-related behaviors. For example, adgrl3.1-/- zebrafish show high levels of hyperactivity. However, our understanding of the mechanisms by which this gene influences behavior is incomplete. Here we characterized, for the first time, externalizing behavioral phenotypes of adgrl3.1-/- zebrafish and found them to be highly impulsive, show boldness in a novel environment, have attentional deficits, and show high levels of hyperactivity. All of these phenotypes were rescued by atomoxetine, demonstrating noradrenergic mediation of the externalizing effects of adgrl3.1. Transcriptomic analyses of the brains of adgrl3.1-/- vs wild type fish revealed several differentially expressed genes and enriched gene clusters that were independent of noradrenergic manipulation. This suggests new putative functional pathways underlying ED-related behaviors, and potential targets for the treatment of ED.

neuroscience↗