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Automated High-throughput Behavioral Analyses in Zebrafish Larvae
Published on: July 4, 2013
Olanzapine exposure disordered lipid metabolism, gut microbiota and behavior in zebrafish (Danio rerio)
Yawei Wang1, Fu You1, Zhenyi Huang1
1College of Fisheries, Henan Normal University, Xinxiang 453007, PR China.
Abstract:
Olanzapine (OLZ) is widely used in the treatment of schizophrenia, and its metabolic side effects have garnered significant attention in recent years. Despite this, the specific side effects of OLZ and the underlying mechanisms remain inadequately understood. To address this gap, zebrafish (Danio rerio) were exposed to OLZ at concentrations of 35.5, 177.5, and 355.5 μg/L. The results indicated that exposure to OLZ significantly increased body weight, total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides (TG). Histological analysis revealed notable lipid accumulation in the liver. Furthermore, lipid synthesis genes, including sterol regulatory element binding protein (srebp), acetyl CoA carboxylase (acc), and fatty acid synthesis gene (fas), were up-regulated. In contrast, genes related to lipid decomposition, such as lipoprotein lipase (lpl), hormone-sensitive triglyceride lipase (hsl), and carnitine palmitoyltransferase 1b (cpt1b), were down-regulated. Subsequent analysis of zebrafish behavior showed reduced motor activity, sociability, and anxiety-like behavior in OLZ-exposed zebrafish, consistent with the results of neurotransmitter related gene expression. Following OLZ treatment, the expression of tryptophan hydroxylase (tph), tyrosine hydroxylase (th), dopamine transporter (dat), glutaminase (glsa), and glutamic acid decarboxylase 1b (gad1b) was upregulated. Additionally, the diversity of intestinal flora decreased after OLZ exposure, and the structure of the intestinal microbiota changed significantly compared to the control group. At the genus level, the abundance of Plesiomonas was upregulated, while the abundances of Bacillus and Cetobacterium were downregulated in the OLZ-exposed group. Furthermore, the results of the correlation analysis indicated that lipid metabolism and behavioral changes were closely associated with the microbiota. This study clarified the side effects of OLZ, and also provided a basis for the reasonable discharge concentration of OLZ in water and clinical drug use.
Insights
Olanzapine (OLZ) exposure in zebrafish caused metabolic changes, including weight gain and altered lipid profiles, alongside behavioral deficits. Gut microbiota dysbiosis was linked to these olanzapine-induced effects.
Area of Science:
- Environmental toxicology
- Pharmacology
- Zebrafish model systems
Background:
- Olanzapine (OLZ) is a key antipsychotic for schizophrenia, but its metabolic side effects and mechanisms require further elucidation.
- Understanding OLZ's impact is crucial for managing patient health and environmental safety.
Purpose of the Study:
- To investigate the metabolic, behavioral, and gut microbiota alterations induced by OLZ exposure in zebrafish (Danio rerio).
- To explore the underlying molecular mechanisms and correlations between microbiota changes and observed side effects.
Main Methods:
- Zebrafish were exposed to varying concentrations of OLZ (35.5, 177.5, 355.5 μg/L).
- Assessed body weight, lipid profiles (TC, LDL, TG), liver histology, gene expression (lipid metabolism, neurotransmitters), behavioral tests (motor activity, sociability, anxiety), and gut microbiota composition.
- Performed correlation analysis between lipid metabolism, behavior, and microbiota.
Main Results:
- OLZ exposure significantly increased body weight, total cholesterol, LDL, and triglycerides, with liver lipid accumulation.
- Upregulation of lipid synthesis genes (srebp, acc, fas) and downregulation of lipid decomposition genes (lpl, hsl, cpt1b) were observed.
- Reduced motor activity, sociability, and anxiety-like behaviors correlated with altered neurotransmitter gene expression (tph, th, dat, glsa, gad1b).
- Gut microbiota diversity decreased, with notable shifts in Plesiomonas, Bacillus, and Cetobacterium abundance.
- Lipid metabolism and behavioral changes were significantly associated with microbiota alterations.
Conclusions:
- Olanzapine induces significant metabolic disturbances, behavioral changes, and gut dysbiosis in zebrafish, highlighting its multifaceted side effects.
- The study provides insights into OLZ's mechanisms of action and establishes a basis for determining safe environmental discharge concentrations and clinical usage guidelines.
