Caffeine exerts a biphasic effect on zebrafish behavior. High doses of caffeine have been associated with increased stress and anxiety, whereas low doses have been found to enhance performance on tasks requiring focus and attention. However, the sex-specific nature of these biphasic effects on behavior and physiology remains unclear. This study assessed the behavioral responses and hormone levels in male and female zebrafish after acute exposure to caffeine ranging from 0.3 to 600 mg/L. The results showed no significant difference in caffeine intake between males and females after acute exposure at each concentration. Caffeine-induced behavioral and physiological responses indicated a threshold dosage existed between 30 and 300 mg/L. Female fish displayed increased anxiety-like behavioral phenotypes, i.e., latency to upper and freezing, whereas males exhibited more erratic movement following acute exposure to a high-dose treatment. In addition, females exhibited a significant increase in whole-body cortisol levels, while males experienced a testosterone elevation at 300 mg/L of caffeine acute exposure. There was a significant decrease in the duration of erratic movements in males treated with the androgen receptor antagonist flutamide compared to the control group. The transcriptome analysis uncovered 511 and 592 up-regulated and 761 and 922 down-regulated differential expression genes in males and females, respectively, compared to the control. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathway analysis revealed that caffeine has the potential to impact various pathways in zebrafish, including phototransduction and steroid hormone biosynthesis. Our findings demonstrate that testosterone and cortisol play a combined role in regulating stress responses in both behavior and physiology. Furthermore, our study highlights the significance of encompassing both male and female zebrafish as a model system.

Fragile X syndrome (FXS) is the most common single gene disorder contributing to autism spectrum disorder (ASD). Although significant sex differences are observed in FXS, few studies have focused on the phenotypic characteristics as well as the differences in brain pathological changes and gene expression in FXS by sex. Therefore, we analyzed sex differences in autism-like behavior and dendritic spine development in two-month-old male and female Fmr1 KO and C57 mice and evaluated the mechanisms at transcriptome level. Results suggest that Fmr1 KO mice display sex differences in autism-like behavior and dendritic spine density. Compared to females, male had more severe effects on anxiety, repetitive stereotype-like behaviors, and socializing, with higher dendritic spine density. Furthermore, two male-biased and five female-biased expressed genes were screened based on KEGG pathway enrichment and protein-protein interaction (PPI) analyses. In conclusion, our findings show mutations in the Fmr1 gene lead to aberrant expression of related genes and affect the sex-differentiated behavioral phenotypes of Fmr1 KO mice by affecting brain development and functional architecture, and suggest future studies should focus on including female subjects to comprehensively reflect the differentiation of FXS in both sexes and develop more precise and effective therapeutic strategies.

DiGeorge Syndrome Critical Region Gene 8 (DGCR8) is a key component of the microprocessor complex governing the maturation of most microRNAs, some of which participate in schizophrenia and neural development. Previous studies have found that the 22q11.2 locus, containing DGCR8, confers a risk of schizophrenia. However, the role of DGCR8 in schizophrenia and the early stage of neural development has remained unknown. In the present study, we try to identify the role of DGCR8 in schizophrenia from human samples and animal models. We found that the G allele and GG genotype of rs3757 in DGCR8 conferred a higher risk of schizophrenia, which likely resulted from higher expression of DGCR8 according to our test of dual-luciferase reporter system. Employed overexpression model in utero and adult mice, we also revealed that the aberrant increase of Dgcr8 delayed neuronal migration during embryological development and consequently triggered abnormal behaviors in adult mice. Together, these results demonstrate that DGCR8 may play a role in the etiology of schizophrenia through regulating neural development.

Benzophenones (BPs) are a class of UV absorber commonly used in skin care products like sunscreens. With its wide range of application, its environmental and human hazards have received much attention in recent days. Previous studies on the toxicity of BPs mainly focused on its endocrine-disrupting effects, but there are limited studies on its neurodevelopment and neurotoxicity. Herein, using the zebrafish model we studied the neurodevelopmental- and neuro-toxicity of benzophenone 1 (BP1) (0.8, 1.0, 1.2, 1.6, and 2.4 μg/mL). As a result, BP1 led to an increase of embryo mortality, a decrease in hatching rate, and an increase in the rate of developmental abnormalities in a concentration-dependent manner. BP1 also caused developmental defects in the central nervous system (CNS) and dopaminergic (DA) neurons. Accordingly, BP1 injured larval zebrafish general locomotion and response to stimuli in light/dark challenge. In adult zebrafish, BP1 exposure (1, 10, 100, 1000 μg/L) caused inhibition of learning and memory abilities in the T-maze tests, and inhibited exploratory behavior and activity in the novel tank diving tests. Further, transcription levels of genes related to neurotoxicity, neurodevelopment, and anxiety revealed that BP1 may affect the development and function of the myelin sheath, inducing structural and functional defects of CNS, manifested as abnormal behaviors such as anxiety. Hence, the current study revealed the neurodevelopmental toxicity and neurotoxicity of BP1, expanded our knowledge about the toxic effects of BP1 on organisms, posing a possible threat to the environment and human health.

Schizophrenia is a relatively common but serious mental illness that results in a heavy burden to patients, their families, and society. The disease can be triggered by multiple factors, while the specific pathogenesis remains unclear. The development of effective therapeutic drugs for schizophrenia relies on a comprehensive understanding of the basic biology and pathophysiology of the disease. Therefore, effective animal experimental models play a vital role in the study of schizophrenia. Based on different molecular mechanisms and modeling methods, the currently used experimental animal experimental models of schizophrenia can be divided into four categories that can better simulate the clinical symptoms and the interplay between susceptible genes and the environment: neurodevelopmental, drug-induced, genetic-engineering, and genetic-environmental interaction of animal experimental models. Each of these categories contains multiple subtypes, which has its own advantages and disadvantages and therefore requires careful selection in a research application. The emergence and utilization of these models are promising in the prediction of the risk of schizophrenia at the molecular level, which will shed light on effective and targeted treatment at the genetic level.

CD36 is a member of the class B scavenger receptor family of cell surface proteins, which plays a major role in fatty acid, glucose and lipid metabolism. Besides, CD36 functions as a microglial surface receptor for amyloid beta peptide. Regarding this, we suggest CD36 might also contribute to neuropsychiatric disease. The aim of this study was to achieve a behavioral phenotype of CD36 knockout (CD36(-/-)) mice. We characterized the behavior of CD36(-/-) mice and C57BL/6J mice by subjecting them to a series of tests, which include SHIRPA primary behavioral screen test, 1% sucrose preference test, elevated plus-maze test, open-field test and forced swimming test. The results showed that CD36(-/-) mice traversed more squares, emitted more defecation, exhibited higher tail elevation and had more aggressive behaviors than C57BL/6J mice. The CD36(-/-) mice spent more time and traveled longer distance in periphery zone in the open-field test. Meanwhile, the numbers that CD36(-/-) mice entered in the open arms of elevated plus-maze were reduced. These findings suggest that CD36(-/-) mice present an anxious phenotype and might be involved in neuropsychiatric disorders.