Biology subjects

Vivian, M. D.

Publications and source records attributed to Vivian, M. D..

4 recordsLinked to original sources

bioRxiv2026

Zebrafish screen of schizophrenia risk genes reveals convergent dysregulation of cholesterol metabolism

Rare coding variants provide a tractable entry point for understanding the molecular mechanisms underlying schizophrenia risk. Here, we generated and characterized zebrafish lines with mutations in the orthologs of >20 human schizophrenia-associated genes, including eight of the top ten SCHEMA genes, genes disrupted in childhood-onset schizophrenia (COS), and genes located within recurrent copy number variants. Whole-brain phospho-Erk activity mapping and behavioral profiling identified phenotypes in multiple mutant lines. We prioritized a protein-truncating mutation in sp4, which encodes an activity-dependent transcription factor, and a COS-associated missense mutation in atp1a3a, which encodes a Na+/K+ ATPase pump, for additional characterization. Both knockout and point mutations in atp1a3a disrupted brain activity and behavior in larvae and impaired navigation of a Y-maze in juveniles. Bulk RNA sequencing data from adult sp4 and atp1a3a brains highlighted convergent upregulation of sterol biosynthesis pathways, including increased expression of srebf2 and msmo1. Analysis of previously published telencephalon single-cell data demonstrated that cholesterol synthesis genes are enriched in astrocyte-like cells and increase in expression during post-larval development. Consistent with transcriptomic findings, filipin staining indicated increased free cholesterol in juvenile sp4 and atp1a3a mutant brains. Our findings identify dysregulation of glial and sterol-associated programs as a shared molecular consequence of two distinct schizophrenia risk mutations. Although whether sterol pathway dysregulation represents a primary pathogenic mechanism or a secondary response to changes in neuronal activity requires further investigation, the convergence observed between genetic models and developmental stages suggests that disruptions to lipid homeostasis could represent a shared feature of schizophrenia disease biology.

genetics↗

bioRxiv2024

Disrupted development of sensory systems and the cerebellum in a zebrafish ebf3a mutant

Mutations in the transcription factor EBF3 results in a neurodevelopmental disorder, and studies in animal models indicate that it has a critical role in neuronal differentiation. The molecular pathways and neuron types disrupted by its loss, however, have not been thoroughly investigated. Nor have the outcomes of these changes on behavior and brain activity. Here, we generated and characterized a zebrafish ebf3a loss-of-function mutant. We discovered morphological and neural phenotypes, including an overall smaller brain size, particularly in the hypothalamus, cerebellum, and hindbrain. Brain function was also compromised, with activity strongly increased in the cerebellum and abnormal behavior at baseline and in response to visual and acoustic stimuli. From RNA-sequencing of developing larvae, notable changes included significant downregulation of genes that mark olfactory sensory neurons, the lateral line, and cerebellar Purkinje neurons. This study sets the stage for determining which downstream pathways underlie the emergence of the observed phenotypes and establishes multiple strong phenotypes that could form the basis of a drug screen.

neuroscience↗

bioRxiv2024

Diencephalic and Neuropeptidergic Dysfunction in Zebrafish with Autism Risk Mutations

Hundreds of human mutations are linked to autism and related disorders, yet the functions of many of these mutated genes during vertebrate neurodevelopment are unclear. We generated 27 zebrafish mutants with presumptive protein-truncating mutations or specific missense variants corresponding to autism-risk alleles in 17 human genes. We observed baseline and stimulus-driven behavioral changes at larval stages, as well as social behavior differences in lines tested as juveniles. Imaging whole-brain activity revealed a near identical activity map for mutations in the unrelated genes kmt5b and hdlbpa, defined by increased activity mainly in the diencephalon. Mutating 7 of the 17 risk genes resulted in substantial brain size differences. Using RNA sequencing, we further defined molecular drivers of the observed phenotypes, identifying targetable disruptions in neuropeptide signaling, neuronal maturation, and cell proliferation. This multi-modal screen nominated brain regions, cell types, and molecular pathways that may contribute to autism susceptibility. TeaserZebrafish screen uncovers diencephalon, social interaction, and neuropeptidergic signaling phenotypes in ASD risk mutants.

genetics↗

bioRxiv2020

A Customizable Low-Cost System for Massively Parallel Zebrafish Behavior Phenotyping

High-throughput behavioral phenotyping is critical to genetic or chemical screening approaches. Zebrafish larvae are amenable to high-throughput behavioral screening because of their rapid development, small size, and conserved vertebrate brain architecture. Existing commercial behavior phenotyping systems are expensive and not easily modified for new assays. Here, we describe a modular, highly adaptable, and low-cost behavior system. Along with detailed assembly and operation instructions, we provide data acquisition software and a robust, parallel analysis pipeline. We validate our approach by analyzing stimulus response profiles in larval zebrafish, confirming prepulse inhibition phenotypes of two previously isolated mutants, and highlighting best practices for growing larvae prior to behavioral testing. Our new design thus allows rapid construction and streamlined operation of many large-scale behavioral setups with minimal resources and fabrication expertise, with broad applications to other aquatic organisms.

neuroscience↗