Cross Scale Interrogation of NPD Genes (SING) in mice

ABSTRACT Neurodevelopmental and psychiatric disorders (NPDs) are highly prevalent and devasting neurological conditions without cure. Recent genetic studies on NPDs identified hundreds of high-risk NPD-related genes, yet it remains unclear how these genes individually or collectively affect neurodevelopmental processes to create pathological conditions in the brain. To identify core biological pathways implicated in NPDs, it is critical to understand how the loss of specific NPD genes leads to changes in the molecular and cellular level to alteration in neural circuits, which ultimately result in pathological behavioral changes. Here, we assemble a team of seven investigators with complementary expertise to create an Assay and Data Generation Center (ADGCs) to comprehensively investigate the impact of loss of NPD genes in mice. We aim to investigate NPD genes through Cross-Scale Interrogation of NPD Genes (SING), focusing on gene expression, cellular changes, neural circuits, and behaviors affected by 100 NPD genes in mice. Utilizing Knockout Mouse Project (KOMP) resources, we will examine the effect of NPD gene deletion in mice across developmental stages, employing high-throughput methodologies and integrative data analysis. First, we will utilize single-cell and spatial transcriptome approaches to examine molecular and cellular changes. Second, we will deploy MRI and high-resolution 3D mapping methods to examine altered neural circuit connectivity and brain anatomy. Third, we will employ a high throughput home cage system to automatically track altered behavior. Moreover, we will perform a pilot study to develop CRISPR based viral approaches to rapidly knockout target genes in developing mice and to examine altered neural circuit maturation patterns. We plan to integrate multiscale data and perform machine learning-based analyses to identify shared biological pathways for specific NPDs, and broadly disseminate the data for public access. We expect to generate critical experimental data at an unprecedented scale, to rapidly advance our understanding of key biological pathways of NPDs, which will inform future therapeutic approaches.