Complex brain disorders such as the autism spectrum disorders (ASDs), schizophrenia, depression, and anxiety disorders stem from heterogeneous genetic predispositions (and at times, with environmental influences). A common hallmark of these disorders is a systems level brain dysfunction. Although human genetic studies have identified a repertoire of disease susceptibility genes with functions ranging from transcriptional and translational regulation to synaptic structural modulation and neurotransmission, at present, little is known as to how disruption of genes and associated molecular and cellular processes alter brain connectivity that define certain behavioral features of each disorder. This exploratory R21 application aims to develop a new platform for understanding, at the basic circuit level, how disruption of genes alters brain connectivity, thereby attempting to connect molecules cells and behavior. Functional Magnetic Resonance Imaging (fMRI) studies have explored resting-state or task-related functional connectivity, which measures correlations among distinct neurophysiological events in human brains. These studies have provided a valuable framework, but the lack of cellular resolution and difficulty to carry out experimental perturbation in humans precludes further cause-effect relationship studies. To uncover brain functional connectivity at systems levels with cellular resolution, we propose to perform brain-wide calcium imaging and computational analyses employing larval zebrafish. As a vertebrate genetic model organism, zebrafish shares considerable neuroanatomical and genomic similarity with humans. Larval zebrafish, with a transparent brain of ~100K neurons (as compared to ~75 million in the mouse, and ~1 billion in the human brain), is particularly suitable for dynamic single-cell resolution imaging in vivo. In this application, through brain-wide calcium imaging and computational data analyses, we propose to determine how genetic alterations may affect brain functional connectivity at cellular resolution in larval zebrafish. Expected outcomes and impact: If successful, this project will establish a new paradigm to uncover, at systems level and with cellular resolution, how genetic changes alter brain connectivity. These studies will lay critical foundation for future understanding of mechanisms between gene alterations and circuit activity changes, as well as expanding the studies to a greater number of genes. We will make technologies including image acquisition, processing, and computational algorithms available to the broad research community. In the long run, new basic knowledge about gene and brain connectivity relationships will aid in developing novel therapeutic ideas. The high risk and high reward nature of the proposed work makes this application well suited for the R21 mechanism.
The proposed research is relevant to public health because our ability to diagnose and treat complex brain disorders is critically dependent on fundamental understanding of brain networks altered by individual genetic changes recently discovered through human genetic studies. The research described in this proposal will establish a new system for understanding how disruption of genes alters brain connectivity. In the long run, new basic knowledge about gene and brain connectivity relationships will aid in developing novel therapeutic ideas.
