HERSHEY, Pa. — Illuminating key biological pathways that underlie neurodevelopmental and psychiatric disorders, such as autism spectrum disorder and attention deficit hyperactivity disorder, is the goal of a new five-year, $17.9 million grant from the National Institutes of Health’s National Institute of Mental Health to a national team of researchers. The research may inform future diagnostic and therapeutic approaches, according to team leader Yongsoo Kim, associate professor of neural and behavioral sciences at the Penn State College of Medicine.
“This is a prestigious recognition of Penn State’s excellence in neuroscience research,” Kim said. “We’re proud to continue advancing critical work in this area.”
Neuropsychiatric disorders affect brain development and often emerge in childhood, presenting in diverse ways, which makes treatment difficult. According to the researchers, such disorders affect more than 20% of children and rates are rising. For example, diagnoses of autism spectrum disorder increased 175% between 2011 and 2022.
Recent studies have identified more than 100 genes that affect neurodevelopmental processes and may increase the likelihood of developing neuropsychiatric conditions, Kim said. But it’s not clear how these genes, individually or collectively, influence the way the brain develops and functions or how these alterations ultimately give rise to changes in behavior that are linked to clinical symptoms.
“The trouble with neurodevelopment disorders like autism is heterogeneity. They’re just so diverse,” Kim said. “If we know the brain or cellular phenotype, or the observable traits that are causally related to these conditions, that gives us a biological signature that we can use to diagnose and potentially to develop treatments.”
The new award will support the creation of an Assay and Data Generation Center (ADGC) to study 100 different high-risk genes associated with neuropsychiatric conditions in a mouse model. The goal, Kim said, is to understand how they disrupt neurodevelopment and lead to a progression of changes, including in gene expression and cell-level alterations across different cell types in the brain, in brain connectivity and, ultimately, in behavior. The project brings together seven investigators across four institutions — Penn State, New York University (NYU) Langone Health, The Jackson Laboratory and University of Texas (UT) Southwestern Medical Center.
This is one of two grants awarded by the National Institute of Mental Health to expand the Scalable and Systematic Neurobiology of Psychiatric and Neurodevelopmental Disorder Risk Genes (SSPsyGene) Consortium, a national effort to investigate the impact of genes linked to neuropsychiatric and neurodevelopmental disease risk. The consortium’s goal is to develop a comprehensive, integrated knowledge base of the associated genes and gene variants and their function that would be available to the biomedical community to advance research on these conditions. The Penn State-led ADGC joins five existing ADGCs in the consortium led by the University of California, Los Angeles; Yale University; Northshore University and Rutgers University; Broad Institute and the Massachusetts Institute of Technology; and Scripps Institute and Broad Institute.
“This is a huge opportunity to leverage our complementary expertise across Penn State’s campuses, continuing our ongoing collaboration,” said Santhosh Girirajan, T. Ming Chu Professor of Genomics and head of the Department of Biochemistry and Molecular Biology at Penn State. “This funded project will bring us closer together, which is especially good for neuroscience and the broader scientific community.”
The project, “Cross Scale Interrogation of NPD Genes (SING),” will examine how high-risk genes interfere with neurological development. NPD refers to neurodevelopmental and psychiatric disorders. The team will conduct a systematic investigation of the genes’ effects on four different levels — genes, cells, neural circuits or the interconnected networks of neurons, and behavior — using standardized methods. It’s complex research, requiring expertise across various domains, but will rapidly scale up research on neuropsychiatric disorders, Kim said. It builds on research in models of human organoids, or simplified organs created for laboratory study, and zebrafish led by other consortium ADGCs.
“The brain is perhaps the most complex organ in the body. Current technologies allows us to investigate the brain from the level of genes to cell types to behavior,” said Anirban Paul, assistant professor of neural and behavioral sciences at the Penn State College of Medicine, who will also serve as a principal investigator on the grant. “With this grant, we can cut across all of these layers to get an emergent understanding of the biological pathways that’s not possible from studying any one level in isolation.”
Paul compared their work to a layered cake, explaining that individual layers taste OK but all the layers together provides a much fuller, richer experience.
At the ADGC led by researchers at Penn State, the team will examine what happens when the100 high-risk genes associated with neuropsychiatric conditions lose function in mice. Mice are widely used as a model in neuroscience research because they share similar physiology as humans, particularly the nervous system. The research aims to capture the full impact of the high-risk genes across developmental stages, from immature to mature, and the data will be integrated into one cohesive framework.
“This grant will allow us to systematically examine physiological functions of hundreds of risk genes involved in neurodevelopmental and neuropsychiatric diseases at the same time using a mouse model,” said Yingwei Mao, professor of biology at Penn State and investigator on the grant.
First, the team will identify molecular and cellular changes that result from the loss of function of the high-risk genes. They will use techniques like single-cell sequencing to generate a high-resolution picture of the genetic material within individual cells, and spatial transcriptomics to study the location of gene expression in cells and tissues. It will help identify the networks regulated by the high-risk genes and the types of cells that depend on these networks. The team will also examine how the high-risk genes impact the way different cell types communicate, which “would have cascading effects as the brain grows,” Paul said.
They will then employ advanced imaging methods, like magnetic resonance imaging (MRI) and 3D-mapping tools, to examine how modifications in gene expression and at the cellular level lead to alterations in brain anatomy and structure, nerve cell composition and connectivity. Behavior, in essence, is an output of the nervous system, the result of how nerve cells interact and communicate with each other. The team will track how these changes result in altered cognitive, social and other behaviors in the mice.
Finally, researchers will integrate and analyze data from across the studies, using machine learning algorithms to identify genes that lead to shared biological pathways across neuropsychiatric disorders, as well as genes that cause those pathways diverge for distinct conditions. Understanding these pathways is crucial for gaining a deeper mechanistic understanding of the genetic basis of these conditions and informing future therapies, according to the research team.
“Pathways that converge would tell us the lowest common denominator across multiple neurodevelopmental disorders. Then, we could possibly target several disorders with the common therapy plan,” Paul said, explaining that understanding where biological pathways diverge could lead to more tailored approaches to diagnosis and treatment. “We may be able to say that this person has autism because of mutation in this gene, which affects this cell type, and that would make our plan for therapy very individualized. That's the grand hope we think would come out of this project.
The team plans to share the data on an interactive web-based platform so that it’s accessible to other researchers, a goal of the SSPsyGene Consortium. In addition, the team will conduct a pilot study to develop innovative methods to knockout target genes in mice using CRISPR, a gene editing technology. This would greatly accelerate future studies of NPD genes by overcoming the limited scalability of current methods, according to Mao.
The research team includes seven investigators with complementary expertise. Kim will serve as principal investigator and main contact for the grant. He will lead work on the advanced imaging alongside Jiangyang Zhang, associate professor of radiology at NYU Langone Health, who will manage the MRI-based imaging studies. Vivek Kumar, associate professor at The Jackson Lab, will also serve as a principal investigator. He will oversee the behavioral analysis while Paul will lead the molecular and cellular analyses. Mao and Yingxi Lin, professor of psychiatry at UT Southwestern Medical Center, will guide the pilot study. Girirajan will implement the integrated data analysis in collaboration with the team.