Two researchers at the University of California, Santa Cruz, have received Young Investigator Awards from the The Brain & Behavior Research Foundation.
Tal Sharf, assistant professor of biomolecular engineering, and Mohammed Mostajo-Radji, associate research scientist at the UC Santa Cruz Genomics Institute, will each receive two-year grants to pursue neuroscience research related to brain and behavior disorders. Both researchers, who are members of the Braingeneers group, will use brain organoids – miniature 3D models of brain tissue grown in the lab – to study the genetic roots of conditions including schizophrenia and autism spectrum disorders.
These awards mark the first time UC Santa Cruz scientists have received funding from the foundation.
Schizophrenia’s genetic roots
DiGeorge syndrome, also known as a 22q11.2 microdeletion, is a genetic disorder caused by a deletion of genetic material on chromosome 22. The syndrome is one of the strongest genetic predictors of schizophrenia, as it greatly increases the risk of psychosis. Sharf will lead research to use brain organoids to better understand how the 22q11.2 microdeletion impacts brain circuits.
Sharf’s approach uses organoid models in combination with high-density neuroelectronics, microfluidics, and computational tools. With these, Sharf will study how imbalances in cortical activity and sensory processing via the thalamus, in combination with dopamine signalling, contribute to early circuit disruptions in a genetic model of schizophrenia. He will examine changes to neuronal activity over different time periods, from milliseconds to months, to understand how early developmental changes lead to long-term dysfunction.
These efforts by researchers at the Baskin School of Engineering will lay the foundation for preclinical models to improve therapeutic targeting and drug testing.
Using organoids to understand the SHANK3 gene
In humans, mutations to the SHANK3 gene, even when inherited from just one parent, are known to be linked to challenges in learning, social behavior, and cognition associated with schizophrenia and autism spectrum disorders. However, when studying this gene in mice models, the same impacts are only observed when mutations are inherited from both the mother and father.
Mostajo-Radji’s project aims to uncover why humans are uniquely vulnerable to mutations in this gene by directly comparing how they affect neural development in the two species.
To do this, Mostajo-Radji will compare organoids derived from the stem cells of humans to those from mice. By studying the electric activity and RNA data of these models, he will seek to understand how SHANK3 mutations impact communication, and how evolution may have made humans more susceptible to SHANK3 related disorders.
Findings from this work could inform new therapeutic strategies, such as drugs that target human-specific risk factors, and establish a framework for future research on neurodevelopmental disorders.