Determining the information processing changes that underlie the phenotype of an ASD risk gene in rats

University Of California, San Francisco, San Francisco CA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Although there has been tremendous progress in identifying high-risk, large effect, genes for psychiatric disease, we continue to have a very limited ability in understanding how single genes cause the complex symptoms associate with the disorder. To bridge that gap, genetically modified animals are invaluable, but to take advantage of such animal models, it is critical to have clear and interpretable behavioral readouts of the effect of the genetic manipulation. I have recently identified a phenotype consistent with restrictive and repetitive behavior in a rat haploinsufficiency for a high-risk ASD gene. Restrictive and repetitive behaviors are one of the core diagnostic features of ASD. Furthermore, I have shown this phenotype to be consistent with improper functioning of the hippocampus in these animals. The scientific objective of this project is to determine the changes to the hippocampus and its communication with other brains regions in the context of this high-risk gene. The specific aims employ automated measurement of rat behavior, large scale neural recordings during behavior, genetically modified rats, and functional ultrasound imaging during behavior. The preliminary data provides a clear phenotype and a strong hypothesis to motivate the physiological studies. The use of these methods will enable the connection between the phenotype and the underlying neural activity. This will provide an invaluable framework for future studies into the changes to neural computations in the context of psychiatric disease processes. In addition to the proposed studies, this proposal develops a plan to train Dr. Kastner for an independent research career as a neuroscientist and psychiatrist. This plan is mentored by Dr. Michael Brainard, an expert in the study of the neurophysiology underlying complex behavior, with the co-mentorship of Dr. Emma Wood Dayan, an expert in hippocampal physiology and how that changes in the context of high-risk disease genes, and Dr. Tommaso Di Ianni, an expert in functional ultrasound imaging.