DESCRIPTION (provided by applicant): Whole-brain mapping of cellular data in animal models will revolutionize our understanding of neural circuits and behavior. Microscopy hardware has progressed to a point where it is becoming routine to archive labeled whole animal brains. Furthermore, computing power and the software ecosystem are now mature enough that very large datasets can be managed. However, bioinformatics tools specifically designed for whole-brain mapping of cellular signals in animal models are lacking. Our collaborative group has recently created a suite of bioinformatics tools capable of reconstructing and then analyzing whole-brain data sets. However, because of their complexity, these tools can only be used by computer scientists in their current form. Thus, the goal of this project is to optimize a streamlined approach to digitally archive mouse brains so that whole-brain cellular measures can be more easily reconstructed and then analyzed. The results of such experiments are expected to vastly increase understanding of brain function. This will be accomplished by developing a seamless protocol for immunolabeling the mouse brain, followed by digital archiving of the brains, detection of cellular signals and analysis of these signals across the entire mouse brain. As part of developing this protocol, a web-based portal will be created that users around the world will be able to utilize to perform 3D reconstructions and subsequent analysis of their own mouse brain digital sections. Importantly, this system will be amenable to any form of cellular labeling, such as signals arising from any number of fluorescent reporters. In order to optimize this workflow and to test the utility of the web-based portal, mapping of whole brain activity is proposed in a mouse model of autism spectrum disorders and intellectual disability in response to social novelty. These would be the first whole brain cellular activation maps in a model of a developmental brain disorder. It is expected that these maps will advance our understanding of the neurobiology of developmental brain disorders by revealing brain areas that are dysfunctional during abnormal social behaviors. Importantly, the web-based portal will make whole brain mapping of cellular signals more accessible to the neuroscience community. This would enable other labs to map whole brain cellular data in any neuropsychiatric disease model. Collectivity, whole-brain mapping data from numerous distinct disease models by labs throughout the world would be expected to reveal common systems-level substrates of severe brain disorders.

PUBLIC HEALTH RELEVANCE: Whole-brain mapping of cellular data in animal models will revolutionize our understanding of neural circuits and behavior. However, streamlined procedures for mapping whole-brain cellular signals are lacking. Here, using a genetic model of autism spectrum disorders, we will create a streamlined whole-brain mapping procedure for mice in order to identify brain areas that are dysfunctional during an abnormal social experience.