Imaging and Perturbing Cortical Network Dysregulation During Social Behavior in Autism Spectrum Disorder - Project Summary Autism spectrum disorder (ASD) affects approximately 1.6% of Americans, with severe cases characterized by pervasive social deficits and altered sensory processing, yet effective treatments for these core symptoms remain elusive. Emerging evidence indicates that ASD arises from distributed cortical network dysregulation driven by imbalances in excitatory–inhibitory (E/I) activity and altered neuromodulatory signaling. Remarkably, optogenetic and pharmacological interventions can rescue social behavior in ASD mouse models, offering a unique opportunity to uncover the network principles underlying behavioral restoration. However, the mechanisms by which local manipulations in key hubs, such as optogenetic inhibition of the medial prefrontal cortex (mPFC), propagate to normalize cortex-wide activity remain unknown. Dissecting these mechanisms is key for developing new therapeutics, but requires tools capable of capturing and controlling distributed cortical networks during behavior—capabilities that current methods lack. To bridge this gap, I will develop and apply next-generation imaging and perturbation technologies to map and manipulate cortex-wide networks during both head-fixed and freely moving social behavior. In the K99 mentored phase, I will use the ultrasensitive, dual-color head-fixed macroscope that I developed to simultaneously measure excitatory, inhibitory, and subthreshold voltage activity across the dorsal cortex, combined with optogenetic and pharmacological interventions, to determine how local restoration of E/I balance reshapes large-scale network dynamics. In parallel, I will deploy a miniaturized macroscope for cortex-wide imaging and targeted optogenetic stimulation in freely moving mice to investigate network dysfunction during naturalistic social interactions. This will establish a unique experimental platform for causal insight into the restoration of E/I balance and social behavior. Building on this foundation, the R00 independent phase will integrate genetically encoded sensors for acetylcholine, serotonin, dopamine, and norepinephrine to map neuromodulatory dynamics alongside neural activity during social behavior. These studies will generate a comprehensive atlas linking neural and neuromodulatory network dysregulation to behavior and to pharmacological or optogenetic rescue. Collectively, this research will reveal the cortex-wide circuit mechanisms underlying ASD, provide mechanistic insight into how pro-social interventions act at the network level, and establish a scalable framework for studying brain-wide circuit dysfunction. I will be mentored to achieve these goals by leaders in systems neuroscience, optogenetics, and theoretical modeling, with guidance from an advisory team at the forefront of brain network and autism research. Stanford’s exceptional resources, training, and collaborative environment will provide the technical and professional foundation to launch an independent research program that bridges technology development and systems neuroscience to uncover fundamental principles of cortical network function and dysfunction.
