Electrical connectomics: an innovative approach for dissecting brain mechanisms underlying behavioral states

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Project Summary: Understanding the mechanisms by which the brain encodes behavior presents a major challenge for developing effective therapies with which to treat neurological and psychiatric disorders. The development of brain-wide measurements of neural connectivity in mammalian models holds great potential for overcoming this challenge. Here we propose an innovative approach for collecting and integrating such data across an unprecedented number of interconnected brain regions for use in elucidating the mechanisms by which sensory processing is altered in disease. A number of neurological and psychiatric disorders are triggered or exacerbated by sensory stimuli, yet little is understood about the brain connectivity underlying such sensory hyper/hypo- sensitization. Sensory processing plays a major role in the pathology of: autism spectrum disorders (ASD), schizophrenia, fibromyalgia, attention deficit hyperactivity disorder (ADHD), sensory perception disorders (SPDs), and migraine. Migraine in particular represents a compelling model of sensory hypersensitization, as the response to sensory stimuli is clear, dose- dependent, and measurable. Using state-of-the-art, multi-site in vivo recordings in a well- characterized migraine model, coupled with machine learning, we will develop network-wide electrical maps of the sensory hypersensitivity that underlies migraine. These networks will be validated for their roles in migraine using multiple behavioral assays and migraine-related pharmacological manipulations. We will additionally dissect the mechanisms underlying the sensory hypersensitivity brain state in a mouse model of migraine using optogenetic circuit manipulations as well as single-cell RNA-Seq, with the aim of identifying the contributions of specific circuits, cells, and molecules to this state. This approach is expected to substantially facilitate the use of neural oscillation-based brain networks in biomedical research, as well as provide: 1) a tool for rapid identification of a sensory hypersensitive brain state that can be tested for mechanisms shared across disorders, 2) a map of features of electrical brain networks, which serve as strong hypotheses regarding the routes whereby sensory hypersensitivity brain networks are regulated, and 3) insight into the contributions of specific cell types and molecules to the hypersensitive brain state. Collectively, this study is expected to provide insights into the etiology of migraine and other sensory hypersensitivity disorders that will be critical to developing brain network-based therapies for these diseases.