Neural activity is regulated by complex interaction between numerous neuronal sub-types and non-neuronal cells. The aim of the project is to elucidate neuronal:neuronal and non-neuronal:neuronal circuitry in the brain. Normal sensory evoked neurophysiology is compared neurophysiology under anesthesia, injury, disease, and neuromodulation to identify mechanisms of neurocircuitry and regulatory mechanisms. Neuromodulation include electrical and optogenetic brain stimulation, which have become a mainstay of fundamental neuroscience exploration and an increasingly prevalent clinical therapy. Despite the growing prevalence of neuromodulation therapies, in many cases the fundamental mechanisms driving the beneficial effect for the patient are poorly understood. This project also aims to greatly improve our understanding of how electrical and optical stimulation alters spatial and temporal interactions in the nervous system across molecular, cellular, and network levels on both neuronal and non-neuronal cells. Understanding of the relationship between stimulation parameters, metabolic demand, tissue safety, and their impact on chronic circuit behavior in-vivo across time have been historically limited by the time-course of in-vivo measurement techniques. In this proposal, we use a multi-modal-approached relying on the complementary expertise of each investigator in leading-edge techniques to systematically evaluate the relationship between stimulation parameters and induced changes over time at the molecular, cellular, local network, and distal network levels. An improved mechanistic understanding of how electrical stimulation impacts the overall tissue health and safety limits will help inform improved stimulation paradigms and device design for basic neuroscience research and therapeutic applications.