OptoDBS · Dissecting the biophysical mechanisms of deep brain stimulation using voltage fluorescence microscopy

Deep brain stimulation (DBS) is a promising neuromodulation technique for the treatment of neurological and psychiatric diseases. DBS electrically stimulates brain tissue via implanted electrodes. However, the biophysical and therapeutic mechanisms underlying DBS remain largely unknown. While long-standing theories suggest that DBS suppresses neurons, subsequent studies have shown that DBS activates neurons via direct axonal excitation modulating membrane dynamics, information transfer, and network synchronization. Unfortunately, this conundrum has been difficult to resolve experimentally because of (1) the electrical interference occurring in electrode-based recordings and (2) the challenge of measuring cellular-level membrane voltage dynamics in the awake brain. In this proposal, I will overcome for the first time both key challenges by using a novel in-vivo voltage fluorescence optical technique that permits the direct recording of the membrane voltage from identified neurons in awake animals, free of electrical interference. I will combine voltage fluorescence microscopy and electrical stimulation in a mouse model of epilepsy to optically dissect the cellular mechanisms underlying therapeutic DBS for reducing seizures in the limbic system. This innovative and comprehensive approach will provide novel insights into the cellular and circuit processes occurring during DBS in the awake epileptic brain. This research program will provide an unprecedented opportunity to build a mechanistic framework of DBS and stimulation parameter selection with the ultimate goal of identifying more effective and targeted DBS protocols for human patients.