Reversal of Opioid-Induced Pathological Neuroplasticity Through Timed Electrical Stimulation

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This project seeks to develop electrical brain stimulation methods to reverse drug-induced pathological neuroplasticity. Addictions are difficult to treat in part because drugs of abuse transform reward and decision- making circuits, persistently remodeling them in ways that lead to persistent cravings. As a result, relapse rates are high even with gold-standard treatment. Animal studies using optogenetics and related technologies suggest that drug-induced plasticity can be reversed by targeted circuit manipulations. This is particularly true in circuits related to the nucleus accumbens (NAc), a “hub” of brain reward circuitry. For instance, co-PI Thomas showed that chronic morphine exposure in mice strengthened an infralimbic cortex (IL) to NAc synapse. Weakening this same synapse blocked reinstatement of drug-seeking after a period of abstinence (a model of relapse). The challenge is that our circuit-directed tools for animals do not translate readily to humans. Electrical deep brain stimulation (DBS), particularly of the nucleus accumbens (NAc), is feasible in humans with addiction, but appears not to work reliably in its current form. This is in part because clinical NAc DBS uses approaches developed for Parkinson disease, without considering addiction biology. That is, it does not address the neuroplasticity problem. We propose to develop an electrical intervention that specifically targets pathological IL-NAc connectivity, based around the concept of timing-dependent plasticity. In short, if one structure (NAc) is stimulated only in response to changes in another’s (IL’s) activity, the synapses between then can be specifically strengthened or weakened, based entirely on the timing between the two events. Co-PI Widge has developed such activity-dependent stimulation methods for modulating fear-related amygdala circuitry. There is a long tradition of using similar approaches for rehabilitation of spinal cord injury and stroke. We will apply activity-dependent electrical stimulation to modify the IL-NAc circuit of Long-Evans rats, as a first step towards a human brain stimulation therapy. We will develop real-time IL-NAc connectivity measurement tools (Aim 1) and identify the electrical stimulation parameters (timing, intensity) that can de-facilitate the IL-NAc connection (Aim 2a). We will then apply those optimized methods to rats exposed to morphine in a conditioned place preference paradigm (Aim 2b), comparing our electrical approach to Dr. Thomas’ existing optogenetic approach. We hypothesize that this activity-dependent electrical approach will be equally effective, while also being much easier to translate. Success would have near-term clinical potential. Dr. Widge is both a neural engineer and a brain stimulation psychiatrist, with specific experience in NAc DBS. Both PIs are affiliated with state-funded initiatives in addiction treatment development. We are well positioned to translate potential outcomes from this effort into novel, mechanism-informed treatments for addiction.