Non-invasive targeting of perineuronal nets for treating excessive repetitive behavior - Project Summary Atypical repetitive behavior is a common and debilitating feature of several neuropsychiatric conditions, including obsessive-compulsive disorder, autism spectrum disorders, and schizophrenia. Unfortunately, medical efforts to improve such behavioral deficits have met with limited success. It is therefore of critical importance to pursue all potential avenues for mitigating such challenges. An emerging therapeutic target for the dysfunction of brain circuitry is perineuronal nets (PNNs), which are specialized components of the extracellular matrix serving diverse physiological roles. Disturbances in PNNs occur in models of multiple neurological disorders, and targeted degradation of PNNs has been shown to improve behavioral function. Notably, focal digestion of PNNs normalizes atypical repetitive behavior in a mouse model of excessive, repetitive behavior. Injection of the enzyme Chondroitinase ABC (ChABC) into the dorsomedial striatum locally degrades PNNs and restores normal levels of grooming behavior and digging behavior. These are promising findings because they define a novel therapeutic target for repetitive behavior and highlight the potential of benefits of focal PNN degradation. However, a major impediment to implementing this therapeutic approach is that it requires multiple, direct injections of ChABC, each necessitating a craniotomy. The current project will develop a novel strategy to non-invasively and focally degrade PNNs to achieve the same behavioral improvements. Magnetic Resonance-guided, low intensity focused ultrasound will be used to focally and transiently open the blood brain barrier (BBB) to deliver intravenously- administered ChABC to the dorsomedial striatum. Intravenous administration of ChABC is well tolerated, and our preliminary data provide the first evidence that this novel strategy is effective for focally degrading PNNs in a targeted area of the brain. The goals of the current project are to optimize the parameters for this new strategy in the dorsomedial striatum, and to test its therapeutic value in a model of excessive, repetitive behavior in which invasive targeting of PNNs has previously been shown to improve repetitive behavior. This project will establish a novel strategy for non-invasively degrading PNNs and will test the efficacy of this approach for treating a critical neurological disorder. This practical strategy could ultimately be applied for the treatment of a range of medically-intractable neurological disorders in which targeting PNNs has been shown to be a promising intervention.
