The Modulation of the Blood-Brain Barrier by Focused Ultrasound Stimulates Oligodendrogenesis

Abstract Objective The current study aims to fill a gap in knowledge on the effects of focused ultrasound (FUS)-mediated blood-brain-barrier (BBB) modulation on the proliferation and development of oligodendrocyte progenitor cells (OPCs). Researchers established that FUS combined with intravenous microbubbles can modulate the BBB in a controlled, reversible, localized, and non-invasive manner to facilitate the delivery of intravenous therapeutics to the brain. Over a decade ago, we discovered that, even without intravenous therapeutics, FUS-BBB modulation stimulates elements of brain repair, including hippocampal neurogenesis. Methods In adult mice, FUS-BBB modulation was targeted unilaterally to the hippocampus and proliferation of OPCs was quantified at 1, 4, 7, and 10 days post-FUS. Mature oligodendrocytes were quantified at 30 days post-FUS. OPC proliferation was assessed at 7 days post-FUS, and mature oligodendrocytes at 30 days. Results The proliferation of hippocampal OPCs was increased by 6.8-fold and 2.3-fold between 1 and 4 days post-sonication, respectively, resulting in a 5.3-fold increase in mature oligodendrocytes one month later. To test the robustness of oligodendrogenesis following FUS-BBB modulation, the striatum was targeted as a second brain region with an independent experimental design. In line with hippocampal results, striatal FUS-BBB modulation promoted the generation of OPCs by 3.9-fold during the first week, leading to a 5.2-fold increase in oligodendrogenesis 30 days post-treatment. Interpretation We conclude that FUS-BBB modulation in the hippocampus and striatum promotes oligodendrogenesis by stimulating the proliferation of OPCs and being permissive to their maturation. Highlights Beyond the potential for the delivery of therapeutics to the brain, the modulation of the BBB by FUS can stimulate regenerative effects, including oligodendrogenesis. FUS-BBB modulation induced a significant proliferation of OPCs which resulted in increases in oligodendrogenesis of 5.3-fold in the hippocampus and 6.7-fold in the striatum