The modulation of the blood-brain barrier by focused ultrasound stimulates oligodendrogenesis

Focused ultrasound (FUS) combined with intravenous microbubbles (MB) enables precise and reversible modulation of the blood-brain barrier (BBB) to enhance the delivery of therapeutics from the blood to targeted brain areas. Beyond this application, we discovered over a decade ago that FUS-BBB modulation, without the addition of exogenous therapeutics, activates endogenous regenerative events, "most notably" hippocampal neurogenesis. Here, we investigate the effects of FUS on oligodendrogenesis, a key process for myelination and white matter integrity. In adult mice, we targeted FUS-BBB modulation unilaterally to the hippocampus. The proliferation of oligodendrocyte precursor cells (OPCs) was quantified at 1, 4, 7, and 10 days post-treatment and myelinating oligodendrocytes were assessed at 30 days. At 1 and 4 days post-sonication, the proliferation of hippocampal OPCs increased by 6.8-fold and 2.3-fold, respectively; this resulted in a 5.3-fold increase in myelinating oligodendrocytes one month later. Next, we tested the robustness of FUS-induced oligodendrogenesis using an independent experimental design and targeting the striatum in a separate cohort of mice. The proliferation of striatal OPCs increased by 3.9-fold at 7 days post-FUS. This led to a 5.2-fold increase in oligodendrogenesis 30 days post-treatment, as observed in the hippocampus. Finally, we found that treatments at the same FUS parameters but without MB and without altering the BBB, did not lead to the proliferation of OPCs or oligodendrogenesis. Therefore, with these FUS parameters, MB-induced BBB modulation emerged as a key factor that promoted oligodendrogenesis. Given the long-validated application of FUS-BBB modulation for drug delivery, the additional stimulation of oligodendrogenesis broadens the therapeutic potential of this modality for white matter repair.