Focused Ultrasound-Induced Neurogenesis Requires an Increase in Blood-Brain Barrier Permeability

Abstract

Transcranial focused ultrasound technology used to transiently open the blood-brain barrier, is capable of stimulating hippocampal neurogenesis; however, it is not yet known what aspects of the treatment are necessary for enhanced neurogenesis to occur. The present study set out to determine whether the opening of blood-brain barrier, the specific pressure amplitudes of focused ultrasound, and/or the intravenous administration of microbubbles (phospholipid microspheres) are necessary for the enhancement of neurogenesis. Specifically, mice were exposed to burst (10ms, 1Hz burst repetition frequency) focused ultrasound at the frequency of 1.68MHz and with 0.39, 0.78, 1.56 and 3.0MPa pressure amplitudes. These treatments were also conducted with or without microbubbles, at 0.39 + 0.78MPa or 1.56 + 3.0MPa, respectively. Only focused ultrasound at the ~0.78 MPa pressure amplitude with microbubbles promoted hippocampal neurogenesis and was associated with an increase in blood-brain barrier permeability. These results suggest that focused ultrasound -mediated neurogenesis is dependent upon the opening of the blood-brain barrier.

Acute effects of focused ultrasound-induced increases in blood-brain barrier permeability on rat microvascular transcriptome

“…Hippocampal neurogenesis has been observed following FUS910, an effect that requires the presence of MBs and for the peak negative pressure of sonication to be sufficient to induce increases in the permeability of the BBB10. While neurogenesis can be induced by a wide variety of stimuli, the production of specific factors related to acute inflammation, such as Ccl2, Ccl3, and Tnfα, has been demonstrated to promote migration, proliferation, differentiation and survival of neural progenitor cells35.…”

“…This mediates a temporary increase in transcellular transport3 and a widening of tight junctions4, allowing increased paracellular diffusion. Magnetic resonance imaging-guided FUS (MRIgFUS) has been shown to enhance the delivery of several therapeutic agents to the brain5678, as well as induce other bioeffects, including increases in hippocampal neurogenesis910 and reduction in Alzheimer’s disease (AD)-like pathology111213.…”

Acoustically targeted chemogenetics for the non-invasive control of neural circuits

“…Comparing these two FUS-treated conditions to each other allowed us to evaluate the efficacy of ATAC while accounting for any potential behavioral effects caused by the FUS treatment itself 38,39 . To confirm that the effect of activation of DREADDs was specific to fear formation, and did not affect basic exploratory behavior, we monitored treated and untreated mice in an open field test.…”

Focused ultrasound as a novel strategy for Alzheimer disease therapeutics

“…Interestingly, some studies have shown that BBB opening alone may lead to significant plaque reductions in transgenic mice and in some instances, to hippocampal neurogenesis (Fig ) . Follow‐up studies revealed increased endogenous IgG and IgM bound to Aβ plaques and glial phagocytic activation.…”