Focused ultrasound-induced blood-brain barrier opening promotes glioprotective phenotypes in ACSA-II+ murine astrocytes.
Authors: Noel RL, Kline-Schoder AR, Batts AJ, Kwon N, Tsitsos F, Konofagou EE
Focused ultrasound-induced blood-brain barrier opening (FUS-BBBO) is a well-established neuroimmune modulation and drug delivery enhancement tool capable of effecting cellular, cognitive, and pathological benefits in the brain. However, the cellular mechanisms underlying these bioeffects remain incompletely characterized, motivating the present study investigating the role of a critical glial cell type: astrocytes. Here, we use single-cell RNA sequencing and flow cytometry to characterize the phenotypic response of hippocampal astrocytes 2, 4, and 7 days after FUS-BBBO exposure in aged WT and Alzheimer's disease mice. The data presented herein indicate that FUS-BBBO increases gene expression related to synapse modification, neurogenesis, ion transport, and neuronal development. Taken together, these data elucidate a glioprotective role for hippocampal astrocytes following FUS-BBBO, offering mechanistic context and support for previously observed benefits of FUS-BBBO. This evidence critically deepens our understanding of the cellular effects of FUS-BBBO as clinical adoption becomes more widespread.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To characterize the phenotypic response of hippocampal astrocytes to focused ultrasound-induced blood-brain barrier opening (FUS-BBBO) in aged wild-type and Alzheimer’s disease mice using single-cell RNA sequencing and flow cytometry at 2, 4, and 7 days post-treatment.
Animal model / Human subject
Mouse (Mus musculus); strain: wild-type (WT) and Alzheimer's disease transgenic (specific strain not specified); age: aged; sex: not specified
Disease model
Alzheimer's disease
MRI or image guidance method
T1-weighted MRI
Targeted brain region(s)
Hippocampus
Outcomes and Safety
Summary of Outcomes
Focused ultrasound–induced BBB opening (FUS-BBBO) targeted to the bilateral hippocampus produced a sustained glioprotective astrocyte response—upregulating genes for synapse modification, neurogenesis, cytoskeletal/process movement, and oligodendrocyte-support signaling—was associated with trends toward increased MOG+ oligodendrocytes (especially in young mice), and did not induce astrocyte proliferation or reactive gliosis. Only a single FUS-BBBO targeting paradigm was used (single, bilateral hippocampal FUS-BBBO as described); no multiple ultrasound parameter sets were tested or compared.
Duration of biological effect
7 days
Safety-related matter
No adverse effects were reported; FUS-BBBO did not induce astrocytic proliferation, reactive gliosis, or glial scarring with the parameters used, and no significant changes in the proportion of ACSA-II+ astrocytes or MOG+ oligodendrocytes were detected.
Brain Region
Ultrasound Parameters
Ultrasound instrument
Single-element, concave FUS transducer
FUS Frequency
1.5 MHz
FUS Pressure
0.45 Mpa
FUS Mode
pulsed
Pulse duration
6.67 ms
Duration of a single FUS session
60 s
Focal Characteristics
focal depth: None; focal length: 60 mm; aperture size: 60 mm
Treatment frequency
single
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