Low-intensity ultrasound restores long-term potentiation and memory in senescent mice through pleiotropic mechanisms including NMDAR signaling

• Published in: Molecular psychiatry Vol. 26; no. 11; pp. 6975 - 6991
• Main Authors: Blackmore, Daniel G., Turpin, Fabrice, Palliyaguru, Tishila, Evans, Harrison T., Chicoteau, Antony, Lee, Wendy, Pelekanos, Matthew, Nguyen, Nghia, Song, Jae, Sullivan, Robert K. P., Sah, Pankaj, Bartlett, Perry F., Götz, Jürgen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-11-2021; Nature Publishing Group
• Subjects: 14/63; 631/378; 631/45; 64/60; 82; 82/58; 9/30; Aging; Animal memory; Animals; Behavioral Sciences; Biological Psychology; Blood-brain barrier; Cognition - physiology; Cognitive ability; Dentate gyrus; Geriatrics; Glutamic acid receptors; Health aspects; Hippocampus; Hippocampus - metabolism; Long-term potentiation; Long-Term Potentiation - physiology; Medicine; Medicine & Public Health; Memory; Mice; N-Methyl-D-aspartic acid receptors; Neurogenesis; Neurosciences; Perineuronal nets; Pharmacotherapy; Physiological aspects; Pleiotropy; Psychiatry; Psychological aspects; Receptors, N-Methyl-D-Aspartate - metabolism; Spatial discrimination learning; Ultrasonic imaging; Ultrasound; Australia
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-021-01129-7

Advanced physiological aging is associated with impaired cognitive performance and the inability to induce long-term potentiation (LTP), an electrophysiological correlate of memory. Here, we demonstrate in the physiologically aged, senescent mouse brain that scanning ultrasound combined with microbubbles (SUS
+MB
), by transiently opening the blood–brain barrier, fully restores LTP induction in the dentate gyrus of the hippocampus. Intriguingly, SUS treatment without microbubbles (SUS
only
), i.e., without the uptake of blood-borne factors, proved even more effective, not only restoring LTP, but also ameliorating the spatial learning deficits of the aged mice. This functional improvement is accompanied by an altered milieu of the aged hippocampus, including a lower density of perineuronal nets, increased neurogenesis, and synaptic signaling, which collectively results in improved spatial learning. We therefore conclude that therapeutic ultrasound is a non-invasive, pleiotropic modality that may enhance cognition in elderly humans.