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

Abstract

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 (SUSonly), 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.

Long term study of motivational and cognitive effects of low-intensity focused ultrasound neuromodulation in the dorsal striatum of nonhuman primates

“…Hence, FUS neuromodulation of the dorsal striatum without BBB opening may have qualitatively different effects that FUS-mediated BBB opening. This is in contrast to the results of a recent study in senescent mice [53] in which FUS was directed to the dentate gyrus of the hippocampus with and without BBB opening. In that study, BBB opening after FUS with microbubbles led to recovery of long-term potentiation (LTP).…”

Therapeutic Ultrasound as a Treatment Modality for Physiological and Pathological Ageing Including Alzheimer’s Disease

“…We therefore used 20-22 month-old WT mice to determine whether therapeutic ultrasound can restore cognitive functions in the aged mouse brain. We made the remarkable observation that six weekly sessions of either SUS +MB or, surprisingly, SUS only , restored LTP induction in these aged mice [11] (Figure 1). This demonstrates that in the physiologically aged brain, BBB opening, i.e., blood-borne factors entering the brain, is not required for the observed restorative effects of SUS.…”

“…Physiological ageing leads to a progressive decline in the functional and cellular constituents of the brain [19]. In a recent study, we explored the neuromodulatory potential of SUS in aged, cognitively impaired C57BL/6 wild-type mice [11]. Earlier studies in the lab in wild-type mice applied SUS +MB and were intended to assess short-and long-term safety.…”

“…Appreciating the overlap between physiological and pathological ageing such as AD is relevant for developing therapeutic interventions. Very recently, we started to apply SUS to senescent wild-type mice, and our data indicate that this approach may be useful as a cognition enhancement tool [11]. We then discuss the current treatment options for AD, what the clinical trial landscape looks like, and which particular challenges are being encountered as one aims to develop a cure or even a disease-modifying therapy for AD.…”

Focused Ultrasound Stimulation as a Neuromodulatory Tool for Parkinson’s Disease: A Scoping Review

“…Interestingly, Blackmore et al corroborated these findings in a recent study that showed FUS restored long-term potentiation and memory in senescent mice. Specifically, they demonstrated that FUS significantly raised levels of TRPA1 levels in synaptosomal hippocampal fractions compared with sham treatments [ 94 ]. This increase, reflected by the changes observed for NMDAR subunits in these fractions, suggests that ultrasound-mediated astrocytic glutamate release is a likely mechanism by which FUS led to the observed improvements in senescent mice, which may also explain the improvements in locomotor behaviour as seen in PD models [ 94 ].…”