BRIEF TRANSCRANIAL FOCUSED ULTRASOUND STIMULATION CAUSES LASTING MODIFICATIONS TO THE SYNAPTIC CIRCUITRY OF THE HIPPOCAMPUS

Brief transcranial focused ultrasound (tFUS) is used in cognitive mapping, where it is assumed that the intervention itself does not cause lasting modifications to the underlying networks being targeted. However, how post-stimulation (‘offline’) effects impact the dynamic function of neural circuits is largely unknown. We found that 40 s of tFUS targeting the hippocampus in 12-week-old male and female rats in vivo led to lasting changes in synaptic circuitry. Following sham or tFUS stimulation, acute hippocampal slices were immediately collected from treated animals (n= 6 (sham) vs 6 (tFUS)) and ex vivo field electrophysiology assays were performed at CA3-CA1 synapses. When compared with sham stimulated tissue, CA3-CA1 synapses in ultrasound stimulated hippocampi showed elevated basal transmission and increased susceptibility to long-term potentiation (LTP); both effects lasted for the duration of experiments (1 – 8 hours post-stimulation). These findings mimicked in vitro experiments in which identical changes to CA3-CA1 synaptic circuitry were observed in acute hippocampal slices following slice exposure to 40 s of ultrasound or sham stimulation. Notably, the application of an AKT inhibitor to the in vitro hippocampal slices before ultrasound stimulation abolished offline changes to LTP, suggesting that a canonical AKT-dependent metaplastic process underlies this ultrasound-mediated effect to hippocampal circuitry. Together, these results indicate that brief ultrasound stimulation can induce persistent changes to synaptic function, driving metaplastic processes beyond the duration of the stimulus itself. Such effects could be leveraged in therapeutic neuromodulation and highlight the capacity for brief ultrasound stimulation to induce significant offline effects.