Abstract
Possessing the ability to noninvasively elicit brain circuit activity yields immense experimental and therapeutic power. Most currently employed neurostimulation methods rely on the somewhat invasive use of stimulating electrodes or photon-emitting devices. Due to its ability to noninvasively propagate through bone and other tissues in a focused manner, the implementation of ultrasound (US) represents a compelling alternative approach to current neuromodulation strategies. Here, we investigated the influence of low-intensity, low-frequency ultrasound (LILFU) on neuronal activity. By transmitting US waveforms through hippocampal slice cultures and ex vivo mouse brains, we determined LILFU is capable of remotely and noninvasively exciting neurons and network activity. Our results illustrate that LILFU can stimulate electrical activity in neurons by activating voltage-gated sodium channels, as well as voltage-gated calcium channels. The LILFU-induced changes in neuronal activity were sufficient to trigger SNARE-mediated exocytosis and synaptic transmission in hippocampal circuits. Because LILFU can stimulate electrical activity and calcium signaling in neurons as well as central synaptic transmission we conclude US provides a powerful tool for remotely modulating brain circuit activity.
Highlights
Neuromodulation techniques such as deep brain stimulation (DBS) and repetitive transcranial magnetic stimulation have gained widespread attention due to their therapeutic utility in managing numerous neurological/psychiatric diseases [1]
By optically monitoring changes in ionic conductance in individual neurons and synaptic transmission from individual release sites we investigated the influence of low-intensity, low-frequency ultrasound (LILFU) on central nervous system activity
Since hypertonic sucrose application is still capable of triggering neurotransmitter release at hippocampal synapses lacking the SNARE-protein SNAP-25 [37], we aimed to determine if LILFU1 was capable of stimulating neurotransmitter release after cleaving SNAP-25 by treating slice cultures with botulinum neurotoxin type-A (BoNT/A; 24–36 h)
Summary
Neuromodulation techniques such as deep brain stimulation (DBS) and repetitive transcranial magnetic stimulation (rTMS) have gained widespread attention due to their therapeutic utility in managing numerous neurological/psychiatric diseases [1]. Coupling its ability to interact with biological tissues [5] and its noninvasive transmission through skull bone and other biological tissues in a focused manner [6,7,8], US holds promise as a potentially powerful neurostimulation tool [9,10], which may be capable of replacing currently invasive DBS strategies. Therapeutic US can be broadly characterized as low-power/low-intensity or high-power/highintensity [5]. High-intensity focused ultrasound (HIFU) used in the thermal ablation of tissue implements peak power levels often exceeding 1000 W/cm, whereas non-thermal therapeutic effects of US have been well described at power levels ranging from 30– 500 mW/cm2 [5,11,12,13]
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