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Noninvasive sub-organ ultrasound stimulation for targeted neuromodulation.

ABSTRACT: Tools for noninvasively modulating neural signaling in peripheral organs will advance the study of nerves and their effect on homeostasis and disease. Herein, we demonstrate a noninvasive method to modulate specific signaling pathways within organs using ultrasound (U/S). U/S is first applied to spleen to modulate the cholinergic anti-inflammatory pathway (CAP), and US stimulation is shown to reduce cytokine response to endotoxin to the same levels as implant-based vagus nerve stimulation (VNS). Next, hepatic U/S stimulation is shown to modulate pathways that regulate blood glucose and is as effective as VNS in suppressing the hyperglycemic effect of endotoxin exposure. This response to hepatic U/S is only found when targeting specific sub-organ locations known to contain glucose sensory neurons, and both molecular (i.e. neurotransmitter concentration and cFOS expression) and neuroimaging results indicate US induced signaling to metabolism-related hypothalamic sub-nuclei. These data demonstrate that U/S stimulation within organs provides a new method for site-selective neuromodulation to regulate specific physiological functions.

SUBMITTER: Cotero V

PROVIDER: S-EPMC6414607 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Noninvasive sub-organ ultrasound stimulation for targeted neuromodulation.

Cotero Victoria V Fan Ying Y Tsaava Tea T Kressel Adam M AM Hancu Ileana I Fitzgerald Paul P Wallace Kirk K Kaanumalle Sireesha S Graf John J Rigby Wayne W Kao Tzu-Jen TJ Roberts Jeanette J Bhushan Chitresh C Joel Suresh S Coleman Thomas R TR Zanos Stavros S Tracey Kevin J KJ Ashe Jeffrey J Chavan Sangeeta S SS Puleo Christopher C

Nature communications 20190312 1

Tools for noninvasively modulating neural signaling in peripheral organs will advance the study of nerves and their effect on homeostasis and disease. Herein, we demonstrate a noninvasive method to modulate specific signaling pathways within organs using ultrasound (U/S). U/S is first applied to spleen to modulate the cholinergic anti-inflammatory pathway (CAP), and US stimulation is shown to reduce cytokine response to endotoxin to the same levels as implant-based vagus nerve stimulation (VNS). ...[more]

PMID: 30862827

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Project description:Sonogenetics is a promising approach for in vivo neuromodulation using ultrasound (US) to non-invasively stimulate cells in deep tissue. However, sonogenetics requires accurate transduction of US-responsive proteins into target cells. Here, we introduce a non-invasive and non-viral approach for intracerebral gene delivery. This approach utilizes temporary ultrasonic disruption of the blood-brain barrier (BBB) to transfect neurons at specific sites in the brain via DNA that encodes engineered US-responsive protein (murine Prestin (N7T, N308S))-loaded microbubbles (pPrestin-MBs). Prestin is a transmembrane protein that exists in the mammalian auditory system and functions as an electromechanical transducer. We further improved the US sensitivity of Prestin by introducing specific amino acid substitutions that frequently occur in sonar species into the mouse Prestin protein. We demonstrated this concept in mice using US with pPrestin-MBs to non-invasively modify and activate neurons within the brain for spatiotemporal neuromodulation. Method: MBs composed of cationic phospholipid and C3F8 loaded with mouse Prestin plasmid (pPrestin) via electrostatic interactions. The mean concentration and size of the pPrestin-MBs were (16.0 ± 0.2) × 109 MBs/mL and 1.1 ± 0.2 ?m, respectively. SH-SY5Y neuron-like cells and C57BL mice were used in this study. We evaluated the gene transfection efficiency and BBB-opening region resulting from pPrestin-MBs with 1-MHz US (pressure = 0.1-0.5 MPa, cycle = 50-10000, pulse repetition frequency (PRF): 0.5-5 Hz, sonication time = 60 s) using green fluorescence protein (Venus) and Evans blue staining. Results: The maximum pPrestin expression with the highest cell viability occurred at a pressure of 0.5 MPa, cycle number of 5000, and PRF of 1 Hz. The cellular transfection rate with pPrestin-MBs and US was 20.2 ± 2.5%, which was 1.5-fold higher than that of commercial transfection agents (LT-1). In vivo data suggested that the most profound expression of pPrestin occurred at 2 days after performing pPrestin-MBs with US (0.5 MPa, 240 s sonication time). In addition, no server erythrocyte extravasations and apoptosis cells were observed at US-sonicated region. We further found that with 0.5-MHz US stimulation, cells with Prestin expression were 6-fold more likely to exhibit c-Fos staining than cells without Prestin expression. Conclusion: Successful activation of Prestin-expressing neurons suggests that this technology provides non-invasive and spatially precise selective modulation of one or multiple specific brain regions.

Dataset Information

Noninvasive sub-organ ultrasound stimulation for targeted neuromodulation.

Publications

Noninvasive sub-organ ultrasound stimulation for targeted neuromodulation.

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