Yaoheng Yang1, Christopher Pham Pacia1, Dezhuang Ye2, Lifei Zhu1, Hongchae Baek1, Yimei Yue1, Jinyun Yuan1, Mark J Miller3, Jianmin Cui1, Joseph P Culver4, Michael R Bruchas5, Hong Chen6. 1. Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO, 63130, USA. 2. Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, Saint Louis, MO, 63130, USA. 3. Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA. 4. Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO, 63130, USA; Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, 63110, USA; Department of Physics, Washington University in St. Louis, Saint Louis, MO, 63110, USA. 5. Department of Anesthesiology and Pain Medicine. Center for Neurobiology of Addiction, Pain, and Emotion. University of Washington, Seattle, WA, 98195, USA. 6. Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO, 63130, USA; Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO, 63108, USA. Electronic address: hongchen@wustl.edu.
Abstract
BACKGROUND: Critical advances in the investigation of brain functions and treatment of brain disorders are hindered by our inability to selectively target neurons in a noninvasive manner in the deep brain. OBJECTIVE: This study aimed to develop sonothermogenetics for noninvasive, deep-penetrating, and cell-type-specific neuromodulation by combining a thermosensitive ion channel TRPV1 with focused ultrasound (FUS)-induced brief, non-noxious thermal effect. METHODS: The sensitivity of TRPV1 to FUS sonication was evaluated in vitro. It was followed by in vivo assessment of sonothermogenetics in the activation of genetically defined neurons in the mouse brain by two-photon calcium imaging. Behavioral response evoked by sonothermogenetic stimulation at a deep brain target was recorded in freely moving mice. Immunohistochemistry staining of ex vivo brain slices was performed to evaluate the safety of FUS sonication. RESULTS: TRPV1 was found to be an ultrasound-sensitive ion channel. FUS sonication at the mouse brain in vivo selectively activated neurons that were genetically modified to express TRPV1. Temporally precise activation of TRPV1-expressing neurons was achieved with its success rate linearly correlated with the peak temperature within the FUS-targeted brain region as measured by in vivo magnetic resonance thermometry. FUS stimulation of TRPV1-expressing neurons at the striatum repeatedly evoked locomotor behavior in freely moving mice. FUS sonication was confirmed to be safe based on inspection of neuronal integrity, inflammation, and apoptosis markers. CONCLUSIONS: This noninvasive and cell-type-specific neuromodulation approach with the capability to stimulate deep brain has the promise to advance the study of the intact nervous system and uncover new ways to treat neurological disorders.
BACKGROUND: Critical advances in the investigation of brain functions and treatment of brain disorders are hindered by our inability to selectively target neurons in a noninvasive manner in the deep brain. OBJECTIVE: This study aimed to develop sonothermogenetics for noninvasive, deep-penetrating, and cell-type-specific neuromodulation by combining a thermosensitive ion channel TRPV1 with focused ultrasound (FUS)-induced brief, non-noxious thermal effect. METHODS: The sensitivity of TRPV1 to FUS sonication was evaluated in vitro. It was followed by in vivo assessment of sonothermogenetics in the activation of genetically defined neurons in the mouse brain by two-photon calcium imaging. Behavioral response evoked by sonothermogenetic stimulation at a deep brain target was recorded in freely moving mice. Immunohistochemistry staining of ex vivo brain slices was performed to evaluate the safety of FUS sonication. RESULTS: TRPV1 was found to be an ultrasound-sensitive ion channel. FUS sonication at the mouse brain in vivo selectively activated neurons that were genetically modified to express TRPV1. Temporally precise activation of TRPV1-expressing neurons was achieved with its success rate linearly correlated with the peak temperature within the FUS-targeted brain region as measured by in vivo magnetic resonance thermometry. FUS stimulation of TRPV1-expressing neurons at the striatum repeatedly evoked locomotor behavior in freely moving mice. FUS sonication was confirmed to be safe based on inspection of neuronal integrity, inflammation, and apoptosis markers. CONCLUSIONS: This noninvasive and cell-type-specific neuromodulation approach with the capability to stimulate deep brain has the promise to advance the study of the intact nervous system and uncover new ways to treat neurological disorders.
Authors: Lifei Zhu; Michael B Altman; Andrei Laszlo; William Straube; Imran Zoberi; Dennis E Hallahan; Hong Chen Journal: Ultrasound Med Biol Date: 2019-02-14 Impact factor: 2.998
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