Noninvasive Neuromodulation via Ultrasonic Activation of Endogenous and Exogenous Ion Channels
Date of Award
Doctor of Philosophy (PhD)
Neuromodulation technology is key to understanding brain function and treating brain diseases. Conventional neuromodulation technologies, such as direct current stimulation, transcranial magnetic stimulation, and optogenetics, predominately rely on electromagnetic waves. However, the fundamental physical law the tradeoff-relationship between penetration and spatial resolution, limits their transcranial penetration within the superficial cortex layer. To overcome this challenge, electrodes or optical fibers need to be surgically implanted into the brain to modulate specific brain regions. Different from electromagnetic waves, ultrasound, as a mechanical wave, can non-invasively penetrate through the intact skull to reach deep brain regions with millimeter spatial focus. Ultrasound has shown great promise in modulating brain activity in animal models and humans. However, there are three major challenges that need to be addressed to enable the braod application of ultrasound in neurmodulation. First, direct evidence is still lacking to demonstrate that ultrasound can activate neurons and evoke a circuit-specific behavior. Second, how ultrasound activates neural activity is largely unknown. Third, conventional ultrasound neuromodulation lacks cell-type selectivity. In this thesis, I first demonstrated that ultrasound can non-invasively induce torpor-like hypothermia and hypometabolism state by modulating the preoptic area (POA) of the hypothalamus. The depth and duration of this state can be precisely controlled by ultrasound parameters. This behavior change was found to be directly related to the ultrasound-induced neuronal activation in POA regions. These neurons act on the dorsomedial hypothalamus to suppress downstream brown adipose tissue thermogenesis and metabolism. This study provides strong and direct evidence that ultrasound can activate the targeted neurons and evoke a circuit-specific behavior change. Second, I discovered that the ultrasound-sensitive ion channels, including TRPV1 and TRPM2, are the key molecular sensors for ultrasound neuromodulation. Chemical blocker and genetic knockdown of the TRPM2 and TRPV1 in the hypothalamus significantly suppressed the ultrasound-induced torpor effect. Overexpression of TRPM2 and TRPV1 in HEK293 cells sensitizes the cells to be activated by ultrasound. This in-vivo screening and in-vitro validation reveal that TRPV1 and TRPM2 are ultrasound-sensitive ion channels that are the fundamental mechanism of ultrasound neuromodulation at the POA region. Lastly, I developed TRPV1-mediated sonogenetics for cell-type selective neuromodulation. Ultrasound targeting 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 ultrasound-targeted brain region as measured by in vivo magnetic resonance thermometry. Ultrasonic stimulation of TRPV1-expressing neurons at the striatum repeatedly evoked locomotor behavior in freely moving mice. Ultrasound sonication was confirmed to be safe based on inspection of neuronal integrity, inflammation, and apoptosis markers. This is one of the pioneering research developing sonogenetics in the mammalian brain and the first study demonstrating that sonogenetic can evoke behavior change in freely moving mice. In summary, this work provided evidence that supports the direct neural activation by ultrasound in the context of evoking specific behavior. It also discovered two ultrasound-sensitive ion channels TRPV1 and TRPM2, demonstrating that the activation of ultrasound-sensitive ion channels is a potential mechanism underlying ultrasound neuromodulation. Furthermore, we developed TRPV1-mediated sonogenetics to activate cell-type selective neuromodulation that can broaden the application of ultrasound neuromodulation to wide-range neural circuits with a superior specificity. Ultrasound neuromodulation via activation of endogenous and exogenous ion channels has the potential to uncover new ways to treat neurological disorders and advance the understanding of brain function.
Hong Chen, Joseph P. Culver, Jianmin Cui, Meaghan Creed,
Available for download on Monday, August 26, 2024
Biomedical Engineering and Bioengineering Commons, Neuroscience and Neurobiology Commons