Elucidating the Role of Mechanosensitive Ion Channels in Ultrasound Stimulation Treatments for Neuroinflammatory Injury and Disease - PROJECT SUMMARY Chronic neuroinflammation negatively impacts health outcomes in brain injury and disease. Microglia, the brain’s resident immune cells, are the primary mediators of the neuroinflammatory response and play a pivotal role in clearing debris and maintaining tissue homeostasis. While their acute response is critical for tissue repair, chronic microglial activation often leads to neurodegeneration, hindering recovery. For example, the implantation of neural electrodes for therapeutic stimulation can trigger glial scarring and chronic neuroinflammation, impairing device performance. Similarly, neuroinflammation drives Alzheimer’s Disease progression, characterized by increased accumulation of amyloid-beta (Aβ) deposits, reduced cerebral blood flow, and worsening dementia. Improving microglial activation at the outset of injury or disease may reduce long-term neuroinflammation. By targeting the early microglial inflammatory response, we can develop new technological or pharmacological interventions that offer promising therapeutic potential for a wide range of brain disorders. Low-intensity pulsed ultrasound stimulation (LIPUS) has emerged as a non-invasive therapy to reduce chronic inflammation, although its mechanisms remain unclear. We hypothesize LIPUS acts through mechanosensitive ion channels (MSICs), such as Piezo1. In microglia, Piezo1 activation causes calcium ion influx, promoting microglial motility and phagocytosis. Alternatively, Piezo1 activation in endothelial cells may lead to vasodilation, enhancing metabolic support in inflamed regions. Overall, this project aims to investigate the potential for LIPUS to improve neuroinflammation in both brain injury and disease and assess the role of MSICs in this process. The experiments in Aim 1 will utilize a genetic mouse model and pharmacological intervention to establish the necessity and sufficiency of microglia Piezo1 activation to generate the LIPUS-induced reduction of microglia activation and migration to the electrode implantation injury. The experiments in Aim 2 will use two-photon microscopy and optical imaging spectroscopy techniques to examine the effect of LIPUS on sensory-evoked hemodynamics, microglial activation, and Aβ clearance in an AD mouse model. Using an MSIC inhibitor, we will then assess whether MSIC activation is needed to generate the observed changes. Achieving these aims will establish the potential for LIPUS to reduce chronic inflammation in brain injury and disease and provide mechanistic targets to optimize efficacy. Through my training plan, my Sponsor and Co-Sponsor will provide the necessary training in ultrasound technologies, genetic mouse models, surgical procedures, and intravital cellular and metabolic imaging, in addition to professional development through the creation of journal publications, scientific conference presentations, and grant proposals. Completing these aims will garner the necessary expertise to further my career as I work to engineer new technologies to improve outcomes for those living with neurological disorders.
