TRANSCRANIAL ULTRASONIC STIMULATION TARGETED TO THE LOCUS COERULEUS INDUCES PARAMETER-DEPENDENT CHANGES IN HIPPOCAMPAL NORADRENALINE LEVELS

Low-intensity transcranial ultrasonic stimulation (TUS) is a promising non-invasive neuromodulation technique able to precisely target central nervous structures, even in deep areas of the brain. The locus coeruleus (LC) is a small pontine nucleus and the primary source of noradrenaline (NA) in the central nervous system. The LC is an attractive target for neuromodulation-based interventions as it regulates cognitive processes and is implicated in the pathophysiology of various neurological disorders. In this study, we targeted the LC using TUS in freely moving awake mice (n = 15) using different sets of stimulation parameters and investigated changes in intracellular Ca²⁺ levels in LC neurons and in hippocampal NA levels using genetically encoded biosensors and fiber photometry. Using positron emission tomography (PET), we investigated effects of LC-targeted FUS on glucose uptake in brain and body. Short trains (5 s) of LC-targeted TUS resulted in significant and sustained increases in LC Ca²⁺ levels. The increased Ca²⁺ levels were accompanied by a brief and transient increase in hippocampal NA levels, followed by a longer lasting and significant decrease. When a longer pulse train (30 s) was used with lower pulse repetition frequencies, sustained hippocampal NA increases throughout the stimulation period were found. PET imaging revealed widespread decrease in glucose uptake in the brain and increased glucose uptake in brown adipose tissue, suggesting that LC-targeted TUS exerts both central and systemic effects. With this study we demonstrated for the first time that LC-targeted TUS can be used to modulate LC-NA function in awake mice.