Research Project: Low-Intensity Focused Ultrasound Neuromodulation for Depressive Behavioral Persistence and Prefrontal Plasticity

Major Depressive Disorder is a leading cause of disability, with ~30% of patients experiencing treatment-resistant depression, often marked by repetitive negative thinking and cognitive rigidity. This project evaluates Low-Intensity Focused Ultrasound (LIFU) as a non-invasive potential approach to modulate prefrontal-striatal circuits underlying behavioral persistence. The study comprises three specific objectives. First, we target the corpus callosum with in vivo LIFU, combined with ex vivo optogenetics and patch-clamp recordings, to evaluate changes in synaptic strength and feedforward inhibition in the medial prefrontal cortex. Second, we assess the behavioral effects of repeated bilateral LIFU targeted to the murine equivalent of the anterior limb of the internal capsule. Third, using a striatal cholinergic interneuron ablation mouse model of compulsive behavioral rigidity, we analyze whether rigid coping strategies facilitate stress chronification following acute social stress. Pilot experiments show that a 5-minute LIFU protocol is sufficient to induce cortical c-Fos expression. Furthermore, preliminary ex vivo patch-clamp recordings on EYFP-positive axonal fields confirm our ability to functionally target and modulate synaptic transmission in prefrontal pathways. This research aims to elucidate the neurobiological mechanisms of LIFU-mediated plasticity, advancing its translation for non-invasive clinical therapies.