Characterization of in vivo neuronal and inter-neuronal responses to transcranial focused ultrasound - Non-invasive neuromodulation approaches have been developed to enable the modulation of neural tissue without necessitating invasive surgical procedures. Low-intensity transcranial focused ultrasound (tFUS) neuromodulation has proven its efficacy and precision in modulating the brain, from the neuron to circuit level. However, there is an urgent unmet need to elucidate the in vivo neuronal and inter-neuronal effects of the tFUS neuromodulation, thus advancing the translational application of tFUS neuromodulation on humans. We propose to investigate the in vivo neuronal cell-type specific response and long-term plasticity effects of tFUS by systematically examining tFUS parameters in both anesthetized and awake rat models using a novel, cutting-edge 128-element random ultrasound array for rodents. The proposed experimental investigations are built upon our preliminary explorations and rigorous understanding of how different low-intensity tFUS parameters lead to unequal responses among unique in vivo neuron populations and the sustained alteration of synaptic connectivity in anesthetized rodent models using intracranial recordings. We will address the following specific aims. Aim 1. Characterization of intrinsic in vivo cell-type specific response of somatosensory cortical circuits to tFUS stimulation on anesthetized rat models. We will characterize the cell-type specific neural responses to tFUS stimulation in somatosensory cortical circuits using multi-channel electrophysiological recordings in an in vivo anesthetized rat model. We will further increase the precision of our interrogations through cell-type specific optogenetic rat models. Aim 2. Investigation of intrinsic in vivo cell-type specificity of tFUS in awake head-fixed rats. Uninhibited by anesthesia effects, the awake head fixed model is ideal for the investigation of tFUS neuromodulation on the spatial and temporal activation of different cell types, as well as the propagation of brain activities across local neural networks in the awake brain. Aim 3. Frequency specific modulation of tFUS to induce plasticity in anesthetized and awake head-fixed rats. We will systematically study the long-term effects of tFUS stimulation on synaptic connectivity. We will test the hypotheses that 1) tFUS stimulation is able to encode frequency specific information inducing sustained synaptic plasticity in the hippocampus, and 2) the pattern of the tFUS stimulation parameters has a significant effect on the degree of change. The successful completion of the proposed research promises to uncover the in vivo cellular mechanism of tFUS by investigating in vivo cell- type specific responses to ultrasound stimulation at somatosensory cortex and the induction of long-term effects at both the hippocampus and somatosensory cortex. We will systematically characterize, model, validate and understand the in vivo neuronal and inter-neuronal responses to tFUS stimulation, not only to propel the translation of neuromodulation therapies to clinical utility but also further the understanding of the specific neural circuits in healthy brains.
