Abstract Magnetogenetics is a recently proposed method for stimulating cells using electromagnetic fields. In one approach, radio-frequency (RF) electromagnetic fields are applied to stimulate membrane channel proteins such as TRPV1 and TRPV4 that are attached to ferritins. The concept is highly attractive as it enables wireless neural stimulation without limitation on penetration depth or the requirement of invasive surgeries. If successful, RF- based magnetogenetics can provide a non-invasive approach for large-scale neural stimulation that can reach anywhere in the brain and achieve cellular specificity. This capability overcomes a significant limitation in other techniques such as electrical stimulation and optogenetics where stimulation is spatially restricted. However, while there have been several independent reports of experimental evidences for magnetogenetic effects using RF waves, the physical and neurobiological underpinnings of such effects remain unclear and controversial. Reported experiments have been conducted only in a few selected frequencies and amplitudes and the responses were mostly measured indirectly based on downstream physiological effects. The objective of the proposed project is to systematically characterize, model and validate the neurobiological and cellular responses upon RF stimulation in neurons expressing ferritin-attached TRPV1 and TRPV4 channels. Specifically, we aim to characterize these magnetogenetic channels of their: 1) neuronal responses to electrical and chemical stimuli and to RF stimulation over a wide range of frequencies and amplitudes; 2) temperature responses to RF stimulation at the protein, cytoplasmic membrane and cellular level; 3) cellular metabolic processes upon RF stimulation. We will systematically evaluate two novel working hypotheses of the underlying mechanisms. If successful, the project will characterize the cellular responses to RF stimulation, quantify activation thresholds and safety limits, establish standard protocols and elucidate the biophysical underpinnings of this reported RF- based magnetogenetic phenomenon. It would resolve a fundamental challenge in advancing this technology and guide a more rationale design and improvement of the techniques. Understanding the mechanisms of the initial reports of magnetogenetics would be a significant addition to the present ensemble of neuro-stimulation technologies such as electrical stimulation and optogenetics and contribute to one central goal of the BRAIN Initiative that is to develop new and improved perturbation technologies suitable for controlling specified cell types and circuits to modulate function in the central nervous system.