Abstract Precisely timed activation of genetically targeted cells is a powerful tool for studying neural circuits. Neuronal modulation (activating or inhibiting select neurons) allows us to investigate how neural activity causes changes in animal behavior. Recent work has led to many tools for genetically targeted neuromodulation; however, the ideal technology should be: 1) Wireless – to enable unrestricted animal behavior and social interactions. 2) Injectable – to minimize tissue damage and ease implementation associated with implants. 3) Fast – (sub-second response times) to synchronize neural stimulation with behaviors or sensory queues. 4) Multiplexed – so that different brain areas, cell types, or animals can be modulated within the same arena. A technology with these capabilities will be a powerful tool for discovering causal relationships between neural circuit activity and behavior. For example, researchers will be able to manipulate the activity of entire neural circuits distributed throughout the brain as animals interact with one another and their environment. Through these experiments, researchers will be able to discover how to select neurons to participate in specific behaviors. To create this type of neuromodulation technology, we will develop the first fast magnetothermal genetics. This technique relies on alternating magnetic fields to heat nanoparticles that activate thermoreceptors expressed in genetically targeted cells. While similar magnetothermal approaches have been recently demonstrated in mice and C. elegans, response latencies have remained in excess of 10 seconds making it impossible to precisely synchronize neural modulation with behaviors or sensory cues. We propose to use highly sensitive rate-dependent thermoreceptors and optimized nanoparticles to achieve magnetic control of genetically targeted cells with sub-second latency. We also propose to make magnetic nanoparticles significantly more selective to specific magnetic field amplitudes and frequencies by tuning their composition. These optimizations will enable multichannel remote stimulation of independent neural circuits or animals located in close proximity. Our tools will bring magnetogenetics closer to the temporal resolution and multiplexed stimulation possible with optogenetics while maintaining the minimal invasiveness and deep-tissue stimulation only possible by magnetic control.

The ability to modulate the activity of specific neuron populations in model animals is essential for studying fundamental neurobiology that is necessary to improve our treatments for neurological disorders. Currently, the methods used to modulate neural activity are slow or inhibit natural animal behavior, which limits our ability to study brain behavior relationships in these animals. Here we propose a fast and minimally invasive method to modulate defined populations of neurons throughout the brain of freely animals using magnetic fields, nanoparticles, and genetically encoded ion channels.