Neuromodulation of Axon Terminals

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Why is it important?

Using electric or magnetic stimulation to modulate neuronal function and thus modify brain functioning has been reported to improve different forms of learning in humans. In addition, brain stimulation techniques are increasingly deployed as alternative therapeutic strategies for debilitating neuropsychiatric disorders and in neurorehabilitation. Nevertheless, despite hundreds of articles spanning decades, many tenets of field remain debated, and fundamental questions on mechanism remain unanswered which hamper progress. Perhaps the canonical question in electrical stimulation mechanisms is “which cellular elements are activated.” Namely, which sub-cellular compartments are first responders to brain stimulation. In this regard, axons – and specifically axon terminals - have been speculated to be the most sensitive element in the brain. However, despite hundreds of modeling studies and indirect measurements, the response of a mammalian axon to electrical stimulation has never before been directly recorded and quantified. For the first time, this article answers this question using state-of-the-art concurrent intracellular soma and axon-bleb electrophysiology under uniform electric fields. A computational model is developed to support a remarkable finding that axon sensitivity exceeds previous maximum estimates due to non-linear amplification. In addition to providing the first direct evidence demonstrating axons are the expected target of a broad swath of brain stimulation interventions, we also show that analog-digital processing is altered – which in turn suggests a new arena of study and applications. Our study thus has appealed to a broad audience spanning the subjects areas of cognitive neuroscience, neurology, and psychiatry along with suggesting a provocative bridge to one of the most exciting areas of neuronal computation.