Genetically encoded sensors enable micro- and nano-scopic decoding of transmission in healthy and diseased brains.

Neural communication orchestrates a variety of behaviors, yet despite impressive effort, delineating transmission properties of neuromodulatory communication remains a daunting task due to limitations of available monitoring tools. Recently developed genetically encoded neurotransmitter sensors, when combined with superresolution and deconvolution microscopic techniques, enable the first micro- and nano-scopic visualization of neuromodulatory transmission. Here we introduce this image analysis method by presenting its biophysical foundation, practical solutions, biological validation, and broad applicability. The presentation illustrates how the method resolves fundamental synaptic properties of neuromodulatory transmission, and the new data unveil unexpected fine control and precision of rodent and human neuromodulation. The findings raise the prospect of rapid advances in the understanding of neuromodulatory transmission essential for resolving the physiology or pathogenesis of various behaviors and diseases.