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Temporal dynamics of neuromodulator release in motor cortex revealed by cell-based optically-active probes /


Stimulus-to-action sequences are believed to involve the release of dopamine (DA) and noradrenaline (NA). However, the electrochemical similarity of these two monoamines has limited real-time measurements of their release. As such, the temporal dynamics of DA and NA release in the cortex during learning and behavior remain poorly understood. To meet the challenge of assessing DA and NA in cortex in real time, here I report the creation of two cell-based neurotransmitter fluorescent-engineered reporters (CNiFERs) that discriminate nanomolar concentrations of DA and NA. These CNiFERs transform neurotransmitter receptor binding into a change in fluorescence and provides a direct and rapid optical read-out of local neurotransmitter activity. This generation of CNiFERs provides a new tool for examining the release of DA and NA in vivo and, by extension, the release of any molecule for which there is a G protein coupled receptor. To probe the temporal patterns of neurotransmitter release, specifically DA, NA, and acetylcholine (ACh), during classical conditioning, CNiFERs were implanted into the motor cortex of mice and imaged using two-photon microscopy. The presentation of the unconditioned stimulus, a drop of sucrose solution, triggered the release of DA, NA, and ACh in the motor cortex. The release of ACh consistently tracked the time of licking. With conditioning, the onset of DA release and licking behavior monotonically shifted, in a correlated manner, from the time of the reward toward that of the cue, the conditioned stimulus. Concurrent release of NA, on the other hand, did not correlate with licking or the cue. Thus, by using newly realized CNiFERs to probe in vivo temporal dynamics of transmitter release, we were able to determine that DA, but not NA, release in motor cortex corresponds to the extent of learning, as defined by changes in the animals' licking behavior and that ACh release in the motor cortex corresponds to the animal's motor output

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