Substance P and dopamine form a "push-pull" system that diurnally regulates retinal gain.

The operation of the retina, like other brain circuits, is under modulatory control. One coordinator of changes in retinal function is dopamine, a neuromodulator released in a light-dependent way to adjust vision on a diurnal cycle. Here, we demonstrate that substance P is a similarly powerful retinal modulator that interacts with the dopamine system. By imaging glutamatergic synaptic transmission in larval zebrafish, we find that substance P decreases the contrast sensitivity of ON and OFF visual channels up to 8-fold, with suppression of visual signals being strongest through the "transient" pathway responding to higher frequencies. These actions are exerted in the morning, in large part by suppressing the amplification of visual signals by dopamine, but substance P is almost completely inactive in the afternoon. Modulation of retinal gain is accompanied by changes in patterns of vesicle release at the synapses of bipolar cells: increased gain shifts coding of stimulus strength from the rate of release events to their amplitude generated by a process of multivesicular release (MVR). Together, these actions of substance P reduce the flow of visual information, measured in bits, ∼3-fold. Thus, whereas dopamine "pushes" the retina to transmit information at higher rates in the afternoon, substance P acts in antiphase to suppress dopamine signaling and "pull down" information transmission in the morning.