Subsequently, Huang et al. (2005) showed that olfactory stimulation by methionine modulates retinal ganglion cell activity in zebrafish, and this modulation is blocked by a dopamine receptor antagonist. Further, they showed that dopamine inhibits activity in most ganglion cells, although in some cells it increased activity. They further showed that olfactory stimulation

with methionine decreases vitreal dopamine concentrations as well as voltage- and ligand-sensitive Ca2 currents in ganglion cells. These results suggest that olfactory stimulation decreases TN activity, although it is possible that these effects on ganglion cells could be mediated by TN fibers synapsing on inhibitory GABAergic amacrine cells, for which there is some p38 protein kinase evidence. Clearly the circuitry and mechanisms underlying the effects of olfactory stimulation on retinal responses are complex and not well understood. The paper by Esposti PFT�� et al. (2013) in this issue of Neuron is thus very welcome and substantially advances the story. It certainly does not answer all the puzzles but brings our understanding to a new level. Using zebrafish, they monitored the activity of bipolar cells in intact zebrafish by imaging Ca2+

signals. Esposti et al. (2013) found that methionine reduced the gain but increased the sensitivity of mainly OFF bipolar cells. A few ON bipolar cells were potentiated by olfactory stimulation, but these were the exception (∼10%). Esposti et al. (2013) demonstrate that these effects are mediated by dopamine by showing that the effects they observe, like other effects of olfactory stimulation on visual

phenomena in zebrafish ( Maaswinkel below and Li, 2003 and Huang et al., 2005), are mediated by the TN modulating the release of dopamine from the IPCs. Many questions remain. Why do the ON and OFF bipolar cells respond so differently to olfactory stimulation? Both have dopamine receptors, as was demonstrated by experiments that Esposti et al. (2013) carried out using a dopamine agonist. Do the ON and OFF pathways have different sensitivities to DA receptors as Esposti et al. (2013) suggest? Another question is the effect of circadian rhythms on the bipolar cell responses. All of the present experiments were carried out in the morning, following after the results of Maaswinkel and Li (2003), who showed a strong effect of olfactory stimulation in early morning hours when the circadian clock depresses visual sensitivity but not later in the day when visual sensitivity is maximal (Li and Dowling, 1998). Does the same phenomenon happen with the bipolar cell responses? And finally, whereas the present and past experiments provide convincing evidence for functional olfactory-visual system interaction, what is its behavioral significance? The terminal nerve has long been implicated in reproductive behavior as well arousal and motivational states.