Figure 2.

Mice learn to use optogenetic manipulations as a cue regardless of the perturbed cell type or brain region. A, Representative images for fiber optics implantation and stimulation sites. Left pictures show unilateral optical fiber implanted in prefrontal cortices in WT (PFC^WT), transgenic Thy1-ChR2 (PFC^Thy1), and VGAT-ChR2 (PFC^VGAT) mice. Right pictures show fiber optics in subcortical regions, including the NAc in Thy1-ChR2 (NAc^Thy1), the TRN in VGAT-ChR2 (TRN^VGAT), and the ventral tegmental area in TH-Cre (VTA^TH) mice. B, Schematic of the optogenetic-cue alternation task, where mice had to alternate between two sippers to receive two drops of 10% sucrose from each one. When the mice broke the photobeam, located halfway between the two sippers (cyan squares), a cue [tone (2 kHz) + laser (20 Hz), 1 s] was randomly delivered. The cue instructed them to return to the previously rewarded port to be rewarded again and avoid punishment. A dry lick is a lick given to the empty sipper. C, Task performance in the initial and last five training sessions. Learning criteria (horizontal dashed line at 50%) were reached when mice avoided punishment in >50% of cue trials in five consecutive sessions. Correct trials separated as Hit and Correct Rejections are shown in Extended Data Figure 2-1, where only Hits increased their proportion when mice learned the task. Note that PFC^WT-10kHz mice were trained with a more easily perceived auditory tone 10 kHz, than a 2-kHz tone that was barely perceptible to mice, as shown in Extended Data Figure 2-2. Error bars indicate SEM. D, Sessions to reach the learning criteria. E, Task performance postlearning in mice with PFC optogenetic stimulation (block 1). In block 2, the tone was removed. In block 3, mice were tested with a “fake laser.” After reacquisition (block 4 laser only), block 5 began, where the tone was the cue only. Then in block 6, we re-tested laser only condition. Finally, we repeated the laser+tone condition in block 7. F, Similar to panel E, except that stimulation was delivered in subcortical structures (NAc^Thy1, TRN^VGAT, and VTA^TH); *p < 0.01 ANOVA Dunnett post hoc relative to PFC^WT control.