For barrel cortex experiments, mice were anesthetized with 100 mg/kg ketamine and 10 mg/kg xylazine i.p. injected, and whiskers were removed under a dissection scope by grasping them at the base with forceps and pulling. After whisker removal, mice were singly housed, and whiskers did not regrow substantially by the time of tamoxifen injection two days later. Approximately 6 hr after TM injection, mice were provided with cardboard tubes (approximately 3.5 cm in

diameter) and nesting material to stimulate whisker exploration. For visual stimulation, the homecages of singly housed mice were placed in individual light-tight cubicles with white walls. Light stimuli were delivered by an Anti-diabetic Compound Library order LED bulb mounted above the cage, which produced light of ∼500 lux at cage level. Drugs were injected with a dim red LED in an otherwise dark room. For the time course experiment, light was delivered at the same time of day (starting at 8 hr after the subjective dawn of the animal’s former light/dark cycle)

to all mice in order to control for possible circadian differences in sensitivity to stimulation, and the timing of drug injections was varied around this fixed time. For auditory stimulation, mice were placed into custom sound isolation cubicles lined with acoustic foam (Auralex Acoustics). Sound stimuli were generated in Audacity (https://audacity.sourceforge.net), produced by a PC sound card (Creative Labs), amplified (Onkyo), and delivered by a speaker (Fostex) mounted directly above the only animal’s cage. Stimuli were delivered at approximately 90 dB. For the novel environment experiments, mice were group housed until at least

Lumacaftor 3 days before the start of the experiment, at which point they were singly housed in standard 20 × 30 cm mouse cages in a normal colony room. Novel environment experiments were performed beginning 1–3 hr after the onset of the animals’ dark cycle, at which point experimental mice were transported to a separate room and placed in a dimly lit (<10 lux) 30 × 60 cm plastic cage with a running wheel, a wooden or plastic “hut,” a plastic tunnel, wooden chips for chewing, and buried food. After 1 hr, mice were removed from the novel environment and injected with either 4-OHT or vehicle before they were returned to the novel environment for another 1 hr, at which point they were returned to the homecage in the animal colony for 1 week before sacrifice. Homecage control mice were similarly injected with 4-OHT 1–3 hr after the onset of the dark cycle under dim white light 1 week prior to sacrifice. For all experiments, mice were subjected to only the minimal handling necessary for genotyping and colony maintenance prior to performing the experiments. Details of cell counting and quantification are available in the Supplemental Experimental Procedures. Statistical analyses were performed in Prism (GraphPad). We thank A. Huberman, A. Mizrahi, and C. Ran for advice; members of the Heller lab for help with preliminary experiments; B.