Dissociating instructive from permissive roles of brain circuits with reversible neural activity manipulations

Recent work has demonstrated that both permanent lesions and acute inactivation experiments can lead to erroneous conclusions about the causal role of brain areas in specific behaviors, casting serious doubt on major avenues by which neuroscientists study the brain. To overcome this challenge, we developed a three-stage optogenetic approach which leverages the ability to precisely control the temporal period of regional inactivation with either brief or sustained illumination, enabling investigators to dissociate between putative permissive and instructive roles of brain areas in behavior. We applied this approach to the mouse primary visual cortex (V1) to probe whether V1 is permissive or instructive for the detection low contrast stimuli. Acute inactivation of V1 drastically suppressed performance, but during persistent inactivation, the animals contrast detection recovered to pre-silencing levels. This recovery was itself reversible, as returning the animals to intermittent V1 inactivation reinstated the behavioral deficit. These results argue that V1 is the default circuit mice use to detect visual stimuli, but in its absence, other regions can compensate for it. This novel, temporally controllable optogenetic perturbation paradigm should be useful in other brain circuits to assess whether they are instructive or permissive in a brain function or behavior.