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

Abstract

The brain has a remarkable capacity to recover from damage. Despite the value of such recovery, it has made determining which areas are critically involved in a specific brain function challenging. Different types of manipulations to brain tissue - from mechanical or chemical lesions to genetic ablations or pharmacological agents - often yield conflicting conclusions. In some cases, ablating a brain area causes only a temporary disruption because a downstream region can homeostatically recover from its loss of input, while in others it leads to permanent impairment due not to the damaged area per se, but because of the degeneration of distant areas. We sought to address these issues by exploiting the flexibility and reversibility of optogenetic manipulations. We applied a three-stage optogenetic approach to the mouse's primary visual cortex (V1) in a contrast detection task, beginning with intermittent silencing, followed by sustained illumination across multiple days of task-related behavior, and concluding with a return to intermittent silencing. Initially, intermittent V1 inactivation strongly impaired task performance, while during persistent multi-session inactivation, the animals' visual detection entirely recovered to pre-silencing levels. However, this recovery was itself reversible, as returning the animals to intermittent V1 inactivation reinstated the behavioral deficit. Suppressing activity in the superior colliculus (SC) concurrent with persistent V1 inactivation reversed the animals' recovery, demonstrating that SC is a key area that drives behavioral compensation in the absence of V1 function, even while under normal conditions V1 activity is crucial. These results support a scenario where primary sensory cortex is in the default circuit mice use to detect visual stimuli, but in its absence, midbrain regions can compensate for it. More generally, this temporally controllable optogenetic perturbation paradigm could be useful to adjudicate whether a brain area instructs or is accessory to a specific brain function.