On the results of causal optogenetic engram manipulations

SUMMARY Cellular-resolution manipulation technologies like optogenetics enable so-called causal engram-cell experiments in which learning-activated neurons are tagged with a light-responsive protein (opsin) such that subsequent photostimulation elicits memory behavior. The opsin-tagged neurons are considered key neural circuit elements with photostimulation demonstrating their sufficiency for memory expression. Can the sufficiency interpretation be correct if the brain is a complex dynamical system with adaptive, non-linear, and homeostatic interactions? We find that during photostimulation of place avoidance memory-tagged neurons, mouse CA1 hippocampus activity maintains intrinsic ensemble discharge relationships and the low-dimensional manifold organization of the population dynamics. Although the photostimulation causes spatially-precise conditioned avoidance, such manipulations, are better interpreted as eliciting the endogenous population dynamics of a complex system, rather than the causal demonstration of neural circuit function.