New technologies always bring (over)excitement, because they allow us to perform “so far only dreamed of” experiments. It is only later that one discovers the caveats. Many of us remember the excitement brought about by the ability to knock out genes. The first papers strongly relied on the belief that if knocking out gene X prevents observation Y from happening, it shows causality, i.e., the function of X is to control Y directly. We now know that we must be more careful with data interpretation. For example, knocking out X may result in a misconstruction of the brain that will lead to an alteration in Y (i.e., X does not control Y directly). Such explanations are particularly important for the interpretation of preclinical studies (Marguet et al., 2015).
Optogenetics is not an exception to the rule. When using light to control cells, transcription, etc., we believe that if we activate cell X with light and observe Y, then Y is due to the activity of X. Let’s review some potential known and unknown confounding factors.
Brain Dynamics
At rest, brain activity displays complex dynamic patterns that can be seen using fMRI, EEG, or mesoscopic Ca2+ imaging. These patterns reflect the activity of all cells, even specific cells (Xiao et al., 2017), and such activity patterns may, in turn, affect the future activity of all …
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