The DREADDful Hurdles and Opportunities of the Chronic Chemogenetic Toolbox

The chronic character of chemogenetics has been put forward as one of the assets of the technique, particularly in comparison to optogenetics. Yet, the vast majority of chemogenetic studies have focused on acute applications, while repeated, long-term neuromodulation has only been booming in the past few years. Unfortunately, together with the rising number of studies, various hurdles have also been uncovered, especially in relation to its chronic application. It becomes increasingly clear that chronic neuromodulation warrants caution and that the effects of acute neuromodulation cannot be extrapolated towards chronic experiments. Deciphering the underlying cellular and molecular causes of these discrepancies could truly unlock the chronic chemogenetic toolbox and possibly even pave the way for chemogenetics towards clinical application. Indeed, we are only scratching the surface of what is possible with chemogenetic research. For example, most investigations are concentrated on behavioral read-outs, whereas dissecting the underlying molecular signature after (chronic) neuromodulation could reveal novel insights in terms of basic neuroscience and deregulated neural circuits. In this review, we highlight the hurdles associated with the use of chemogenetic experiments, as well as the unexplored research questions for which chemogenetics offers the ideal research platform, with a particular focus on its long-term application.