Toward biomimetic optogenetics: Drug-free activation of acute opiate reward.

Functional brain mapping studies typically involve tonic optogenetic stimulation. This does not always reflect natural firing patterns, which could be critical for information encoding. Adopting a biomimetic approach to optogenetics - wherein stimulation intervals mirror those observed to reflect context - we reconcile conflicting data on ventral tegmental area (VTA) GABA neurons in acute opiate reward. Activation using laser pulse sequences mimicking morphine-induced firing patterns is rewarding, while continuous light is aversive. When interspike intervals in rewarding morphine firing patterns are randomized, aversions also result, demonstrating the importance of temporal encoding in this system. We further establish the existence of VTA GABA projections to the tegmental pedunculopontine nucleus that drive reward in a dopamine-independent manner. Overall, our findings are consistent with non-optical studies characterizing VTA GABA neurons, and explain why previous optogenetic manipulations failed to corroborate those outcomes; proof-of-principle that temporal firing patterns are of critical importance in optogenetic toolkits.