Towards Biomimetic Optogenetics: Drug-Free Activation of Acute Opiate Reward

Functional brain mapping studies typically involve tonic optogenetic stimulation, wherein neurons are driven to fire action potentials at evenly spaced intervals. This does not usually replicate natural firing patterns, which may be necessary for information encoding. Adopting a more biomimetic approach to optogenetics – wherein stimulation intervals mirror those observed in vivo to reflect a given context – could reveal behaviours that may otherwise go undetected. I demonstrated the value of this strategy by using it to reconcile conflicting data on ventral tegmental area (VTA) GABA neurons in acute (previously naïve) opiate reward. I established that either reward or aversion can be elicited from this neuronal population, depending on the type of optogenetic stimulation applied. Activation using laser pulse sequences mimicking acute morphine-induced firing patterns produced reward behaviour, while continuous light was aversive. I next mathematically analyzed the naturalistic interspike interval data to discover how they may differ across baseline and acute morphine conditions. Critically, this investigation revealed that VTA GABA neurons use higher-order temporal patterns to encode acute opiate reward, as suggested by two key experiments: First, I computed models to fit interspike interval distributions corresponding to drug-free and morphine conditions. I then engineered a synthetic stimulation pattern from the morphine model, tested it in vivo, and found that it was not reinforcing. Second, to determine why the synthetic pattern did not reconstitute reward, we sought to investigate whether it was the specific distribution of real interspike intervals or the order of those intervals that are key for encoding. We randomized the interspike intervals in a rewarding morphine firing pattern (while maintaining its overall distribution) prior to optogenetic playback – destroying any specific arrangements or repeating sequences – and this resulted in aversions, further emphasizing the necessity of higher-order temporal patterning over more simplistic alternative encoding hypotheses. To elucidate the broader reward circuit, we mapped this VTA GABA-mediated rewarding effect to projections terminating in the tegmental pedunculopontine nucleus (TPP). Stimulation of this TPP terminal field resulted in even stronger, more robust reward than stimulation of GABAergic cell bodies in the VTA. To explain this phenomenon, I demonstrated that reward resultant from cell body stimulation is likely dampened by simultaneously active projections governing opposing motivational effects, namely terminals in the dorsal raphe, found to drive aversions. Finally, we demonstrated that this optogenetic GABA-mediated reward was dopamine-independent. Overall, these findings explain why previous optogenetic activation of this population failed to corroborate outcomes from a myriad of chemical and genetic studies that implicated VTA GABA neurons in acute opiate reward processing, as we do here. Our work strongly suggests that firing patterns – and by extension, stimulation patterns – should be granted serious consideration when using optogenetics for neurobehavioural research.

Keywords: Addiction
GABA
Opiates
Optogenetics
Reward
VTA
Advisor: van der Kooy, Derek