MEASUREMENT AND MANIPULATION OF SUBCORTICAL NEUROMODULATORY POPULATIONS DURING REWARD LEARNING

Abstract

The ability to adapt behavior so as to maximize reward and avoid threats is vital for an animal’s survival and reproductive success. To do this, animals must learn associations between rewards and the contexts in which they are received, and appropriately update these associations over time as reward availability changes. Extinction learning describes the experience-driven decrease in the strength of a learned reward-context association.Understanding the neural substrates of the acquisition and extinction of reward-context associations has long been of interest to researchers, both because these processes represent fundamental features of reward learning and because findings may have translational value. Notably, individuals with substance use disorders (SUDs) are frequently driven to relapse by context cues even when they have been abstinent for years, outcomes that highlight the persistence and power of learned drug-context associations. There is a rich literature implicating neuromodulation of neural circuitry in reward learning. The neuromodulator dopamine (DA) is released upon receipt of unexpected natural rewards, and every drug of abuse causes high levels of DA release. DA has powerful plasticity effects, which in effect teach neural circuits about which contexts predict reward. In addition, there is growing appreciation for a complementary role of another neuromodulator, acetylcholine (ACh), in regulating reward-context memories through plasticity effects. However, previous work that has probed the role of ACh in drug-context extinction has relied on artificial manipulation of neurons. Whether natural variations in ACh are predictive of persistence of drug-context associations across individuals is unknown. Also unknown is whether ACh differentially modulates striatal plasticity based on output neurons’ molecular identities. In determining ACh’s mechanistic role in drug-context extinction, we stand to refine the understanding of DA-ACh dynamics in reward learning and potentially define future targets for therapies for SUD patients seeking to remain abstinent.