Neural control of Reinforcement Learning in SUD

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Project Summary/Abstract Substance use disorder (SUD) has proven challenging to effectively treat due to the long-term changes in both behavior and neuronal function that persist long after drug has left the system. Drug-induced changes in neuronal plasticity are particularly important as they can disrupt both drug-associated behaviors as well as adaptive behaviors in basal states, thus necessitating a more comprehensive understanding of how the neuronal populations that underlie this plasticity control basal behaviors as they relate to reward processing and motivation. At the core of value-based decision making and motivation is the nucleus accumbens, which is primarily composed of D1 and D2 medium spiny projection neurons (MSNs) that are thought to have opposing actions on behavior with D1 MSNs promoting reward and D2 MSNs promoting aversion. A large body of work has outlined the transcriptional, physiological, and in vivo encoding alterations in these populations that occur as a result of drug exposure and has linked these alterations to drug seeking and consumption. However, these cellular populations are also integrally involved in learning, selecting, and executing goal-oriented behaviors, and function as a key neural substrate of cue-reward associations for drug and non-drug stimuli. Currently, the precise information that is encoded within these populations, and how they guide adaptive behaviors in different contexts, remains to be definitively elucidated. By combining complex reinforcement tasks that can dissociate behavioral action from stimulus and outcome value with optical approaches for recording and manipulating D1 and D2 MSNs in awake, behaving mice we will define the specific information that is encoded within these cellular populations. In Aim 1, I will utilize fiber photometry calcium imaging to define the temporal signature of D1 and D2 medium spiny neurons (MSNs) during complex behavioral tasks. We hypothesize - based on robust preliminary data - that D1 and D2 MSNs are not simply “rewarding” and “aversive”, but instead encode specific components of learned and executed behavior. In Aim 2, I will utilize optogenetics to manipulate activity in D1 and D2 MSNs respectively during discrete time points to demonstrate the functional importance of these neuronal populations to reinforcement learning. While this proposal encompasses the use of a number of innovative techniques, it is the technical and theoretical training, gained in combining these techniques with complex behavioral tasks, that will provide the foundational expertise and conceptual thinking needed to address larger questions regarding how plastic changes in the brain in response to drug exposure support development of SUD. Together, this proposal will provide an exceptional training opportunity while simultaneously providing foundational evidence for the specific changes that occur within genetically defined neuronal populations in adaptive – and maladaptive – states. Furthermore, these findings can ultimately inform our understanding of how to therapeutically approach treatment of a disorder that hijacks normal adaptive systems.