The role of striatal dopamine and acetylcholine activity in adaptive reward-seeking behaviors

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PROJECT SUMMARY Environmental reward-predictive cues provide a major source of motivation for reward-seeking behaviors. This motivation is regulated by homeostatic and cognitive control factors. Dysregulation of these control factors produce maladaptive reward-seeking behaviors, which is a common feature of a variety of mental health illnesses, such as major depressive disorder, compulsive overeating, substance use disorder, and schizophrenia. However, little is known of the neurobiological mechanisms that regulate homeostatic and cognitive control of cue-motivated behavior. Previous work from our lab and others have identified dopamine release in the nucleus accumbens core (NAc) as a critical substrate of cue-motivated reward seeking. We also recently demonstrated NAc cholinergic interneurons acting at b2-containing nicotinic acetylcholine receptors (b2- nAChRs) provide a terminal regulatory influence on NAc dopamine that may be crucial to its function in motivation. How these motivational systems are regulated to ensure adaptive homeostatic and cognitive control over cue-motivated behavior remains to be fully understood. The principal goals of this proposal are to investigate the novel hypotheses that dopamine release is regulated by homeostatic and cognitive factors to promote an adaptive motivational message in NAc terminals, and that NAc cholinergic activity via β2-nAChRs gates local dopamine release to ensure adaptive reward seeking. In Aim 1, I will examine the regulation of cue-evoked NAc dopamine release by homeostatic and cognitive control to promote adaptive cue-motivated reward seeking. In Aim 2, I will examine how NAc cholinergic signaling is regulated by homeostatic and cognitive control factors and whether this activity regulates terminal dopamine release, independently of midbrain dopamine neurons, to promote an adaptive motivational message in NAc terminals. To address these hypotheses, a translationally relevant Pavlovian-to-instrumental (PIT) assay will be used in all aims to determine the neurobiological mechanisms underlying adaptive regulation of cue-motivated behavior. In this task, preliminary studies show rats are able to suppress exploratory reward seeking in favor of a situationally advantageous waiting strategy. Experiments in Aim 1 will utilize real-time dopamine measurements with in vivo fiber photometry imaging of a genetically encoded fluorescent dopamine sensor, chemogenetic inhibition, or optical stimulation of VTA dopamine terminals in the NAc to reveal the endogenous activity, necessity, and sufficiency of NAc dopamine release in adaptive cue-motivated behavior. Aim 2 will utilize in vivo fiber photometry to measure real-time acetylcholine levels and assess the influence of NAc b2-nAChR inactivation on cue-motivated behavior. Collectively, the novel findings from these studies identify the behavioral and neurochemical mechanisms underlying adaptive regulation of reward-seeking behaviors and provide mechanistic understanding of how maladaptive motivation arises in mental health illnesses.