The role of spatiotemporal dopamine coordination in disrupted state representation processes in mice

PROJECT 2 - PROJECT SUMMARY The purpose of PROJECT 2 is to use mice as an experimental model to help clarify the relationship between cortical and subcortical dopamine (DA) activity disruptions and state representation changes in psychosis, specifically by focusing on how striatal hyperdopaminergia relates to cortical synchrony and NMDAR dysfunction. Deficits in representing and learning about states of the world underlie maladaptive cognitive control and reward learning in psychosis, and frontostriatal-DA interactions are critical to adaptively regulating these processes in service of behavioral flexibility. Despite decades of research, our understanding of the precise computational and circuit-level mechanisms that contribute to the manifestations of psychosis—particularly the role of DA activity across spatial and temporal scales —remains incomplete. Specifically, what spatiotemporal circuit interactions link DA dynamics in the caudate striatum to state estimation, state representational stability (maintenance), and learning of reward-predictive states? Using our novel optical preparation for manipulating and imaging large-scale DA dynamics across the entire rodent dorsal striatum, we will specifically focus on how striatal hyperdopaminergia and NMDAR dysregulation affect parameters of tightly coordinated spatiotemporal DA patterns within and across the dorsal striatum, ventral striatum, and medial prefrontal cortex (mPFC). Our goal is to combine circuit, behavioral, and computational approaches to link state representation disruptions seen in psychosis to computational operations regulated by dopaminergic modulation of frontostriatal circuits. Aim 1: Assess how DS spatiotemporal DA coordination is affected by various models of psychopathology. We will image DA in mPFC, dorsal, and ventral striatum with i) pharmacological modeling of hyperdopaminergia using modafinil (in synergy with PROJECT 5) and ii) pharmacological blockade and genetic ablation of cortical NMDA receptors (in synergy with PROJECTS 1, 3, and 5). We will also assess whether the DA effects of psychotomimetic conditions are restored by risperidone, a D2R antagonist used in the treatment of psychosis. Aim 2: Investigate the coordination of cortical and striatal DA signals during a probabilistic behavioral task that parametrizes state learning. Using simultaneous, multi-region DA measurement across mPFC, caudate, putamen, and accumbens in the Translational Bandit Task (TBT), we will extend our previous analysis of decision signals relayed by regional DA signals in motivation and action value learning. Task manipulations and analyses will parallel other Projects to maximize the translation interpretability of our findings across species.