Alcohol Use Disorder (AUD) can induce long lasting alterations to executive function. This includes altered action control, which can manifest as dysfunctional goal-directed control. Cortical and striatal circuits mediate goal-directed control over behavior, and prior research has found chronic alcohol disrupts these circuits. In particular, prior in vivo and ex vivo work have identified alterations to function and activity of dorsal medial striatum (DMS), which is necessary for goal-directed control. However, unknown is whether these alterations manifest as altered activity of select DMS populations during behavior. Here we examine effects of prior chronic alcohol exposure on calcium activity modulation during action-related behaviors via fiber photometry of genetically-identified DMS populations including the direct and indirect output pathways, and fast-spiking interneurons. We find that prior chronic alcohol exposure leads to increased calcium modulation of the direct pathway during action related behavior. In contrast, prior chronic alcohol exposure led to decreased calcium activity modulation of the indirect pathway and the fast-spiking interneuron population around action-related events. Together, our findings suggest an imbalance in striatal activity during action control. This disruption may contribute to the altered goal-directed control previously reported.

Decision-making is a continuous and dynamic process with prior experience reflected in and used by the brain to guide adaptive behavior. However, most neurobiological studies constrain behavior and/or analyses to task-related variables, not accounting for the continuous internal and temporal space in which they occur. We show mice rely on information learned through recent and longer-term experience beyond just prior actions and reward - including checking behavior and the passage of time - to guide self-initiated, self-paced, and self-generated actions. These experiences are represented in secondary motor cortex (M2) activity and its projections into dorsal medial striatum (DMS). M2 integrates this information to bias strategy-level decision-making, and DMS projections reflect specific aspects of this recent experience to guide actions. This suggests diverse aspects of experience drive decision-making and its neural representation, and shows premotor corticostriatal circuits are crucial for using selective aspects of experiential information to guide adaptive behavior.

Recent hypotheses have posited that orbital frontal cortex (OFC) is important for using inferred consequences to guide behavior. Less clear is OFC's contribution to goal-directed or model-based behavior, where the decision to act is controlled by previous experience with the consequence or outcome. Investigating OFC's role in learning about changed outcomes separate from decision-making is not trivial and often the two are confounded. Here we adapted an incentive learning task to mice, where we investigated processes controlling experience-based outcome updating independent from inferred action control. We found chemogenetic OFC attenuation did not alter the ability to perceive motivational state-induced changes in outcome value but did prevent the experience-based updating of this change. Optogenetic inhibition of OFC excitatory neuron activity selectively when experiencing an outcome change disrupted the ability to update, leaving mice unable to infer the appropriate behavior. Our findings support a role for OFC in learning that controls decision-making.

Addiction involves a predominance of habitual control mediated through action selection processes in dorsal striatum. Research has largely focused on neural mechanisms mediating a proposed progression from ventral to dorsal lateral striatal control in addiction. However, over reliance on habit striatal processes may also arise from reduced cortical input to striatum, thereby disrupting executive control over action selection. Here, we identify novel mechanisms through which chronic intermittent ethanol exposure and withdrawal (CIE) disrupts top-down control over goal-directed action selection processes to produce habits. We find CIE results in decreased excitability of orbital frontal cortex (OFC) excitatory circuits supporting goal-directed control, and, strikingly, selectively reduces OFC output to the direct output pathway in dorsal medial striatum. Increasing the activity of OFC circuits restores goal-directed control in CIE-exposed mice. Our findings show habitual control in alcohol dependence can arise through disrupted communication between top-down, goal-directed processes onto basal ganglia pathways controlling action selection.

Psychiatric disease often produces symptoms that have divergent effects on neural activity. For example, in drug dependence, dysfunctional value-based decision-making and compulsive-like actions have been linked to hypo- and hyperactivity of orbital frontal cortex (OFC)-basal ganglia circuits, respectively; however, the underlying mechanisms are unknown. Here we show that alcohol-exposed mice have enhanced activity in OFC terminals in dorsal striatum (OFC-DS) associated with actions, but reduced activity of the same terminals during periods of outcome retrieval, corresponding with a loss of outcome control over decision-making. Disrupted OFC-DS terminal activity was due to a dysfunction of dopamine-type 1 receptors on spiny projection neurons (D1R SPNs) that resulted in increased retrograde endocannabinoid signaling at OFC-D1R SPN synapses reducing OFC-DS transmission. Blocking CB1 receptors restored OFC-DS activity in vivo and rescued outcome-based control over decision-making. These findings demonstrate a circuit-, synapse-, and computation-specific mechanism gating OFC activity in alcohol-exposed mice.