Orbital Frontal Cortex Projections to Secondary Motor Cortex Mediate Exploitation of Learned Rules.

Animals face the dilemma between exploiting known opportunities and exploring new ones, a decision-making process supported by cortical circuits. While different types of learning may bias exploration, the circumstances and the degree to which bias occurs is unclear. We used an instrumental lever press task in mice to examine whether learned rules generalize to exploratory situations and the cortical circuits involved. We first trained mice to press one lever for food and subsequently assessed how that learning influenced pressing of a second novel lever. Using outcome devaluation procedures we found that novel lever exploration was not dependent on the food value associated with the trained lever. Further, changes in the temporal uncertainty of when a lever press would produce food did not affect exploration. Instead, accrued experience with the instrumental contingency was strongly predictive of test lever pressing with a positive correlation between experience and trained lever exploitation, but not novel lever exploration. Chemogenetic attenuation of orbital frontal cortex (OFC) projection into secondary motor cortex (M2) biased novel lever exploration, suggesting that experience increases OFC-M2 dependent exploitation of learned associations but leaves exploration constant. Our data suggests exploitation and exploration are parallel decision-making systems that do not necessarily compete

Corticostriatal circuitry and habitual ethanol seeking

The development of alcohol-use disorders is thought to involve a transition from casual alcohol use to uncontrolled alcohol-seeking behavior. This review will highlight evidence suggesting that the shift toward inflexible alcohol seeking that occurs across the development of addiction consists, in part, of a progression from goal-directed to habitual behaviors. This shift in “response strategy” is thought to be largely regulated by corticostriatal network activity. Indeed, specific neuroanatomical substrates within the prefrontal cortex and the striatum have been identified as playing opposing roles in the expression of actions and habits. A majority of the research on the neurobiology of habitual behavior has focused on non-drug reward seeking. Here, we will highlight recent research identifying corticostriatal structures that regulate the expression of habitual alcohol seeking and a comparison will be made when possible to findings for non-drug rewards

Prior chronic alcohol exposure enhances Pavlovian-to-instrumental transfer

Alcohol dependence is associated with aberrant decision-making processes, particularly in the presence of alcohol-related environmental cues. For instance, alcohol cues can trigger alcohol seeking, consumption, and even relapse behavior. Recently, works have suggested that alcohol dependence may induce more general alterations in cued processes that support adaptive behavior, including enhanced cue control of volitional behavior unrelated to alcohol use. Here we examine this hypothesis by combining prior exposure to chronic intermittent ethanol and repeated withdrawal (CIE) procedures with a Pavlovian-to-instrumental transfer (PIT) task in mice. The PIT task entails training a Pavlovian association, separately training an instrumental contingency, and a final test during which the Pavlovian cue and instrumental action are combined for the first time. We first tested two variants of the PIT procedure in ethanol-naïve mice, differing in part in the duration of Pavlovian conditioned cues (short or long). We found in the PIT test that the short cue procedure produced negative transfer, whereas the long cue procedure produced positive transfer. We then used the long cue variant to examine PIT behavior in mice previously exposed to either CIE or air vapor. We found that prior CIE exposure strengthened PIT behavior, with enhanced instrumental responding during presentation of the food-associated cue. We further found that this enhancement in CIE mice persisted even after devaluation of the food outcome. Our findings suggest that ethanol dependence can enhance the influence of reward-predictive cues on ongoing behavior. Greater non-alcohol cue control of behavior may reflect the effect of chronic ethanol exposure on neural circuitry critical for cue-guided behavior in general

Chronic alcohol exposure disrupts top-down control over basal ganglia action selection to produce habits.

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

Chronic alcohol exposure disrupts top-down control over basal ganglia action selection to produce habits

Drug dependence shifts the balance in action selection away from goal-directed to habitual responding. Here, the authors report that chronic passive exposure to alcohol leads to suppression of orbitofrontal cortex inputs to dorsomedial striatum resulting in downregulation of goal-directed behavior

Different Effects of Alcohol Exposure on Action and Outcome-Related Orbitofrontal Cortex Activity.

Alcohol dependence can result in long-lasting deficits to decision-making and action control. Neurobiological investigations have identified orbitofrontal cortex (OFC) as important for outcome-related contributions to goal-directed actions during decision-making. Prior work has shown that alcohol dependence induces long-lasting changes to OFC function that persist into protracted withdrawal and disrupts goal-directed control over actions. However, it is unclear whether these changes in function alter representation of action and outcome-related neural activity in OFC. Here, we used the well-validated chronic intermittent ethanol (CIE) exposure and withdrawal procedure to model alcohol dependence in mice and performed in vivo extracellular recordings during an instrumental task in which lever-press actions made for a food outcome. We found alcohol dependence disrupted goal-directed action control and increased OFC activity associated with lever-pressing but decreased OFC activity during outcome-related epochs. The ability to decode outcome-related information, but not action information, from OFC activity following CIE exposure was reduced. Hence, chronic alcohol exposure induced a long-lasting disruption to OFC function such that activity associated with actions was enhanced, but OFC activity contributions to outcome-related information was diminished. This has important implications for hypotheses regarding compulsive and habitual phenotypes observed in addiction

Information normally considered task-irrelevant drives decision-making and affects premotor circuit recruitment

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

Gestational alcohol exposure disrupts cognitive function and striatal circuits in adult offspring.

Fetal alcohol exposure (FAE) is the leading preventable developmental cause of cognitive dysfunction. Even in the absence of binge drinking, alcohol consumption during pregnancy can leave offspring deficient. However, the mechanisms underlying these deficiencies are unknown. Using a mouse model of gestational ethanol exposure (GEE), we show increased instrumental lever-pressing and disruption of efficient habitual actions in adults, indicative of disrupted cognitive function. In vivo electrophysiology reveals disrupted action encoding in dorsolateral striatum (DLS) associated with altered habit learning. GEE mice exhibit decreased GABAergic transmission onto DLS projection neurons, including inputs from parvalbumin interneurons, and increased endocannabinoid tone. Chemogenetic activation of DLS parvalbumin interneurons reduces the elevated lever pressing of GEE mice. Pharmacologically increasing endocannabinoid tone mimics GEE effects on cognition and synaptic transmission. These findings show GEE induces long-lasting deficits in cognitive function that may contribute to human FAE, and identify potential mechanisms for future therapeutic targeting

Orbital frontal cortex updates state-induced value change for decision-making.

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

Effects of chronic alcohol exposure on motivation-based value updating

Dysfunctional decision-making has been observed in alcohol dependence. However, the specific underlying processes disrupted have yet to be identified. Important to goal-directed decision-making is one's motivational state, which is used to update the value of actions. As ethanol dependence disrupts decision-making processes, we hypothesized that ethanol dependence could alter sensitivity to motivational state and/or value updating, thereby reducing the capability for adaptive behavior. Here we employed a sequential instrumental learning task to examine this hypothesis. In two experiments, mice underwent chronic intermittent ethanol (CIE) or air (Air) vapor exposure and repeated withdrawal procedures to induce ethanol dependence. Mice were then trained on a sequence of distal and proximal lever pressing for sucrose under either mild or more severe food restriction. Half of all Air and CIE mice then underwent a motivational shift to a less hungry state and effects of this motivational shift were evaluated across three days. First, mice were re-exposed to sucrose, and effects of food restriction state and CIE exposure on lick and consummatory behavior were examined in the absence of lever pressing. Over the next two days, mice underwent a brief non-rewarded test and then a rewarded test where the ability to retrieve and infer sucrose value to guide lever pressing was measured. In the sucrose re-exposure session, prior CIE exposure altered sucrose-seeking in mice with a history of mild but not more severe food restriction, suggesting altered motivational sensitivity. During lever press testing, CIE mice were insensitive to decreases in motivational state and did not reduce proximal lever pressing regardless of food restriction state. Mildly restricted CIE mice, but not severely restricted CIE mice, also did not reduce distal pressing to the same degree as Air mice following a downshift in motivational state. Our findings suggest that ethanol dependence may disrupt motivational processes supporting value updating that are important for decision-making