Chronic alcohol exposure differentially alters calcium activity of striatal cell populations during actions.

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.

Chronic alcohol exposure alters action control via hyperactive premotor corticostriatal activity.

Alcohol use disorder (AUD) alters decision-making control over actions, but disruptions to the responsible neural circuit mechanisms are unclear. Premotor corticostriatal circuits are implicated in balancing goal-directed and habitual control over actions and show disruption in disorders with compulsive, inflexible behaviors, including AUD. However, whether there is a causal link between disrupted premotor activity and altered action control is unknown. Here, we find that mice chronically exposed to alcohol (chronic intermittent ethanol [CIE]) showed impaired ability to use recent action information to guide subsequent actions. Prior CIE exposure resulted in aberrant increases in the calcium activity of premotor cortex (M2) neurons that project to the dorsal medial striatum (M2-DMS) during action control. Chemogenetic reduction of this CIE-induced hyperactivity in M2-DMS neurons rescued goal-directed action control. This suggests a direct, causal relationship between chronic alcohol disruption to premotor circuits and decision-making strategy and provides mechanistic support for targeting activity of human premotor regions as a potential treatment in AUD.

Orbitofrontal cortex populations are differentially recruited to support actions.

The ability to use information from one's prior actions is necessary for decision-making. While orbitofrontal cortex (OFC) has been hypothesized as key for inferences made using cue and value-related information, whether OFC populations contribute to the use of information from volitional actions to guide behavior is not clear. Here, we used a self-paced lever-press hold-down task in which mice infer prior lever-press durations to guide subsequent action performance. We show that the activity of genetically identified lateral OFC (lOFC) subpopulations differentially instantiate current and prior action information during ongoing action execution. Transient state-dependent lOFC circuit disruptions of specified subpopulations reduced the encoding of ongoing press durations but did not disrupt the use of prior action information to guide future action performance. In contrast, a chronic functional loss of lOFC circuit activity resulted in increased reliance on recently executed lever-press durations and impaired contingency reversal, suggesting the recruitment of compensatory mechanisms that resulted in repetitive action control. Our results identify a novel role for lOFC in the integration of action information to guide adaptive behavior.

Effects of central amygdala chemogenetic manipulation and prior chronic alcohol exposure on Pavlovian-to-instrumental transfer.

BACKGROUND: Recent work suggests that a history of chronic alcohol exposure can enhance the influence of nondrug reward cues on ongoing actions. This is often modeled in Pavlovian-to-instrumental transfer (PIT) tasks that examine the interaction between Pavlovian and instrumental learning processes, usually reflected as an increase in action vigor during the presentation of a reward-associated cue. Though prior chronic alcohol exposure strengthens this type of cue-guided behavior, the neural mechanisms underlying such enhancements are not known. METHODS: In the present work, we examined the contribution of the central amygdala (CeA), a region strongly implicated in PIT behaviors and functionally altered by chronic alcohol exposure. We utilized Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to examine the impact of inhibitory and excitatory CeA manipulation on PIT behaviors in alcohol-naïve mice and mice with a history of chronic intermittent ethano vapor exposure and withdrawal (CIE). RESULTS: Replicating previous work, we found that a history of CIE strengthened baseline PIT, in the absence of any CeA manipulation. We also found that activation of both inhibitory and excitatory DREADDs expressed in CeA enhanced PIT in alcohol-naïve mice, though the latter markedly reduced response rates. However, in mice exposed to CIE, activation of excitatory DREADD receptors expressed in CeA appeared to weaken PIT. CONCLUSIONS: These results suggest that alcohol-induced disruptions in amygdala function may contribute to changes in appetitive behaviors, such as cue-guided responding, following chronic exposure to alcohol. Better elucidating the neural mechanisms that underlie disrupted cue-guided behavior following chronic alcohol exposure may help to understand and treat deficits in adaptive behavior associated with chronic alcohol use in humans.

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.

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.

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.

Control of exploration, motor coordination and amphetamine sensitization by cannabinoid CB1 receptors expressed in medium spiny neurons.

Activation of cannabinoid 1 receptors (CB1 R) modulates multiple behaviours, including exploration, motor coordination and response to psychostimulants. It is known that CB1 R expressed by either excitatory or inhibitory neurons mediates different behavioural responses to CB1 R activation, yet the involvement of CB1 R expressed by medium spiny neurons (MSNs), the neuronal subpopulation that expresses the highest level of CB1 R in the CNS, remains unknown. We report a new genetically modified mouse line that expresses functional CB1 R in MSN on a CB1 R knockout (KO) background (CB1 R(MSN) mice). The absence of cannabimimetic responses measured in CB1 R KO mice was not rescued in CB1 R(MSN) mice, nor was decreased spontaneous locomotion, impaired instrumental behaviour or reduced amphetamine-triggered hyperlocomotion measured in CB1 R KO mice. Significantly, reduced novel environment exploration of an open field and absence of amphetamine sensitization (AS) measured in CB1 R KO mice were fully rescued in CB1 R(MSN) mice. Impaired motor coordination in CB1 R KO mice measured on the Rotarod was partially rescued in CB1 R(MSN) mice. Thus, CB1 R expressed by MSN control exploration, motor coordination, and AS. Our study demonstrates a new functional roles for cell specific CB1 R expression and their causal link in the control of specific behaviors.

Call for a more balanced approach to understanding orbital frontal cortex function.

Orbital frontal cortex (OFC) research has historically emphasized the function of this associative cortical area within top-down theoretical frameworks. This approach has largely focused on mapping OFC activity onto human-defined psychological or cognitive constructs and has often led to OFC circuitry bearing the weight of entire theoretical frameworks. New techniques and tools developed in the last decade have made it possible to revisit long-standing basic science questions in neuroscience and answer them with increasing sophistication. We can now study and specify the genetic, molecular, cellular, and circuit architecture of a brain region in much greater detail, which allows us to piece together how they contribute to emergent circuit functions. For instance, adopting such systematic and unbiased bottom-up approaches to elucidating the function of the visual system has paved the way to building a greater understanding of the spectrum of its computational capabilities. In the same vein, we argue that OFC research would benefit from a more balanced approach that also places focus on novel bottom-up investigations into OFC's computational capabilities. Furthermore, we believe that the knowledge gained by employing a more bottom-up approach to investigating OFC function will ultimately allow us to look at OFC's dysfunction in disease through a more nuanced biological lens. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

A Push For Examining Subjective Experience in Value-Based Decision-Making.

Subjective experience is a powerful contributor to value-based decision-making. Not every decision is the same, nor made in isolation. Rather, decision-making relies on historical information and internal states for adaptive control. Hence, it is inherently continuous with respect to time - one decision or action evolves into the next. However, forays into the neurobiological underpinnings of decision-making have too frequently ignored the contribution of such continuous subjective experience, instead tying circuit activity and brain area involvement to discrete averaged behaviors and task parameters. While much information has been gained through these investigations, recent works have demonstrated the potential for a greater understanding of neural mechanisms when the continuous, experiential nature of behavior is integrated into the investigation. Such integration has important implications for disease states with disordered decision-making such as addiction, where subjective experience is a large contributor to the disorder.

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.

Mechanism for differential recruitment of orbitostriatal transmission during actions and outcomes following chronic alcohol exposure.

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.

A Circuit-Based Information Approach to Substance Abuse Research.

Recent animal research on substance-use disorders (SUDs) has emphasized learning models and the identification of 'addiction-prone' animals. Meanwhile, basic neuroscientific research has elucidated molecular, cellular, and circuit functions with increasing sophistication. However, SUD-related research is hampered by continued arguments over which animal models are more 'addiction like', as well as the facile assignment of behaviors to a given brain region and vice versa. We argue that SUD-related research would benefit from a 'bottom-up' approach including: (i) the characterization of different brain circuits to understand their normal function as well as how they respond to drugs and contribute to SUDs; and (ii) a focus on the use patterns and neurobiological effects of different substances to understand the range of critical SUD-related in vivo phenotypes.

Review of Orbitofrontal Cortex in Alcohol Dependence: A Disrupted Cognitive Map?

Alcoholism is a persistent worldwide problem associated with long-lasting impairments to decision making processes. Some aspects of dysfunction are thought to reflect alcohol-induced changes to relevant brain areas such as the orbitofrontal cortex (OFC). In this review, we will examine how chronic alcohol exposure alters OFC function to potentially contribute to maladaptive decision making, and explore experimental behavioral approaches that may be better suited to test whether alcohol dependence disrupts OFC's function. We argue that although past works suggest impairments in aspects of OFC function, more information may be gained by specifically targeting tasks to the broader function of OFC as put forth by the recent hypothesis of OFC as a "cognitive map" of task space. Overall, we suggest that such a focus could provide a better understanding of how OFC function changes in alcohol dependence, and could inform better assessment tools and treatment options for clinicians working with this population.

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.

Habitual Ethanol Seeking and Licking Microstructure of Enhanced Ethanol Self-Administration in Ethanol-Dependent Mice.

BACKGROUND: A significant component of ethanol (EtOH) dependence is the disruption to decision-making processes. Prior work has shown EtOH dependence biases habitual seeking of EtOH and disrupts neural mechanisms supporting decision-making. This has contributed to the hypothesis that habitual EtOH seeking in EtOH dependence may promote excessive habitual or compulsive EtOH consumption. However, decision-making and behavioral processes underlying seeking and consummatory behaviors differ. Here, we examine the microstructure of EtOH consummatory behavior in the context of habitual EtOH seeking. METHODS: Following home cage pre-exposure to EtOH, C57Bl/6J mice underwent 4 rounds of chronic intermittent EtOH (CIE) or air exposure. Following acute withdrawal, mice began training for operant self-administration of 15% EtOH. Training consisted of 16-hour sessions in which mice were trained in a random ratio (RR) schedule of reinforcement for 30-second access to the EtOH sipper. To test for CIE-induced changes in action control, we used sensory-specific satiation and assessed the effect of outcome devaluation on EtOH seeking. Importantly, the use of a lickometer during operant training allowed us to measure the microstructure of lick behavior. RESULTS: Prior induction of EtOH dependence led to increased EtOH seeking, consumption, and an insensitivity to outcome devaluation, the latter indicative of habitual EtOH seeking. We also found altered consummatory lick patterns in CIE-exposed mice compared to Air controls. While CIE mice had significantly more licks in a burst and a longer burst duration, there were no differences in the total number of bursts compared to Air controls. Furthermore, these EtOH consummatory behaviors correlated with blood EtOH concentrations (BECs), while EtOH-seeking responses did not. CONCLUSIONS: Our results confirm that EtOH dependence can produce habitual EtOH seeking and suggests the increased EtOH consummatory behaviors following EtOH dependence are separable from decision-making processes controlling EtOH seeking.

Fractionating the all-or-nothing definition of goal-directed and habitual decision-making.

Goal-directed and habitual decision-making are fundamental processes that support the ongoing adaptive behavior. There is a growing interest in examining their disruption in psychiatric disease, often with a focus on a disease shifting control from one process to the other, usually a shift from goal-directed to habitual control. However, several different experimental procedures can be used to probe whether decision-making is under goal-directed or habitual control, including outcome devaluation and contingency degradation. These different experimental procedures may recruit diverse behavioral and neural processes. Thus, there are potentially many opportunities for these disease phenotypes to manifest as alterations to both goal-directed and habitual controls. In this review, we highlight the examples of behavioral and neural circuit divergence and similarity, and suggest that interpretation based on behavioral processes recruited during testing may leave more room for goal-directed and habitual decision-making to coexist. Furthermore, this may improve our understanding of precisely what the involved neural mechanisms underlying aspects of goal-directed and habitual behavior are, as well as how disease affects behavior and these circuits.

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.

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.

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.