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

ABSTRACT: 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.

SUBMITTER: Cazares C

PROVIDER: S-EPMC8174034 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cocaine use during adolescence decreases the likelihood that individuals will seek treatment for recurrent drug use. In rodents, developmental cocaine exposure weakens action-consequence decision-making, causing a deferral to familiar, habit-like behavioral response strategies. Here, we aimed to improve action-outcome decision-making. We found that acute pharmacological stimulation of the tyrosine/tropomyosin receptor kinase B (trkB) via 7,8-dihydroxyflavone (7,8-DHF) or 3,4-methylenedioxymethamphetamine (MDMA) blocked cocaine-induced habit biases by strengthening memory for action-outcome associations. We believe that MDMA acts by stimulating neurotrophin/trkB systems in the orbitofrontal cortex (OFC), a region involved in prospectively evaluating the consequences of one's action, because 1) MDMA also increased brain-derived neurotrophic factor (BDNF) in the OFC, 2) MDMA corrected habit biases due to Bdnf loss in the OFC, and 3) overexpression of a truncated isoform of trkB occluded the memory-enhancing effects of MDMA. Thus, selecting actions based on their consequences requires BDNF-trkB in the OFC, the stimulation of which may improve goal attainment in both drug-naïve and cocaine-exposed individuals. SIGNIFICANCE STATEMENT: Cocaine use during adolescence decreases the likelihood that individuals will seek treatment for recurrent drug use, even as adults. Understanding how early-life cocaine exposure impacts goal-oriented action and prospective decision-making in adulthood is thus important. One key aspect of goal-directed decision-making is anticipating the consequences of one's actions, a process that likely involves the orbitofrontal cortex (OFC). In rodents, developmental cocaine exposure weakens action-consequence decision-making, causing a deferral to familiar, habit-like behavioral response strategies. Here, we report that we can improve memory for action-consequence relationships by stimulating neurotrophic factors, which support cell survival, development, and plasticity in the brain. With strengthened action-consequence associations, cocaine-exposed mice regain the ability to optimally select actions based on their likely outcomes. Brain region-selective manipulations reveal that neurotrophin systems in the OFC are necessary for stable memory of action-consequence relationships.

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

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