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 goaldirected 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 exposure and withdrawal procedure (CIE) 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. Significance StatementAlcohol dependence produces long-lasting deficits in decision-making including to actions made with regard to their outcome or consequence. This type of decision-making has been shown to involve orbitofrontal cortex (OFC). Here using a mouse model of chronic alcohol exposure, we show that chronic alcohol exposure leads to bidirectional changes in activity of OFC neurons dependent on the behavioral computation being performed.Mice that underwent previous chronic alcohol show increased OFC activity during actions for a food reward, but reduced OFC activity during reward-associated periods and reduced OFC contribution to reward prediction.

Orbitofrontal cortex populations are differentially recruited to support actions

“…This result aligned with prior findings that raise questions about what behavioral mechanisms control remaining lever presses in goal-directed responding. 33, 42 Thus, broad behavioral performance measures suggested that mice used inferred contingency and expected outcome information to guide their lever press behavior.…”

“…However, disrupting lOFC activity during every lever press as described above prevented us from determining whether lOFC activity contributed to the encoding of action information, or to the use of prior action information to guide ongoing performance. Another possibility is that inhibiting lOFC during the lever press was akin to enhancing the general reduction in activity normally observed when the animal holds down the lever (Figure 2D), 42 thereby facilitating lOFC processes that could be competing with other action-related processes and associated circuits. Furthermore, inducing interneuron mediated inhibition during every lever press may have recruited compensatory mechanisms for task performance, such that the observed behavioral effects may not be directly attributable to a loss of lOFC function.…”

“…Group averaged CaMKII+ OFC projection population activity was modulated prior to the onset of a lever press, similarly to previously reported single-unit recordings. 40,42 Permutation testing 77 revealed that pre onset lOFC Ca 2+ activity differed with respect to its eventual outcome (Figure 2C; ps < 0.05). Future success-related differences persisted during the lever press (Figure 2D; ps < 0.05) and success-related differences were observed after the lever press release (Figure 2E; ps < 0.05).…”

“…We used a self-paced instrumental task in which prior actions and the continuous context in which they occur are used to guide subsequent actions. 33, 42 In this task, mice had to learn to press and hold a lever down beyond a fixed minimum duration criterion to earn a food reward, with the reward only delivered after a successful lever press was terminated. This allowed us to examine adjustments to action control while keeping broad action-outcome relationships stable.…”

“…However, whether such action-related inferences recruit OFC-based contributions is less clear. On one hand, prior investigations have observed modulation of lateral OFC (lOFC) neurons during actions [39][40][41][42] and found that disrupting lOFC activity perturbs actions sensitive to decreases in expected outcome value. 40,[43][44][45][46] Additional work has suggested lOFC is recruited when action-outcome contingencies change during learning.…”