Subunit-selective PI3-kinase control of action strategies in the medial prefrontal cortex.

PI3-kinase (PI3K) is an intracellular signaling complex that is stimulated upon cocaine exposure and linked with the behavioral consequences of cocaine. We recently genetically silenced the PI3K p110β subunit in the medial prefrontal cortex following repeated cocaine in mice, reinstating the capacity of these mice to engage in prospective goal-seeking behavior. In the present short report, we address two follow-up hypotheses: 1) The control of decision-making behavior by PI3K p110β is attributable to neuronal signaling, and 2) PI3K p110β in the healthy (i.e., drug-naïve) medial prefrontal cortex has functional consequences in the control of reward-related decision-making strategies. In Experiment 1, we found that silencing neuronal p110β improved action flexibility following cocaine. In Experiment 2, we reduced PI3K p110β in drug-naïve mice that were extensively trained to respond for food reinforcers. Gene silencing caused mice to abandon goal-seeking strategies, unmasking habit-based behaviors that were propelled by interactions with the nucleus accumbens. Thus, PI3K control of goal-directed action strategies appears to act in accordance with an inverted U-shaped function, with "too much" (following cocaine) or "too little" (following p110β subunit silencing) obstructing goal seeking and causing mice to defer to habit-like response sequences.