Disinhibition of the orbitofrontal cortex biases decision making in obesity

Abstract The lateral orbitofrontal cortex (lOFC) receives sensory information about food and integrates these signals with expected outcomes to guide future actions, and thus may play a key role in a distributed network of neural circuits that regulate feeding behaviour. Here, we reveal a novel role for the lOFC in the cognitive control of behaviour in obesity. Food-seeking behaviour is biased in obesity such that in male obese mice, behaviours are less flexible to changes in the perceived value of the outcome. Obesity is associated with reduced lOFC inhibitory drive, and chemogenetic reduction in GABAergic neurotransmission in the lOFC induces obesity-like impairments in goal-directed behaviour. Conversely, pharmacological or optogenetic restoration of inhibitory neurotransmission in the lOFC of obese mice reinstates flexible behaviour. Our results indicate that obesity-induced disinhibition of the lOFC leads to a failure to update changes in the value of food with satiety, which in turn may influence how individuals make decisions in an obesogenic environment.