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. Goal-directed behaviour is biased in obesity such that in obese animals, actions are no longer influenced by 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, goal-directed behaviour. Our results indicate that obesity hinders an individual’s ability to make value representations about rewards, which in turn may influence how individuals make decisions in an obesogenic environment.

Enhanced food motivation in obese mice is controlled by D1R expressing spiny projection neurons in the nucleus accumbens

“…Diet-induced obesity increases physical work during food seeking It has been challenging to determine whether obese animals are more or less motivated to obtain food than lean animals: on one hand, obese rodents eat more than lean rodents when food is provided freely [23][24][25] ; but on the other hand, they expend less effort to obtain food when they have to work for it [26][27][28] . This decrease in effort has primarily been observed in progressive ratio tasks that require increasing numbers of operant responses to obtain food, which we also observed (Suppl Fig 1).…”

Linking drug and food addiction: an overview of the shared neural circuits and behavioral phenotype

“…Notably, lateral OFC is crucial for goaldirected behavior. A recent study showed how in a mouse model of obesity, lateral OFC-dependent impairments in devaluation (mediated by GABAergic transmission) may alter the ability to use the value of the outcome to guide behavior (Seabrook et al, 2023). Increased activation of OFC is also evident in drug-addicted subjects in response to drugrelated cues (Sell et al, 2000;Wang et al, 2007;Kufahl et al, 2008;Goldstein and Volkow, 2011;Ceceli et al, 2022), and it is considered an index of craving (Volkow et al, 2010).…”