Discussion
impairment of metabolic signalling, obesity, impaired learning of sensory associations, impaired outcome learning, deficiencies in associative learning
OBESITY, EVENTS, INSULIN SENSITIVITY
Arguing that the motivational force prompting behavioural adaptation must ultimately rely on learned sensory associations, we scrutinize a general role for metabolic sensing in associative learning. Here, our main hypothesis rests on the assumption that metabolic signals from the periphery affect DA neuron function in the mesoaccumbens pathway and hence alter learning. We further consider impaired insulin sensitivity of the DA midbrain as a possible cause for impaired learning of sensory associations and investigate whether augmenting the endogenous metabolic feedback signal with the GLP-1 receptor agonist liraglutide normalizes associative learning. By applying a generative model with sufficient hierarchical depth to handle events that unfold at different spatial and temporal scales and that have already been established to provide reliable estimates of individual learning performanceOur behavioural results revealed similar patterns of sensory prediction error formation under placebo and intervention conditions irrespective of insulin sensitivity. Participants with impaired insulin sensitivity exhibited a reduced amplitude of behavioural updating, which was normalized by the liraglutide intervention. This effect of the GLP-1 receptor agonist on behavioural updating is driven by the enhanced encoding of adaptive prediction errors in the ventral striatum and its cortical projection sites, including prefrontal (vmPFC) and orbitofrontal cortices related to the adaptive encoding of decision variablesNotably, the learning task used did not involve explicit reinforcement (food or any other reward) but merely sensory cues. Thus, the documented regulation of prediction error learning by metabolic signals is not restricted to learning about homeostatically relevant cue–outcome associations. Interestingly, midbrain dopaminergic neurons are capable of facilitating associations between contiguously occurring events, regardless of the content of those eventsOur results support a growing body of literature indicating that metabolic signals profoundly influence neuronal processing (particularly those signalling energy restoration in an energy deprivation scenario, such as insulin and GLP-1 signalling a postprandial state in our participants after an overnight fasting period). Fundamental neural processes, such as coding precision of visual information in the neocortexWe further show that impairment of metabolic signalling (such as impairment of insulin sensitivity in obesity) causes deficiencies in associative learning. In line with this finding, previous studies revealed impaired outcome learning in obesityRegarding the question of which pathway the peripherally administered GLP-1 receptor agonist liraglutide recruits to affect DA function in the mesoaccumbens pathway, we currently lack evidence that liraglutide enters the VTA or NAc. Ultimately, vagal afferents may be relevant for systemic GLP-1 sensing