Distinct patterns of abnormal lateral orbitofrontal cortex activity during compulsive grooming and reversal learning normalize after fluoxetine

The orbitofrontal cortex (OFC) is critical for updating reward-directed behaviours flexibly when outcomes are devalued or when task contingencies are reversed. Failure to update behaviour in outcome devaluation and reversal learning procedures are considered canonical deficits following OFC lesions in non-human primates and rodents. We examined the generality of these findings in rodents using lesions of the rodent lateral OFC (LO) in instrumental action-outcome and Pavlovian cue-outcome devaluation procedures. LO lesions disrupted outcome devaluation in Pavlovian but not instrumental procedures. Furthermore, although both anterior and posterior LO lesions disrupted Pavlovian outcome devaluation, only posterior LO lesions were found to disrupt reversal learning. Posterior but not anterior LO lesions were also found to disrupt the attribution of motivational value to Pavlovian cues in sign-tracking. These novel dissociable task- and subregion-specific effects suggest a way to reconcile contradictory findings between rodent and non-human primate OFC research.

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Cortical and thalamic influences on striatal involvement in instructed, serial reversal learning; implications for the organisation of flexible behaviour.

10.1101/2021.12.20.472804 ◽

2021 ◽

Author(s):

Brendan Williams ◽

Anastasia Christakou

Keyword(s):

Functional Connectivity ◽

Cognitive Flexibility ◽

Reversal Learning ◽

Orbitofrontal Cortex ◽

Dorsal Striatum ◽

Response Strategy ◽

Flexible Control ◽

The Right ◽

Serial Reversal

Cognitive flexibility is essential for enabling an individual to respond adaptively to changes in their environment. Evidence from human and animal research suggests that the control of cognitive flexibility is dependent on an array of neural architecture. Cortico-basal ganglia circuits have long been implicated in cognitive flexibility. In particular, the role of the striatum is pivotal, acting as an integrative hub for inputs from the prefrontal cortex and thalamus, and modulation by dopamine and acetylcholine. Striatal cholinergic modulation has been implicated in the flexible control of behaviour, driven by input from the centromedian-parafascicular nuclei of the thalamus. However, the role of this system in humans is not clearly defined as much of the current literature is based on animal work. Here, we aim to investigate the roles corticostriatal and thalamostriatal connectivity in serial reversal learning. Functional connectivity between the left centromedian-parafascicular nuclei and the associative dorsal striatum was significantly increased for negative feedback compared to positive feedback. Similar differences in functional connectivity were observed for the right lateral orbitofrontal cortex, but these were localised to when participants switched to using an alternate response strategy following reversal. These findings suggest that connectivity between the centromedian-parafascicular nuclei and the striatum may be used to generally identify potential changes in context based on negative outcomes, and the effect of this signal on striatal output may be influenced by connectivity between the lateral orbitofrontal cortex and the striatum.

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