Deep Projection Neurons in the Prefrontal Cortex Enable Cognitive Flexibility via Feedback Monitoring

Post by Elisa Guma

What's the science?

Cognitive flexibility refers to our ability to adapt and update strategies in response to changing environmental stimuli and is impaired in individuals across a range of psychiatric disorders. A large body of evidence from both rodent and human studies suggests that the prefrontal cortex (PFC) plays a critical role in supporting this behaviour, however, the mechanisms underlying this role of the PFC in cognitive flexibility remain to be elucidated. The PFC is thought to provide an attentional filter for the brain that biases sensorimotor responses during set-shifting (task switching to focus on a new, relevant stimulus), however, an alternative hypothesis suggests that the PFC supports set-shifting by monitoring feedback in response to recent decisions. This week in Cell, Spellman and colleagues investigate whether the PFC supports set-shifting behaviour through feedback monitoring or through attentional modulation of sensorimotor responses in a series of experiments in mice.

How did they do it?

The authors trained adult male water-deprived mice on an attentional set-shifting task comprising a successive series of stimulus-response discriminations in which the relevant stimuli (signifying a reward) and irrelevant stimuli were changed. Briefly, mice were presented one of two possible whisker vibration stimuli, and one of two possible odor stimuli to which they had to respond by licking either a left or right lick port to receive a water reward. They had to learn that either a specific whisker or odor stimulus signaled the location of the reward and to ignore irrelevant stimuli. These associations changed throughout the task, requiring mice to unlearn the previous association and learn the new one. Trials were classified into congruent trials in which whisker and odor rules cued the same response direction, or incongruent trials, in which whisker and odor rules cued opposite directions.

While the mice performed this task, the authors used GcaMP6f-mediated two-photon calcium imaging to examine neural activity in the PFC, for all neurons, as well as for two specific projections hypothesized to be critical for this task: a projection to the ventromedial striatum (PFC-VMS), or a projection to the mediodorsal thalamus (PFC-MDT). Neural activity data were classified, using a machine learning model (a support vector machine-based decoder), into different categories including whisker stimulus (ex: 35 versus 210 Hz), odor stimulus (ex: almond versus olive oil), response (left/right), outcome (correct/incorrect), and rule (attend to whisker or odor). Based on these categories, the authors were able to investigate the specific within-trial timepoints at which neurons were encoding either response or outcome, and how these signals were carried over into subsequent trials.

In order to shed light on the circuitry underlying the PFC’s role in attentional set-shifting, the authors used optogenetics to selectively inhibit PFC activity either during the attentional set-shifting trials or during the intertrial period following either congruent or incongruent trials. In addition to assessing the role of the PFC-VMS and PFC-MDT pathways in supporting rule-guided response, they also investigated the role of the posterior parietal cortex based on previous research implicating this region in cognitive flexibility and monitoring sensory history. Finally, the authors examined whether the spatial distribution of PFC neurons played an important role. They used retrograde tracers to specifically target either deep or superficial projection neurons from the PFC to ACC.

What did they find?

The authors found that the temporal components associated with whisker and odor stimulus peaked during the stimulus presentation, as expected, while components associated with outcome peaked during the inter-trial interval and persisted for up to four trials. This suggests that the response-associated patterns lag, rather than lead, the animal’s behavioural choice.

The optogenetic manipulation of PFC activity during the attentional set-shifting task led to an impairment in performance only when activation was silenced during the intertrial interval following incongruent trials, but not congruent trials, and not during the stimulus presentation. This suggests that interference with prior trial feedback, rather than preparation for the subsequent trial, caused impairment in performance. Additionally, silencing the posterior parietal cortex neurons during trials impaired performance on the incongruent but not congruent trials, suggesting that the posterior parietal cortex mediates responding in the task in a specifically rule-dependent manner.

Contrary to expectations, the two populations of neurons from the PFC-VMS and PFC-MDT pathways showed a striking degree of overall similarity in their task responsiveness. Even though there was no distinction between these two pathways, there was a great degree of heterogeneity in the functional properties of the neurons studies, with a range of correct- or incorrect-preferring neurons, which they probed further. They found that the heterogeneity in neural response was attributed to the depth of the cortical layer, highlighting the importance of deep cortical projection to the anterior cingulate cortex.

What's the impact?

These findings provide a novel model for the role of the PFC in cognitive flexibility. Rather than mediating top-down cognitive control, the PFC was shown to integrate and maintain representations of recent behaviours and their consequences. Future work may seek to elucidate the potential role of certain neurotransmitter systems, such as acetylcholine, as it plays a key role in mediating feedback monitoring signals in the brain. Further, this work could aid in our understanding of how neural circuitry may be impaired in neurodevelopmental disorders exhibiting attentional set-shifting deficits but should include the use of female mice.

Spellman al., Prefrontal deep projection neurons enable cognitive flexibility via persistent feedback monitoring. Cell (2021). The original scientific publication here.