Cognitive control of behavior and hippocampal information processing without medial prefrontal cortex

Reviewer #1 (Public review):

Summary:

The authors examine the role of the medial prefrontal cortex (mPFC) in cognitive control, i.e. the ability to use task-relevant information and ignore irrelevant information, in the rat. According to the central-computation hypothesis, cognitive control in the brain is centralized in the mPFC and according to the local hypothesis, cognitive control is performed in task-related local neural circuits. Using the place avoidance task which involves cognitive control, it is predicted that if mPFC lesions affect learning, this would support the central computation hypothesis whereas no effect of lesions would rather support the local hypothesis. The authors thus examine the effect of mPFC lesions in learning and retention of the place avoidance task. They also look at functional interconnectivity within a large network of areas that could be activated during the task by using cytochrome oxydase, a metabolic marker. In addition, electrophysiological unit recordings of CA1 hippocampal cells are made in a subset of (lesioned or intact) animals to evaluate overdispersion, a firing property that reflects cognitive control in the hippocampus. The results indicate that mPFC lesions do not impair place avoidance learning and retention (though flexibility is altered during conflict training), do not affect cognitive control seen in hippocampal place cell activity (alternation of frame-specific firing), a measure of location-specific firing variability, in pretraining. It nevertheless has some effect on functional interconnections. The results overall support the local hypothesis.

Strengths:

(1) Straightforward hypothesis: clarification of the involvement of the mPFC in the brain is expected and achieved. Appropriate use of fully mastered methods (behavioral task, electrophysiological recordings, measure of metabolic marker cytochrome oxidase) and rigorous analysis of the data. The conclusion is strongly supported by the data.

(2) Weaknesses: No notable weaknesses in the conception, making of the study, and data analysis. The introduction does not mention important aspects of the work, i.e. cytochrome oxidase measure and electrophysiological recordings. The study is actually richer than expected from the introduction.

Reviewer #2 (Public review):

Park et al. set out to test two competing hypotheses about the role of the medial prefrontal cortex (PFC) in cognitive control, the ability to use task-relevant cues and ignore task-irrelevant cues to guide behavior. The "central computation" hypothesis assumes that cognitive control relies on computations performed by the PFC, which then interacts with other brain regions to accomplish the task. Alternatively, the "local computation" hypothesis suggests that computations necessary for cognitive control are carried out by other brain regions that have been shown to be essential for cognitive control tasks, such as the dorsal hippocampus and the thalamus. If the central computation hypothesis is correct, PFC lesions should disrupt cognitive control. Alternatively, if the local computation hypothesis is correct, cognitive control would be spared after PFC lesions. The task used to assess cognitive control is the active place avoidance task in which rats must avoid a section of a rotating arena using the stationary room cues and ignoring the local olfactory cues on the rotating platform. Performance on this task has previously been shown to be disrupted by hippocampal lesions and hippocampal ensembles dynamically represent the room and arena depending on the animal's proximity to the shock zone. They found no group (lesion vs. sham) differences in the three behavioral parameters tested: distance traveled, latency to enter the shock zone, and number of shock zone entries for both the standard task and the "conflict" task in which the shock zone was rotated by 180 degrees. The only significant difference was the savings index; the lesion group entered the new shock zone more often than the sham group during the first 5 minutes of the second conflict session. This deficit was interpreted as a cognitive flexibility deficit rather than a cognitive control failure. Next, the authors compared cytochrome oxidase activity between sham and lesion groups in 14 brain regions and found that only the amygdala showed significant elevation in the lesion vs. sham group. Pairwise correlation analysis revealed a striking difference between groups, with many correlations between regions lost in the lesion group (between reuniens and hippocampus, reuniens and amygdala and a correlation between dorsal CA1 and central amygdala that appeared in the lesion group and were absent in the sham group. Finally, the authors assessed dorsal hippocampal representations of the spatial frame (arena vs. room) and found no differences between lesion and sham groups. The only difference in hippocampal activity was reduced overdispersion in the lesion group compared to the sham group on the pretraining session only and this difference disappeared after the task began. Collectively, the authors interpret their findings as supporting the local computation hypothesis; computations necessary for cognitive control occur in brain regions other than the PFC.

Strengths:

(1) The data were collected in a rigorous way with experimental blinding and appropriate statistical analyses.

(2) Multiple approaches were used to assess differences between lesion and sham groups, including behavior, metabolic activity in multiple brain regions, and hippocampal single-unit recording.

Weaknesses:

(1) Only male rats were used with no justification provided for excluding females from the sample.

(2) The conceptual framework used to interpret the findings was to present two competing hypotheses with mutually exclusive predictions about the impact of PFC lesions on cognitive control. The authors then use mainly null findings as evidence in support of the local computation hypothesis. They acknowledge that some people may question the notion that the active place avoidance task indeed requires cognitive control, but then call the argument "circular" because PFC has to be involved in cognitive control. This assertion does not address the possibility that the active place avoidance task simply does not require cognitive control.

(3) The authors did not link the CO activity with the behavioral parameters even though the CO imaging was done on a subset of the animals that ran the behavioral task nor did they make any attempt to interpret these findings in light of the two competing hypotheses posed in the introduction. Moreover, the discussion lacks any mechanistic interpretations of the findings. For example, there are no attempts to explain why amygdala activity and its correlation with dCA1 activity might be higher in the PFC lesioned group.

(4) Publishing null results is important to avoid wasting animals, time, and money. This study's results will have a significant impact on how the field views the role of the PFC in cognitive control. Whether or not some people reject the notion that the active place avoidance task measures cognitive control, the findings are solid and can serve as a starting point for generating hypotheses about how brain networks change when deprived of PFC input.

Reviewer #3 (Public review):

Summary:

This study by Park and colleagues investigated how the medial prefrontal cortex (mPFC) influences behavior and hippocampal place cell activity during a two-frame active place avoidance task in rats. Rats learned to avoid the location of mild shock within a rotating arena, with the shock zone being defined relative to distal cues in the room. Permanent chemical lesions of the mPFC did not impair the ability to avoid the shock zone by using distal cues and ignoring proximal cues in the arena. In parallel, hippocampal place cells alternated between two spatial tuning patterns, one anchored to the distal cues and the other to the proximal cues, and this alteration was not affected by the mPFC lesion. Based on these findings, the authors argue that the mPFC is not essential for differentiating between task-relevant and irrelevant information.

Strengths:

This study was built on substantial work by the Fenton lab that validated their two-frame active place avoidance task and provided sound theoretical and analytical foundations. Additionally, the effectiveness of mPFC lesions was validated by several measures, enabling the authors to base their argument on the lack of lesion effects on behavior and place cell dynamics.

Weaknesses:

The authors define cognitive control as "the ability to judiciously use task-relevant information while ignoring salient concurrent information that is currently irrelevant for the task." (Lines 77-78). This definition is much simpler than the one by Miller and Cohen: "the ability to orchestrate thought and action in accordance with internal goals (Ref. 1)" and by Robbins: "processes necessary for optimal scheduling of complex sequence of behaviour." (Dalley et al., 2004, PMID: 15555683). Differentiating between task-relevant and irrelevant information is required in various behavioral tasks, such as differential learning, reversal learning, and set-shifting tasks. Previous rodent behavioral studies have shown that the integrity of the mPFC is necessary for set-shifting but not for differential or reversal learning (e.g., Enomoto et al., 2011, PMID: 21146155; Cho et al., 2015, PMID: 25754826). In the present task design, the initial training is a form of differential learning between proximal and distal cues, and the conflict training is akin to reversal learning. Therefore, the lack of lesion effects is somewhat expected. It would be interesting to test whether mPFC lesions impair set-shifting in their paradigm (e.g., the shock zone initially defined by distal cues and later by proximal cues). If the mPFC lesions do not impair this ability and associated hippocampal place dynamics, it will provide strong support for the authors' local-computation hypothesis.