Male rodent perirhinal cortex, but not ventral hippocampus, inhibition induces approach bias under object-based approach-avoidance conflict
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Evaluation Summary:
In this interesting study the authors combined innovative object-based conflict assays with optogenetic silencing to probe the role of the perirhinal cortex in motivational conflict. The manuscript is well-written and the approach was adequate. The findings provide new insight into how conflicting motivation is processed and would benefit from additional analysis and experimental investigation to more conclusively support the interpretations.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)
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Abstract
Neural models of approach-avoidance (AA) conflict behavior and its dysfunction have focused traditionally on the hippocampus, with the assumption that this medial temporal lobe (MTL) structure plays a ubiquitous role in arbitrating AA conflict. We challenge this perspective by using three different AA behavioral tasks in conjunction with optogenetics, to demonstrate that a neighboring region in male rats, perirhinal cortex, is also critically involved but only when conflicting motivational values are associated with objects and not contextual information. The ventral hippocampus, in contrast, was found not to be essential for object-associated AA conflict, suggesting its preferential involvement in context-associated conflict. We propose that stimulus type can impact MTL involvement during AA conflict and that a more nuanced understanding of MTL contributions to impaired AA behavior (e.g., anxiety) is required. These findings serve to expand upon the established functions of the perirhinal cortex while concurrently presenting innovative behavioral paradigms that permit the assessment of different facets of AA conflict behavior.
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Evaluation Summary:
In this interesting study the authors combined innovative object-based conflict assays with optogenetic silencing to probe the role of the perirhinal cortex in motivational conflict. The manuscript is well-written and the approach was adequate. The findings provide new insight into how conflicting motivation is processed and would benefit from additional analysis and experimental investigation to more conclusively support the interpretations.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
Dhawan et al examine the involvement of the perirhinal cortex (PRC) and ventral hippocampus (vHPC) in different forms of approach-avoidance conflict. The paper is well written, the methods used are appropriate for the question asked and, in general, the authors have succeeded in identifying the PRC and vHPC involvement. As such, the paper will eventually have an impact on thinking about the roles of the PRC and vHPC in different forms of learning and memory. However, this impact is conditional on the authors' responses to queries regarding experimental design, group allocations and statistical analyses.
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Reviewer #2 (Public Review):
Here, the authors employed optogenetic silencing of the perirhinal cortex (PRC) and the CA3 subarea of the ventral hippocampus (vCA3) during object-based approach/avoidance conflict assays. Silencing of PRC, but not vCA3, impaired passive avoidance in a runway conflict task and active avoidance in a shuttle avoidance task. Interestingly, silencing of PRC had no effect on avoidance in a context-based conflict Y-maze assay. Together, these result reveal a novel role for PRC in mediating threat avoidance during risky reward opportunities. One of the main strengths of this study is the use of innovative object-based conflict assays, which were key for unveiling the novel role for PRC. The main weaknesses of the study are the unjustified exclusion of female subjects and the lack of histological verification of …
Reviewer #2 (Public Review):
Here, the authors employed optogenetic silencing of the perirhinal cortex (PRC) and the CA3 subarea of the ventral hippocampus (vCA3) during object-based approach/avoidance conflict assays. Silencing of PRC, but not vCA3, impaired passive avoidance in a runway conflict task and active avoidance in a shuttle avoidance task. Interestingly, silencing of PRC had no effect on avoidance in a context-based conflict Y-maze assay. Together, these result reveal a novel role for PRC in mediating threat avoidance during risky reward opportunities. One of the main strengths of this study is the use of innovative object-based conflict assays, which were key for unveiling the novel role for PRC. The main weaknesses of the study are the unjustified exclusion of female subjects and the lack of histological verification of viral injections and fiber placements.
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Reviewer #3 (Public Review):
The manuscript by Dawani et al. extends previous work by the same group and others to dissect brain circuits that implement decision-making in the presence of conflicting motivation using approach-avoidance behavioral tasks. The current investigation introduces multiple behavioral paradigms in which different types of signals or cues are associated with rewarding or anxiety-inducing conditions. The authors then place these cues in conflict in an attempt to identify the involvement of key brain areas in different aspects of motivational conflict. In particular, they compare processing when objects are used as cues vs when "contextual" features of the overall environment (wall color and texture) convey the motivational conflict. They then use optogenetic inactivation of brain areas that have been implicated in …
Reviewer #3 (Public Review):
The manuscript by Dawani et al. extends previous work by the same group and others to dissect brain circuits that implement decision-making in the presence of conflicting motivation using approach-avoidance behavioral tasks. The current investigation introduces multiple behavioral paradigms in which different types of signals or cues are associated with rewarding or anxiety-inducing conditions. The authors then place these cues in conflict in an attempt to identify the involvement of key brain areas in different aspects of motivational conflict. In particular, they compare processing when objects are used as cues vs when "contextual" features of the overall environment (wall color and texture) convey the motivational conflict. They then use optogenetic inactivation of brain areas that have been implicated in this type of behavior to identify their involvement in each of the different task variations. Using these approaches, they find evidence suggesting that the perirhinal cortex is important for processing conflicting motivational signals under certain conditions. While the idea that the perirhinal cortex plays such a role had been proposed in previous models it had not been tested directly making this a novel finding. In addition, the authors are able to contrast the involvement of this circuit with that of the hippocampus, which had previously been considered the major region responsible for this type of conflict processing. Consistent with previous work, their findings suggest that the Hippocampus is involved when cues are contextual but that the Perirhinal cortex, rather than the Hippocampus, plays an analogous role when conflicting signals are communicated by combinations of objects.
In general, the behavioral experiments as well as controls are well designed, and analysis of the resulting data is also consistent with current practices. Despite this overall quality as well as the strength of some of the optogenetic effects, however, the known involvement of the perirhinal cortex in encoding and recognition of object memory, particularly for complex or combined stimuli (e.g. Haskins et al. Neuron 2008, Ohnuki et al. Comm. Bio. 2020) creates a confound that the authors do not completely overcome. Specifically, they do not exclude the possibility that this area may be involved in recognizing objects with different motivational associations when they are presented together. While some of the evidence presented argues against this possibility, additional analysis and experiments are needed to more conclusively establish that the perirhinal cortex is involved in motivational conflict itself, and that the suppression effects they observe are not simply due to its memory-related functions. In particular, it would be beneficial to suppress the region at distinct time periods within the task to isolate different contributions. Beyond this major issue, there are also several minor changes to the figures and text needed for overall clarity.
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