Number, order and time influence how the brain integrates distinct experiences
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eLife Assessment
This work provides an important set of findings using sensory preconditioning procedures that advance our understanding of the circumstances that influence the integration of discrete learning experiences. The evidence supporting the conclusions is solid, as the study used multiple different conditions to differentiate between different theories of memory integration. Moreover, the findings should be of broader interest to the learning and memory field for considering the role of the medial temporal lobe in how separate experiences are integrated.
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Abstract
How does the brain integrate experiences that are separated in time? The present study addressed this question using sensory preconditioning protocols in rats. In these protocols, rats integrate an A-B association (e.g., tone-light) formed in stage 1 with a B- shock association (e.g., light-shock) formed in stage 2 to generate fear responses (freezing) when tested with A alone in stage 3. Here we show that the mechanism of integration depends on the number, order and timing of events across the two stages of training. When the events are novel (low number of exposures) and the interval between stages 1 and 2 is short (24 hours), the A-B and B-shock associations are integrated through formation of a mediated A- shock association during stage 2. By contrast, when the events are more familiar (greater number of exposures), ordered in a particular way, and the interval between stages 1 and 2 is long (14-days), the A-B and B-shock associations are integrated through their chaining at the time of testing with A alone. Thus, number, order and time determine how distinct experiences are integrated in the brain. These findings are discussed with respect to theories of integration and information processing in the medial temporal lobe.
Article activity feed
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eLife Assessment
This work provides an important set of findings using sensory preconditioning procedures that advance our understanding of the circumstances that influence the integration of discrete learning experiences. The evidence supporting the conclusions is solid, as the study used multiple different conditions to differentiate between different theories of memory integration. Moreover, the findings should be of broader interest to the learning and memory field for considering the role of the medial temporal lobe in how separate experiences are integrated.
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Reviewer #1 (Public review):
Summary:
Sensory preconditioning protocols have been used to understand how the brain controls aversive or appetitive behavioral responses towards stimuli that have never been directly reinforced. In this study, the authors combine pharmacological NMDA blockade in a specific brain region previously involved in sensory preconditioning (i.e., perirhinal cortex) and different versions of a light-tone sensory preconditioning task in rats (i.e., different number of associations during preconditioning, distinct temporal separation between stage 1 and stage 2, stimuli order) to better understand how the integration between separated stimuli occurs. Overall, the main conclusion of the study is that the number, order, and time determine how distinct experiences are encoded and stored in the brain, which clearly …
Reviewer #1 (Public review):
Summary:
Sensory preconditioning protocols have been used to understand how the brain controls aversive or appetitive behavioral responses towards stimuli that have never been directly reinforced. In this study, the authors combine pharmacological NMDA blockade in a specific brain region previously involved in sensory preconditioning (i.e., perirhinal cortex) and different versions of a light-tone sensory preconditioning task in rats (i.e., different number of associations during preconditioning, distinct temporal separation between stage 1 and stage 2, stimuli order) to better understand how the integration between separated stimuli occurs. Overall, the main conclusion of the study is that the number, order, and time determine how distinct experiences are encoded and stored in the brain, which clearly advances the understanding of how these complex cognitive processes are regulated by the brain.
Strengths:
(1)The manuscript is very well written, and the methodology is well detailed, fully aligned with previous work by the research group.
(2) Results from each pharmacological manipulation and/or protocol configuration are clear, demonstrating the robustness of their findings.
(3) The overall conclusions are very interesting and clearly advance our understanding of higher-order conditioning processes.
Weaknesses:
(1) The Discussion is overly redundant with the Results and should be rewritten to place the findings more clearly within the existing literature and add specific important topics for the field (e.g., type of stimulus presentation, other brain circuits involved, etc).
(2) Before-after and sex-disaggregated data should be presented to better show statistical differences between periods with or without cue during the test and between sexes.
(3) The authors should broaden their coverage of recent literature on light-tone higher-order conditioning beyond their own previous work.
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Reviewer #2 (Public review):
Summary:
In a series of experiments, the authors addressed the effect of the number of CS1-CS2 pairings, their order, and the time between their pairings and the second phase (CS2-US) in a sensory-preconditioning procedure. They hypothesized that:
(1) A higher number of CS1-CS2 pairings would favor the integration of CS1-CS2 and CS2-US associations via chaining at Test of CS1, as the CS2 develops a stronger prediction of the absence of CS1 in Phase 1, thus preventing the formation of a CS1-US association in Phase 2 and a chaining mechanism at Test of CS1 (CS1-->CS2-->US). In contrast, when the order is reversed (CS2-->CS1), a higher number of pairings should not change the mechanism of integration, as CS2 becomes a predictor of the presence of CS1. This would preserve the retrieval of CS1 and the formation …
Reviewer #2 (Public review):
Summary:
In a series of experiments, the authors addressed the effect of the number of CS1-CS2 pairings, their order, and the time between their pairings and the second phase (CS2-US) in a sensory-preconditioning procedure. They hypothesized that:
(1) A higher number of CS1-CS2 pairings would favor the integration of CS1-CS2 and CS2-US associations via chaining at Test of CS1, as the CS2 develops a stronger prediction of the absence of CS1 in Phase 1, thus preventing the formation of a CS1-US association in Phase 2 and a chaining mechanism at Test of CS1 (CS1-->CS2-->US). In contrast, when the order is reversed (CS2-->CS1), a higher number of pairings should not change the mechanism of integration, as CS2 becomes a predictor of the presence of CS1. This would preserve the retrieval of CS1 and the formation of a CS1-US association in Phase 2 (mediated learning), while weakening the CS1-->CS2 link required for chaining at Test.
(2) A longer interval between the two phases of sensory-preconditioning would disrupt the retrieval of the order of the CS1-->CS2 association. Consequently, CS2 is no longer a good predictor of the absence of CS1, and the latter gets associated with the US in Phase 2, thus favoring a chaining mechanism at Test of CS1.
(3) A reminder of the CS1-CS2 order after a long interval between the two phases of sensory-preconditioning should restore the retrieval of the order of the CS1-->CS2 association, thus reversing the effect of time, and favoring a chaining strategy at Test of CS1.
To distinguish the two mechanisms, the authors blocked NMDA receptors in the PRh with DAPV before Stage 2. If integration occurs through a mediated CS1-US association formed in Stage 2, DAPV should reduce freezing to CS1 at test; if it occurs through chaining at test, DAPV should have no effect.
Strengths:
The strategies developed by the authors to address this issue are elegant and well controlled. While the sensory-preconditioning procedure has been extensively investigated, the mechanisms underlying the integration of separately acquired associations remain unclear. This study determines - in a convincing manner - the conditions under which a conditioned response is expressed via a chaining or mediated learning mechanism.
Weaknesses:
The role of NMDA antagonism is somewhat ambiguous throughout the manuscript. Does it prevent retrieval or acquisition or both?
(The Introduction (lines 98 to 101) refers to retrieval, while the Results (lines 128 to 132) and Discussion (lines 329 to 331) refer to acquisition.
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Authors used Crl:LE from #RatGenomeDatabase(RG in their study. Including #RRIDs will make this less ambiguous. SciScore made a table with this resource, see “Automated Services” module (download as csv, xml or #jats) #OpenScience #RRID
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Number, order and time influence how the brain integrates distinct experiences https://www.biorxiv.org/content/10.64898/2026.09.15.751783v1
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Number, order and time influence how the brain integrates distinct experiences https://www.biorxiv.org/content/10.64898/2026.09.15.751783v1
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