Sleep Spindles Promote the Restructuring of Memory Representations in Ventromedial Prefrontal Cortex through Enhanced Hippocampal-Cortical Functional Connectivity

Abstract

Memory consolidation is hypothesized to involve the distribution and restructuring of memory representations across hippocampal and cortical regions. Theories suggest that, through extended hippocampal-cortical interactions, cortical ensembles come to represent more integrated, or overlapping, memory traces that prioritize commonalities across related memories. Sleep processes, particularly fast sleep spindles, are thought to support consolidation, but evidence for this relationship has been mostly limited to memory retention benefits. Whether fast spindles provide a mechanism for neural changes hypothesized to support consolidation, including the strengthening of hippocampal-cortical networks and integration across memory representations, remains unclear, as does the specificity of regions involved. Using functional connectivity analyses of human fMRI data (both sexes), we show that fast spindle density during overnight sleep is related to enhanced hippocampal-cortical functional connectivity the next day, when restudying information learned before sleep. Spindle density modulated connectivity in distinct hippocampal-cortical networks depending on the category of the consolidated stimuli. Specifically, spindle density correlated with functional connectivity between anterior hippocampus and ventromedial prefrontal cortex (vmPFC) for object-word pairs, and posterior hippocampus and posteromedial cortex for scene-word pairs. Using multivariate pattern analyses, we also show that fast spindle density during postlearning sleep is associated with greater pattern similarity, or representational overlap, across individual object-word memories in vmPFC the next day. Further, the relationship between fast spindle density and representational overlap in vmPFC was mediated by the degree of anterior hippocampal-vmPFC functional connectivity. Together, these results suggest that fast spindles support the network distribution of memory traces, potentially restructuring memory representations in vmPFC.SIGNIFICANCE STATEMENT How new experiences are transformed into long-term memories remains a fundamental question for neuroscience research. Theories suggest that memories are stabilized as they are reorganized in the brain, a process thought to be supported by sleep oscillations, particularly sleep spindles. Although sleep spindles have been associated with benefits in memory retention, it is not well understood how spindles modify neural memory traces. This study found that spindles during overnight sleep correlate with changes in neural memory traces, including enhanced functional connectivity in distinct hippocampal-cortical networks and increased pattern similarity among memories in the cortex. The results provide critical evidence that spindles during overnight sleep may act as a physiological mechanism for the restructuring of neural memory traces.

Keywords: fMRI; hippocampus; memory consolidation; sleep; sleep spindles; vmPFC.

Figure 1.

Study design. For all encoding and restudy sessions, participants were asked to form an association between a word and image. Participants first encoded the Sleep List (blue) before sleeping overnight while polysomnography was recorded. The next morning (day 2), participants encoded a second set of word–image pairs (Morning List). After a short delay (∼2 h), participants restudied these two sets of pairs, intermixed with novel pairs (Single Study List) in the fMRI scanner. Source memory was tested immediately after the scan and after a 24 h delay (day 3).

Figure 2.

Correct associative memory on immediate and delayed memory tests. Correct source memory was greater for the twice-studied Sleep and Morning List pairs than the once presented Single Study List pairs (main effect of list: F_(2,36) = 57.44, p < 0.0001; SL < SS: p < 0.0001; ML < SS: p < 0.0001), and better for the immediate test than delayed test (main effect test: F_(1,18) = 136, p < 0.001), consistent with forgetting over time. There was additionally a main effect of category (F_(1,18) = 13.03, p = 0.002), with scene–word pairs generally better remembered than object–word pairs. A significant list × category × test interaction (F_(2,36) = 4.42, p = 0.019) seemed driven by a significant difference between accuracy on the object and scene pairs for all comparisons except the Sleep List during the immediate test (p = 0.21), including the delayed test (p = 0.036, object < scene). Lines represent significant differences p < 0.05, error bars denote SEM.

Figure 3.

Hippocampal–neocortical functional connectivity correlates with fast spindle density for the Sleep List. a, Greater fast spindle density during overnight sleep positively correlated with increased right anterior hippocampal–vmPFC functional connectivity only during restudy of the Sleep List (blue), but not the Morning List (red), object–word pairs. b, In a control analysis, the sleep-specific functional connectivity (SL–ML) for object–word pairs still positively correlated with fast spindle density during overnight sleep. c, Greater fast spindle density positively correlated with right posterior hippocampal–PMC functional connectivity only for the Sleep List (blue), and not for Morning List (red), scene–word pairs. d, Fast spindle density also positively correlated with the control, sleep-specific posterior hippocampal–PMC functional connectivity (SL–ML) for scene–word pairs. Black dots represent individual participants and gray ribbon indicates 95% confidence intervals.

Figure 4.

Inter-item pattern similarity. a, To compute the inter-item pattern analysis, patterns of activation across voxels within ROIs were extracted for each trial and sorted by the Encoding List it was first learned during. All trials within a list were correlated, across runs, and averaged, resulting in a similarity metric within each list. b, Fast spindle density correlated with inter-item pattern similarity in vmPFC for object-word pairs (left: r = 0.54, p = 0.017) but not for scene-word pairs in PMC (right: r = −0.05). For all plots, black dots represent individual participants and gray ribbon indicates 95% confidence intervals.

Figure 5.

Relationship between right anterior hippocampal–vmPFC functional connectivity and inter-item pattern similarity in vmPFC. For remembered object–word pairs (left), sleep-specific functional connectivity positively correlates with sleep-specific inter-item pattern similarity (r = 0.62, p = 0.005), such that greater connectivity for the Sleep List, relative to the Morning List, was related to greater similarity across these pairs in vmPFC. For object–word pairs that were subsequently forgotten (right), anterior hippocampal–vmPFC functional connectivity did not correlate with the representational similarity (r = −0.09). These correlations are significantly different from one another (z = 2.17, p = 0.03). For all plots, black dots represent individual participants and gray ribbon indicates 95% confidence intervals.

Figure 6.

Schematic illustration of mediation analysis. A significant mediation effect demonstrated that fast spindle density during overnight sleep is related to greater right anterior hippocampal–vmPFC functional connectivity for the sleep-specific remembered object–word pairs and, through this relationship, is indirectly associated with greater representational overlap in vmPFC among these pairs.