Subgenual Cingulum Microstructure Supports Control of Emotional Conflict.

Major depressive disorder (MDD) is associated with specific difficulties in attentional disengagement from negatively valenced material. Diffusion MRI studies have demonstrated altered white matter microstructure in the subgenual cingulum bundle (CB) in individuals with MDD, though the functional significance of these alterations has not been examined formally. This study explored whether individual differences in selective attention to negatively valenced stimuli are related to interindividual differences in subgenual CB microstructure. Forty-six individuals (21 with remitted MDD, 25 never depressed) completed an emotional Stroop task, using happy and angry distractor faces overlaid by pleasant or unpleasant target words and a control gender-based Stroop task. CBs were reconstructed in 38 individuals using diffusion-weighted imaging and tractography, and mean fractional anisotropy (FA) computed for the subgenual, retrosplenial, and parahippocampal subdivisions. No significant correlations were found between FA and performance in the control gender-based Stroop task in any CB region. However, the degree of interference produced by angry face distractors on time to identify pleasant words (emotional conflict) correlated selectively with FA in the subgenual CB (r = -0.53; P = 0.01). Higher FA was associated with reduced interference, irrespective of a diagnosis of MDD, suggesting that subgenual CB microstructure is functionally relevant for regulating attentional bias toward negative interpersonal stimuli.

Functional neuroanatomy supporting judgments of when events occurred.

The neural substrates of memory for when events occurred are not well described. One reason for this is that the paradigms used to date have permitted isolation of only some of the relevant memory processes. In this experiment, functional magnetic resonance imaging was used to identify for the first time brain regions that support two distinct bases upon which "when" judgments can be made. Seventeen human participants (6 male) completed a continuous recognition memory task where the interval between presentation and re-presentation of words varied between 5 and 25 intervening words (the lag). The task on each trial was to distinguish repeated words from those presented for the first time, and to indicate the lag for repeated words. The inferior parietal lobe showed greater activation for shorter lag judgments, regardless of judgment accuracy. The lingual gyrus, by contrast, was more active for correct than for incorrect lag judgments, regardless of the interval between first and second item presentations. Both of these regions have been linked in previous work to the process of recollection, and the findings described here represent a novel neural dissociation across regions that deploy mnemonic information in fundamentally different ways to support judgments about when events occurred.

Separating content-specific retrieval from post-retrieval processing.

According to cortical reinstatement accounts, neural processes engaged at the time of encoding are re-engaged at the time of memory retrieval. The temporal precision of event-related potentials (ERPs) has been exploited to assess this possibility, and in this study ERPs were acquired while people made memory judgments to visually presented words encoded in two different ways. There were reliable differences between the scalp distributions of the signatures of successful retrieval of different contents from 300 to 1100 ms after stimulus presentation. Moreover, the scalp distributions of these content-sensitive effects changed during this period. These findings are, to our knowledge, the first demonstration in one study that ERPs reflect content-specific processing in two separable ways: first, via reinstatement, and second, via downstream processes that operate on recovered information in the service of memory judgments.

The Regulation of Cytokine Networks in Hippocampal CA1 Differentiates Extinction from Those Required for the Maintenance of Contextual Fear Memory after Recall.

We investigated the distinctiveness of gene regulatory networks in CA1 associated with the extinction of contextual fear memory (CFM) after recall using Affymetrix GeneChip Rat Genome 230 2.0 Arrays. These data were compared to previously published retrieval and reconsolidation-attributed, and consolidation datasets. A stringent dual normalization and pareto-scaled orthogonal partial least-square discriminant multivariate analysis together with a jack-knifing-based cross-validation approach was used on all datasets to reduce false positives. Consolidation, retrieval and extinction were correlated with distinct patterns of gene expression 2 hours later. Extinction-related gene expression was most distinct from the profile accompanying consolidation. A highly specific feature was the discrete regulation of neuroimmunological gene expression associated with retrieval and extinction. Immunity-associated genes of the tyrosine kinase receptor TGFß and PDGF, and TNF families' characterized extinction. Cytokines and proinflammatory interleukins of the IL-1 and IL-6 families were enriched with the no-extinction retrieval condition. We used comparative genomics to predict transcription factor binding sites in proximal promoter regions of the retrieval-regulated genes. Retrieval that does not lead to extinction was associated with NF-κB-mediated gene expression. We confirmed differential NF-κBp65 expression, and activity in all of a representative sample of our candidate genes in the no-extinction condition. The differential regulation of cytokine networks after the acquisition and retrieval of CFM identifies the important contribution that neuroimmune signalling plays in normal hippocampal function. Further, targeting cytokine signalling upon retrieval offers a therapeutic strategy to promote extinction mechanisms in human disorders characterised by dysregulation of associative memory.