Alterations of the brain extracellular matrix (ECM) can perturb the structure and function of brain networks like the hippocampus, a key region in human memory that is commonly affected in psychiatric disorders. Here, we investigated the potential effects of a genome-wide psychiatric risk variant in the NCAN gene encoding the ECM proteoglycan neurocan (rs1064395) on memory performance, hippocampal function and cortical morphology in young, healthy volunteers. We assessed verbal memory performance in two cohorts (N = 572, 302) and found reduced recall performance in risk allele (A) carriers across both cohorts. In 117 participants, we performed functional magnetic resonance imaging using a novelty-encoding task with visual scenes. Risk allele carriers showed higher false alarm rates during recognition, accompanied by inefficiently increased left hippocampal activation. To assess effects of rs1064395 on brain morphology, we performed voxel-based morphometry in 420 participants from four independent cohorts and found lower grey matter density in the This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Activation of parietal cortex structures like the precuneus is commonly observed during explicit memory retrieval, but the role of parietal cortices in encoding has only recently been appreciated and is still poorly understood. Considering the importance of the precuneus in human visual attention and imagery, we aimed to assess a potential role for the precuneus in the encoding of visuospatial representations into long-term memory. We therefore investigated the acquisition of constant versus repeatedly shuffled configurations of icons on background images over five subsequent days in 32 young, healthy volunteers. Functional magnetic resonance imaging was conducted on Days 1, 2, and 5, and persistent memory traces were assessed by a delayed memory test after another 5 days. Constant compared to shuffled configurations were associated with significant improvement of position recognition from Day 1 to 5 and better delayed memory performance. Bilateral dorsal precuneus activations separated constant from shuffled configurations from Day 2 onward, and coactivation of the precuneus and hippocampus dissociated recognized and forgotten configurations, irrespective of condition. Furthermore, learning of constant configurations elicited increased functional coupling of the precuneus with dorsal and ventral visual stream structures. Our results identify the precuneus as a key brain structure in the acquisition of detailed visuospatial information by orchestrating a parieto-occipitotemporal network. K E Y W O R D SfMRI, hippocampus, long-term memory, precuneus, visuospatial memory

BackgroundLimbic-cortical imbalance is an established model for the neurobiology of major depressive disorder (MDD), but imaging genetics studies have been contradicting regarding potential risk and resilience mechanisms. Here, we re-assessed previously reported limbic-cortical alterations between MDD relatives and controls in combination with a newly acquired sample of MDD patients and controls, to disentangle pathology, risk, and resilience.MethodsWe analyzed functional magnetic resonance imaging data and negative affectivity (NA) of MDD patients (n = 48), unaffected first-degree relatives of MDD patients (n = 49) and controls (n = 109) who performed a faces matching task. Brain response and task-dependent amygdala functional connectivity (FC) were compared between groups and assessed for associations with NA.ResultsGroups did not differ in task-related brain activation but activation in the superior frontal gyrus (SFG) was inversely correlated with NA in patients and controls. Pathology was associated with task-independent decreases of amygdala FC with regions of the default mode network (DMN) and decreased amygdala FC with the medial frontal gyrus during faces matching, potentially reflecting a task-independent DMN predominance and a limbic-cortical disintegration during faces processing in MDD. Risk was associated with task-independent decreases of amygdala-FC with fronto-parietal regions and reduced faces-associated amygdala-fusiform gyrus FC. Resilience corresponded to task-independent increases in amygdala FC with the perigenual anterior cingulate cortex (pgACC) and increased FC between amygdala, pgACC, and SFG during faces matching.ConclusionOur results encourage a refinement of the limbic-cortical imbalance model of depression. The validity of proposed risk and resilience markers needs to be tested in prospective studies. Further limitations are discussed.