Throughout life, new neurons are continuously added to the dentate gyrus. As this continuous addition remodels hippocampal circuits, computational models predict that neurogenesis leads to degradation or forgetting of established memories. Consistent with this, increasing neurogenesis after the formation of a memory was sufficient to induce forgetting in adult mice. By contrast, during infancy, when hippocampal neurogenesis levels are high and freshly generated memories tend to be rapidly forgotten (infantile amnesia), decreasing neurogenesis after memory formation mitigated forgetting. In precocial species, including guinea pigs and degus, most granule cells are generated prenatally. Consistent with reduced levels of postnatal hippocampal neurogenesis, infant guinea pigs and degus did not exhibit forgetting. However, increasing neurogenesis after memory formation induced infantile amnesia in these species.

Long-term memories are thought to depend upon the coordinated activation of a broad network of cortical and subcortical brain regions. However, the distributed nature of this representation has made it challenging to define the neural elements of the memory trace, and lesion and electrophysiological approaches provide only a narrow window into what is appreciated a much more global network. Here we used a global mapping approach to identify networks of brain regions activated following recall of long-term fear memories in mice. Analysis of Fos expression across 84 brain regions allowed us to identify regions that were co-active following memory recall. These analyses revealed that the functional organization of long-term fear memories depends on memory age and is altered in mutant mice that exhibit premature forgetting. Most importantly, these analyses indicate that long-term memory recall engages a network that has a distinct thalamic-hippocampal-cortical signature. This network is concurrently integrated and segregated and therefore has small-world properties, and contains hub-like regions in the prefrontal cortex and thalamus that may play privileged roles in memory expression.

In patients with schizophrenia neuroimaging studies have revealed global differences with some brain regions showing focal abnormalities. Examining neurocircuitry, diffusion-weighted imaging studies have identified altered structural integrity of white matter in frontal and temporal brain regions and tracts such as the cingulum bundles, uncinate fasciculi, internal capsules and corpus callosum associated with the illness. Furthermore, structural co-variance analyses have revealed altered structural relationships among regional morphology in the thalamus, frontal, temporal and parietal cortices in schizophrenia patients. The distributed nature of these abnormalities in schizophrenia suggests that multiple brain circuits are impaired, a neural feature that may be better addressed with network level analyses. However, even with the advent of these newer analyses, a large amount of variability in findings remains, likely partially due to the considerable heterogeneity present in this disorder.

In the hippocampus, the production of dentate granule cells (DGCs) persists into adulthood. As adult-generated neurons are thought to contribute to hippocampal memory processing, promoting adult neurogenesis therefore offers the potential for restoring mnemonic function in the aged or diseased brain. Within this regenerative context, one key issue is whether developmentally generated and adult-generated DGCs represent functionally equivalent or distinct neuronal populations. To address this, we labeled separate cohorts of developmentally generated and adult-generated DGCs and used immunohistochemical approaches to compare their integration into circuits supporting hippocampus-dependent memory in intact mice. First, in the water maze task, rates of integration of adult-generated DGCs were regulated by maturation, with maximal integration not occurring until DGCs were five or more weeks in age. Second, these rates of integration were equivalent for embryonically, postnatally, and adult-generated DGCs. Third, these findings generalized to another hippocampus-dependent task, contextual fear conditioning. Together, these experiments indicate that developmentally generated and adult-generated DGCs are integrated into hippocampal memory networks at similar rates, and suggest a functional equivalence between DGCs generated at different developmental stages.

Schizophrenia and bipolar disorder (BD) may be disorders of accelerated aging. Direct comparison of healthy aging populations with schizophrenia and BD patients across the adult lifespan may help inform this theory. In total, 225 individuals (91 healthy controls, 81 schizophrenia, 53 euthymic BD) underwent 3T T1-weighted magnetic resonance imaging, diffusion tensor imaging, and cognitive testing. We analyzed associations among age, diagnosis, and cognition with cortical thickness and fractional anisotropy (FA) using general linear models. We then assessed "brain age" using a random forest algorithm, which was also assessed in an independent sample (n = 147). Participants with schizophrenia had lower cortical thickness and FA compared with the other two groups, most prominently in fronto-temporal circuitry. These brain changes were more evident in younger participants than in older ones, yet were associated with cognitive performance independent of diagnosis. Predicted age was 8 years greater than chronological age in individuals with schizophrenia in the first sample and 6 years greater in the second sample. Predicted and chronological age were not different in BD. Differences in brain circuitry are present from illness onset most prominently in schizophrenia and to a lesser extent in BD. These results support a non-progressive "early hit" hypothesis/etiology of illness in the major psychoses. Brain age differences support the hypothesized early aging mechanism in schizophrenia but not in BD.

Although the clarity of many memories fades with time, some memories may maintain their original precision. Here we used a context discrimination procedure to evaluate whether the hippocampus is important in maintaining precision as memories mature. Spared discrimination in hippocampal-lesioned mice indicated that precise, remote context memories may be supported by extra-hippocampal brain regions.

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The clinical heterogeneity of schizophrenia has hindered neurobiological investigations aimed at identifying neural correlates of the disorder.OBJECTIVE To identify network-based biomarkers across the spectrum of impairment present in schizophrenia by separately evaluating individuals with deficit and nondeficit subtypes of this disorder. DESIGN, SETTING, AND PARTICIPANTSA university hospital network-based neuroimaging study was conducted between February 1, 2007, and February 28, 2012. Participants included patients with schizophrenia (n = 128) and matched healthy controls (n = 130) from two academic centers and patients with bipolar I disorder (n = 39) and matched healthy controls (n = 43) from a third site. Patients with schizophrenia at each site in the top quartile on the proxy scale for the deficit syndrome were classified as having deficit schizophrenia and those in the bottom quartile were classified as having nondeficit schizophrenia.EXPOSURE All participants underwent magnetic resonance brain imaging. MAIN OUTCOMES AND MEASURESNetwork-level properties of cortical thickness were assessed in each group. Interregional cortexwide coupling was compared among the groups, and graph theoretical approaches were used to assess network density and node degree, betweenness, closeness, and eigenvector centrality.RESULTS Stronger frontoparietal and frontotemporal coupling was found in patients with deficit schizophrenia compared with those with nondeficit schizophrenia (17 of 1326 pairwise relationships were significantly different, P < .05; 5% false discovery rate) and in patients with deficit schizophrenia compared with healthy controls (49 of 1326 pairwise relationships were significantly different, P < .05; 5% false discovery rate). Participants with nondeficit schizophrenia and bipolar I disorder did not show significant differences in coupling relative to those in the control groups (for both comparisons, 0 of 1326 pairwise relationships were significantly different, P > .05; 5% false discovery rate). The networks formed from patients with deficit schizophrenia demonstrated increased density of connections relative to controls and nondeficit patients (range, 0.07-0.45 in controls, 0.09-0.43 in the nondeficit group, and 0.18-0.67 in the deficit group). High centrality nodes were identified in the supramarginal, middle, and superior temporal and inferior frontal regions in deficit schizophrenia networks based on ranking of 4 centrality metrics. High centrality regions were identified as those that ranked in the top 10 in 50% or more of the thresholded networks in 3 or more of the centrality measures. Network properties were similar in patients with deficit schizophrenia from both study sites. CONCLUSIONS AND RELEVANCEPatients with schizophrenia at one end of a spectrum show characteristic signatures of altered intracortical relationships compared with those at the other end of that spectrum, patients with bipolar I disorder, and healthy individuals. Cortical connectomic approaches can be used to reliably identify...