Fake or Fantasy: Rapid Dissociation between Strategic Content Monitoring and Reality Filtering in Human Memory

Memory verification is crucial for meaningful behavior. Orbitofrontal damage may impair verification and induce confabulation and inappropriate acts. The strategic retrieval account explains this state by deficient monitoring of memories' precise content, whereas the reality filter hypothesis explains it by a failure of an orbitofrontal mechanism suppressing the interference of memories that do not pertain to reality. The distinctiveness of these mechanisms has recently been questioned. Here, we juxtaposed these 2 mechanisms using high-resolution evoked potentials in healthy subjects who performed 2 runs of a continuous recognition task which contained pictures that precisely matched or only resembled previous pictures. We found behavioral and electrophysiological dissociation: Strategic content monitoring was maximally challenged by stimuli resembling previous ones, whereas reality filtering was maximally challenged by identical stimuli. Evoked potentials dissociated at 200-300 ms: Strategic monitoring induced a strong frontal negativity and a distinct cortical map configuration, which were particularly weakly expressed in reality filtering. Recognition of real repetitions was expressed at 300-400 ms, associated with ventromedial prefrontal activation. Thus, verification of a memory's concordance with the past (its content) dissociates from the verification of its concordance with the present. The role of these memory control mechanisms in the generation of confabulations and disorientation is discusse

Behaviorally spontaneous confabulation in limbic encephalitis: The roles of reality filtering and strategic monitoring

Behaviorally spontaneous confabulation is characterized by a confusion of reality evident in currently inappropriate acts that patients justify with confabulations and in disorientation. Here, we describe a 38-year-old woman lawyer hospitalized because of non-herpetic, presumably autoimmune, limbic encephalitis. For months, she considered herself at work and desperately tried to respect her falsely believed professional obligations. In contrast to a completely erroneous concept of reality, she did not confabulate about her remote personal past. In tasks proposed to test strategic retrieval monitoring, she produced no confabulations. As expected, she failed in tasks of reality filtering, previously shown to have high sensitivity and specificity for behaviorally spontaneous confabulation and disorientation: she failed to suppress the interference of currently irrelevant memories and she had deficient extinction capacity. The observation underscores the special status of behaviorally spontaneous confabulation among confabulatory phenomena and of reality filtering as a thought control mechanism. We suggest that different processes may underlie the generation of false memories and their verbal expression. We also emphasize the need to present theories of confabulation together with experimental tasks that allow one to empirically verify the theories and to explore underlying physiological mechanisms. (JINS, 2010, 16, 995-1005.

Abnormal Cortical Network Activation in Human Amnesia: A High-resolution Evoked Potential Study

Little is known about how human amnesia affects the activation of cortical networks during memory processing. In this study, we recorded high-density evoked potentials in 12 healthy control subjects and 11 amnesic patients with various types of brain damage affecting the medial temporal lobes, diencephalic structures, or both. Subjects performed a continuous recognition task composed of meaningful designs. Using whole-scalp spatiotemporal mapping techniques, we found that, during the first 200ms following picture presentation, map configuration of amnesics and controls were indistinguishable. Beyond this period, processing significantly differed. Between 200 and 350ms, amnesic patients expressed different topographical maps than controls in response to new and repeated pictures. From 350 to 550ms, healthy subjects showed modulation of the same maps in response to new and repeated items. In amnesics, by contrast, presentation of repeated items induced different maps, indicating distinct cortical processing of new and old information. The study indicates that cortical mechanisms underlying memory formation and re-activation in amnesia fundamentally differ from normal memory processin

Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic β cells

Insulin resistance, hyperinsulinemia, and hyperproinsulinemia occur early in the pathogenesis of type 2 diabetes (T2D). Elevated levels of proinsulin and proinsulin intermediates are markers of β-cell dysfunction and are strongly associated with development of T2D in humans. However, the mechanism(s) underlying β-cell dysfunction leading to hyperproinsulinemia is poorly understood. Here, we show that disruption of insulin receptor (IR) expression in β cells has a direct impact on the expression of the convertase enzyme carboxypeptidase E (CPE) by inhibition of the eukaryotic translation initiation factor 4 gamma 1 translation initiation complex scaffolding protein that is mediated by the key transcription factors pancreatic and duodenal homeobox 1 and sterol regulatory element-binding protein 1, together leading to poor proinsulin processing. Reexpression of IR or restoring CPE expression each independently reverses the phenotype. Our results reveal the identity of key players that establish a previously unknown link between insulin signaling, translation initiation, and proinsulin processing, and provide previously unidentified mechanistic insight into the development of hyperproinsulinemia in insulin-resistant states

XBP1, Downstream of Blimp-1, Expands the Secretory Apparatus and Other Organelles, and Increases Protein Synthesis in Plasma Cell Differentiation

AbstractThe differentiation of B cells into immunoglobulin-secreting plasma cells is controlled by two transcription factors, Blimp-1 and XBP1. By gene expression profiling, we defined a set of genes whose induction during mouse plasmacytic differentiation is dependent on Blimp-1 and/or XBP1. Blimp-1-deficient B cells failed to upregulate most plasma cell-specific genes, including xbp1. Differentiating xbp1-deficient B cells induced Blimp-1 normally but failed to upregulate genes encoding many secretory pathway components. Conversely, ectopic expression of XBP1 induced a wide spectrum of secretory pathway genes and physically expanded the endoplasmic reticulum. In addition, XBP1 increased cell size, lysosome content, mitochondrial mass and function, ribosome numbers, and total protein synthesis. Thus, XBP1 coordinates diverse changes in cellular structure and function resulting in the characteristic phenotype of professional secretory cells

Human Processing of Behaviorally Relevant and Irrelevant Absence of Expected Rewards: A High-Resolution ERP Study

Acute lesions of the posterior medial orbitofrontal cortex (OFC) in humans may induce a state of reality confusion marked by confabulation, disorientation, and currently inappropriate actions. This clinical state is strongly associated with an inability to abandon previously valid anticipations, that is, extinction capacity. In healthy subjects, the filtering of memories according to their relation with ongoing reality is associated with activity in posterior medial OFC (area 13) and electrophysiologically expressed at 220–300 ms. These observations indicate that the human OFC also functions as a generic reality monitoring system. For this function, it is presumably more important for the OFC to evaluate the current behavioral appropriateness of anticipations rather than their hedonic value. In the present study, we put this hypothesis to the test. Participants performed a reversal learning task with intermittent absence of reward delivery. High-density evoked potential analysis showed that the omission of expected reward induced a specific electrocortical response in trials signaling the necessity to abandon the hitherto reward predicting choice, but not when omission of reward had no such connotation. This processing difference occurred at 200–300 ms. Source estimation using inverse solution analysis indicated that it emanated from the posterior medial OFC. We suggest that the human brain uses this signal from the OFC to keep thought and behavior in phase with reality