Turnover and exchange of nucleosomal histones and their variants, a process long believed to be static in post-replicative cells, remains largely unexplored in brain. Here, we describe a novel ...mechanistic role for HIRA (histone cell cycle regulator) and proteasomal degradation-associated histone dynamics in the regulation of activity-dependent transcription, synaptic connectivity, and behavior. We uncover a dramatic developmental profile of nucleosome occupancy across the lifespan of both rodents and humans, with the histone variant H3.3 accumulating to near-saturating levels throughout the neuronal genome by mid-adolescence. Despite such accumulation, H3.3-containing nucleosomes remain highly dynamic—in a modification-independent manner—to control neuronal- and glial-specific gene expression patterns throughout life. Manipulating H3.3 dynamics in both embryonic and adult neurons confirmed its essential role in neuronal plasticity and cognition. Our findings establish histone turnover as a critical and previously undocumented regulator of cell type-specific transcription and plasticity in mammalian brain.
•H3.3 displays a unique saturating profile of nucleosome occupancy in postnatal brain•Histones turn over rapidly to promote activity-dependent neuronal transcription•Nucleosomal dynamics are required for synaptic development and behavioral plasticity•Histone turnover is critical for cell type-specific gene expression
Maze et al. demonstrate a critical role for histone turnover in the regulation of neuronal transcription and synaptic development. Histone dynamics are essential for cognitive plasticity and represent a novel epigenetic mechanism with far-reaching implications for human neurobiology and disease.
Objective:Clinical phenomenology remains the primary means for classifying psychoses despite considerable evidence that this method incompletely captures biologically meaningful differentiations. ...Rather than relying on clinical diagnoses as the gold standard, this project drew on neurobiological heterogeneity among psychosis cases to delineate subgroups independent of their phenomenological manifestations.Method:A large biomarker panel (neuropsychological, stop signal, saccadic control, and auditory stimulation paradigms) characterizing diverse aspects of brain function was collected on individuals with schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis (N=711), their first-degree relatives (N=883), and demographically comparable healthy subjects (N=278). Biomarker variance across paradigms was exploited to create nine integrated variables that were used to capture neurobiological variance among the psychosis cases. Data on external validating measures (social functioning, structural magnetic resonance imaging, family biomarkers, and clinical information) were collected.Results:Multivariate taxometric analyses identified three neurobiologically distinct psychosis biotypes that did not respect clinical diagnosis boundaries. The same analysis procedure using clinical DSM diagnoses as the criteria was best described by a single severity continuum (schizophrenia worse than schizoaffective disorder worse than bipolar psychosis); this was not the case for biotypes. The external validating measures supported the distinctiveness of these subgroups compared with clinical diagnosis, highlighting a possible advantage of neurobiological versus clinical categorization schemes for differentiating psychotic disorders.Conclusions:These data illustrate how multiple pathways may lead to clinically similar psychosis manifestations, and they provide explanations for the marked heterogeneity observed across laboratories on the same biomarker variables when DSM diagnoses are used as the gold standard.
Substance abuse increases an individual's vulnerability to stress-related illnesses, which is presumably mediated by drug-induced neural adaptations that alter subsequent responses to stress. Here, ...we identify repressive histone methylation in nucleus accumbens (NAc), an important brain reward region, as a key mechanism linking cocaine exposure to increased stress vulnerability. Repeated cocaine administration prior to subchronic social defeat stress potentiated depressive-like behaviors in mice through decreased levels of histone H3 lysine 9 dimethylation in NAc. Cre-mediated reduction of the histone methyltransferase, G9a, in NAc promoted increased susceptibility to social stress, similar to that observed with repeated cocaine. Conversely, G9a overexpression in NAc after repeated cocaine protected mice from the consequences of subsequent stress. This resilience was mediated, in part, through repression of BDNF-TrkB-CREB signaling, which was induced after repeated cocaine or stress. Identifying such common regulatory mechanisms may aid in the development of new therapies for addiction and depression.
► Cocaine exposure enhances vulnerability to chronic social stress ► Histone H3 dimethylation in nucleus accumbens links cocaine to stress vulnerability ► G9a overexpression in NAc after repeated cocaine protects mice from social stress ► Resilience to stress via repression of BDNF-TrkB-CREB signaling
Background Current definitions of psychotic illness lack biological validity, motivating alternative biomarker-driven disease entities. Building on experimental constructs—Biotypes—previously ...developed from cognitive and neurophysiologic measures (1), we contrast brain anatomy characteristics across Biotypes alongside conventional diagnoses, examining gray matter density (GMD) as an independent validator for the Biotypes. Methods Whole brain GMD measures were examined in probands, their relatives, and healthy subjects organized by Biotype, and then by DSM diagnosis (n=1,409), using Voxel-Based Morphometry with subsequent subject-level regional characterization and distribution analyses. Results Probands grouped by Biotype vs. healthy showed a step-wise pattern of GMD reductions: Biotype1, extensive and diffusely distributed GMD loss, with the largest effects in frontal, anterior/middle cingulate, temporal regions; Biotype2, intermediate and more localized reductions, with the largest effects in insula, fronto-temporal regions; Biotype3, small reductions localized to anterior limbic regions. Relatives showed regionally distinct GMD reductions vs. healthy, with primarily anterior (fronto-temporal) effects in Biotype1; posterior (temporo-parieto-cerebellar) in Biotype2; and normal GMD in Biotype3. Schizophrenia and schizoaffective probands vs. healthy showed overlapping GMD reductions, with the largest effects in fronto-temporal and parietal regions; psychotic bipolar probands had small reductions, primarily in frontal regions. GMD changes in relatives followed regional patterns observed in probands, albeit less extensive. Biotypes showed stronger between-group separation based on GMD than the conventional diagnoses, and were the strongest predictor of GMD change. Conclusions The GMD biomarkers depicted unique brain structure characteristics within Biotypes consistent with their cognitive and sensorimotor profiles, and provided stronger discrimination for biologically-driven Biotypes than symptom-based diagnoses.
The Hippocampal Formation in Schizophrenia Tamminga, Carol A; Stan, Ana D; Wagner, Anthony D
American Journal of Psychiatry,
10/2010, Letnik:
167, Številka:
10
Journal Article
Recenzirano
The hippocampal formation is one of the most extensively studied regions of the brain, with well-described anatomy and basic physiology; moreover, aspects of human memory mediated by the hippocampus ...are well characterized. In schizophrenia, alterations in hippocampal anatomy, perfusion, and activation are consistently reported; impairments in declarative memory function, especially in the flexible use of event memories (e.g., in the service of memory-based inference), are common. Postmortem molecular changes suggest a selective reduction in glutamate transmission in the dentate gyrus and in its efferent fibers, the mossy fiber pathway. A reduction in dentate gyrus glutamatergic output and in its information processing functions could generate two co-occurring outcomes in the hippocampus: 1) a change in homeostatic plasticity processes in cornu ammonis 3 (CA3), accompanied by increased activity due to reduced afferent stimulation from the dentate gyrus onto CA3 neurons, a process that could increase the pattern completion functions of CA3, and 2) the loss of mnemonic functions specific to the dentate gyrus, namely pattern separation, a change that could increase the prevalence of illusory pattern completion and reduce discrimination between present and past experiences in memory. The resulting increase in “runaway” CA3-mediated pattern completion could result in cognitive “mistakes,” generating psychotic associations and resulting in memories with psychotic content. Tests of this model could result in novel approaches to the treatment of psychosis and declarative memory alterations and in novel animal preparations for basic schizophrenia research.
ObjectiveDeveloping categorical diagnoses that have biological meaning within the clinical phenotype of psychosis (schizophrenia, schizoaffective disorder, and bipolar I disorder with psychosis) is ...as important for developing targeted treatments as for nosological goals. The Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) was formed to examine a broad array of intermediate phenotypes across psychotic disorders and to test the hypothesis that intermediate phenotype characteristics are homogeneous within phenomenologically derived DSM-IV diagnoses.MethodThe consortium recruited 933 stable probands with schizophrenia, schizoaffective disorder, or psychotic bipolar I disorder, 1,055 of their first-degree relatives, and 459 healthy comparison subjects for clinical characterization and dense phenotyping. Clinical, psychosocial, and family characteristics were contrasted.ResultsAll proband groups showed lower psychosocial functioning than the relatives or comparison group. On average, schizophrenia probands showed more symptoms and lower psychosocial functioning than probands with psychotic bipolar disorder, but there was considerable overlap in clinical manifestations. The characteristics of schizoaffective disorder were more often similar to schizophrenia than to psychotic bipolar disorder. The rates of lifetime suicide attempts were high across all proband groups, with the highest reported frequencies in the schizoaffective and bipolar groups. Proband family lineages included both families with “pure” psychosis diagnoses and families with mixed schizophrenia-bipolar diagnoses.ConclusionsSymptoms, psychosocial functioning, and familial lineage overlap across the three DSM-IV psychosis diagnoses used in B-SNIP. The comingling of psychosis diagnoses within families suggests overlapping genetic determinants across psychoses. These data provide scant evidence for distinct phenotypic clustering around traditional phenomenological diagnoses.
Currently, no drugs exist that effectively treat cognition in people with schizophrenia. What is known about the neurobiology of cognition in schizophrenia is derived from the animal literature; it ...is inadequate and superficial. Despite this lack, pharmacologic research into potential molecular targets has uncovered several viable possibilities from animal studies. A subcommittee of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) program investigated the range of putative molecular targets for treating cognition. Those targets that show promise for pharmacologic focus include the dopamine receptors (especially D1) in the prefrontal cortex (PFC), the serotonin receptors in the PFC and anterior cingulate cortex, the glutamatergic excitatory synapse, the acetylcholine nicotinic receptors in the hippocampus, the acetylcholine muscarinic receptors, and the brain gamma-aminobutyric acid (GABA) system. Once developed and tested, the effective compounds will be valuable for the treatment of the symptom domains of cognitive dysfunction and negative symptoms.
Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood–brain barrier ...(BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is prominent within the nucleus accumbens, a brain region associated with mood regulation; however, the mechanisms involved are unclear. Moreover, compensatory responses leading to proper behavioral strategies and active resilience are unknown. Here we identify active molecular changes within the BBB associated with stress resilience that might serve a protective role for the neurovasculature. We also confirm the relevance of such changes to human depression and antidepressant treatment. We show that permissive epigenetic regulation of cldn5 expression and low endothelium expression of repressive cldn5-related transcription factor foxo1 are associated with stress resilience. Regionand endothelial cell-specific whole transcriptomic analyses revealed molecular signatures associated with stress vulnerability vs. resilience. We identified proinflammatory TNFα/NFκB signaling and hdac1 as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued cldn5 expression in the NAc and promoted resilience. Importantly, we confirmed changes in HDAC1 expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious CLDN5-related molecular changes were reduced in postmortem NAc from antidepressanttreated subjects. These findings reinforce the importance of considering stress-induced neurovascular pathology in depression and provide therapeutic targets to treat this mood disorder and promote resilience.
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