Significance Depression and anxiety have been linked to increased inflammation. However, we do not know if inflammatory status predates onset of disease or whether it contributes to depression symptomatology. We report preexisting individual differences in the peripheral immune system that predict and promote stress susceptibility. Replacing a stress-naive animal’s peripheral immune system with that of a stressed animal increases susceptibility to social stress including repeated social defeat stress (RSDS) and witness defeat (a purely emotional form of social stress). Depleting the cytokine IL-6 from the whole body or just from leukocytes promotes resilience, as does sequestering IL-6 outside of the brain. These studies demonstrate that the emotional response to stress can be generated or blocked in the periphery, and offer a potential new form of treatment for stress disorders.
The etiology and pathophysiology of schizophrenia remain unknown. A parallel transcriptomics, proteomics and metabolomics approach was employed on human brain tissue to explore the molecular disease signatures. Almost half the altered proteins identified by proteomics were associated with mitochondrial function and oxidative stress responses. This was mirrored by transcriptional and metabolite perturbations. Cluster analysis of transcriptional alterations showed that genes related to energy metabolism and oxidative stress differentiated almost 90% of schizophrenia patients from controls, while confounding drug effects could be ruled out. We propose that oxidative stress and the ensuing cellular adaptations are linked to the schizophrenia disease process and hope that this new disease concept may advance the approach to treatment, diagnosis and disease prevention of schizophrenia and related syndromes.
In development, timing is of the utmost importance, and the timing of developmental processes often changes as organisms evolve. In human evolution, developmental retardation, or neoteny, has been proposed as a possible mechanism that contributed to the rise of many human-specific features, including an increase in brain size and the emergence of human-specific cognitive traits. We analyzed mRNA expression in the prefrontal cortex of humans, chimpanzees, and rhesus macaques to determine whether human-specific neotenic changes are present at the gene expression level. We show that the brain transcriptome is dramatically remodeled during postnatal development and that developmental changes in the human brain are indeed delayed relative to other primates. This delay is not uniform across the human transcriptome but affects a specific subset of genes that play a potential role in neural development.human evolution ͉ brain development ͉ gene expression ͉ heterochrony ͉ chimpanzee
Kainate-preferring receptors are a subclass of ionotropic glutamate receptors that might play a role in brain development. The expression of the five known genes encoding kainate receptor subunits (GluR-5, -6, -7, KA-1, and KA-2) was studied by in situ hybridization during pre- and postnatal development of the rat brain. We compared the combined expression patterns of these genes with autoradiography using 3H- kainate in the developing brain from embryonic day 12 (E12) through to adult. Although mRNAs for the receptor subunits (except KA-1) can be detected at stage E12, 3H-kainic acid binding (as an index of receptor protein) is not found at this stage. However, by E14 high-affinity kainate sites are found throughout the gray matter, but particularly in spinal cord, primordial cerebellum, and ventral forebrain structures. All genes undergo a peak in their expression in the late embryonic/early postnatal period. GluR-5 expression during development shows the most interesting features because the changes are qualitative. The GluR-5 gene shows peaks of expression around the period of birth in the sensory cortex (layers II, III, and IV), in CA1 hippocampal interneurons in the stratum oriens, in the septum, and in the thalamus. GluR-6 shows a prenatal expression peak in the cingulate gyrus of the neocortex. KA-1 transcripts appear with the development of the hippocampus and remain largely confined to discrete areas such as the CA3 region, the dentate gyrus, and subiculum. KA-2 transcripts are found throughout the CNS from as early as E12 and remain constant until adulthood. The GluR-5 and GluR-6 genes are coexpressed in multiple peripheral ganglia (e.g., cranial nerve ganglia, dorsal root ganglia, and mural ganglia) at E14.
Cerebellar granule cells express six GABAA receptor subunits abundantly (alpha1, alpha6, beta2, beta3, gamma2, and delta) and assemble various pentameric receptor subtypes with unknown subunit compositions; however, the rules guiding receptor subunit assembly are unclear. Here, removal of intact alpha6 protein from cerebellar granule cells allowed perturbations in other subunit levels to be studied. Exon 8 of the mouse alpha6 subunit gene was disrupted by homologous recombination. In alpha6 -/- granule cells, the delta subunit was selectively degraded as seen by immunoprecipitation, immunocytochemistry, and immunoblot analysis with delta subunit-specific antibodies. The delta subunit mRNA was present at wild-type levels in the mutant granule cells, indicating a post-translational loss of the delta subunit. These results provide genetic evidence for a specific association between the alpha6 and delta subunits. Because in alpha6 -/- neurons the remaining alpha1, beta2/3, and gamma2 subunits cannot rescue the delta subunit, certain potential subunit combinations may not be found in wild-type cells.
Transcript changes and altered pathways in schizophrenia prefrontal cortex. (a) Mitochondria are the most affected cellular components at the transcript level in schizophrenia. Cellular localization of the significantly altered genes (both up-and downregulated) that passed RMA and filtering procedures were analyzed and visualized using GO Surfer (http://biosun1.harvard.edu/complab/gosurfer/). Branches and nodes represent pathways containing greater than five genes. Significantly altered 'cellular components' (Po0.05) are highlighted in red and their categories are indicated. (b) Metabolic categories found to be most significantly altered at the transcript level. EASE (http://david.niaid.nih.gov/david/ease.htm) was used for pathway analysis of microarray results and to determine significantly up-and/or downregulated GO biological processes and KEGG metabolic pathways. (c) Hierarchical clustering tree of schizophrenia (vertical blue lines) and controls (vertical gray lines) microarray chips on the basis of 59 significantly altered genes related to energy metabolism and oxidative stress. Drug-naive schizophrenia patients are denoted by ** (n ¼ 7), while minimally treated patients are marked by * (o6000 lifetime fluphenazine units; n ¼ 4). Note that the schizophrenia group appears to fall into two subclusters with respect to lowered transcript expression as indicated by the prominent blue shading. For more information on this topic, please see the article by Prabakaran et al on pp 684-697.
The mechanisms by which trisomy 21 leads to the characteristic Down syndrome (DS) phenotype are unclear. We used whole genome microarrays to characterize for the first time the transcriptome of human adult brain tissue (dorsolateral prefrontal cortex) from seven DS subjects and eight controls. These data were coanalyzed with a publicly available dataset from fetal DS tissue and functional profiling was performed to identify the biological processes central to DS and those that may be related to late onset pathologies, particularly Alzheimer disease neuropathology. A total of 685 probe sets were differentially expressed between adult DS and control brains at a stringent significance threshold (adjusted p value (q) < 0.005), 70% of these being up-regulated in DS. Over 25% of genes on chromosome 21 were differentially expressed in comparison to a median of 4.4% for all chromosomes. The unique profile of up-regulation on chromosome 21, consistent with primary dosage effects, was accompanied by widespread transcriptional disruption. The critical Alzheimer disease gene, APP, located on chromosome 21, was not found to be up-regulated in adult brain by microarray or QPCR analysis. However, numerous other genes functionally linked to APP processing were dysregulated. Functional profiling of genes dysregulated in both fetal and adult datasets identified categories including development (notably Notch signaling and Dlx family genes), lipid transport, and cellular proliferation. In the adult brain these processes were concomitant with cytoskeletal regulation and vesicle trafficking categories, and increased immune response and oxidative stress response, which are likely linked to the development of Alzheimer pathology in individuals with DS.
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