Pathology In Major Depression Research Articles

Brain derived neurotrophic factor deficiency exacerbates inflammation-induced anhedonia in mice

Brain-derived neurotrophic factor (BDNF) is implicated in the pathology of major depression and influences the inflammatory response. Prolonged immune system activation can cause depression symptoms, and individuals with low BDNF expression may be vulnerable to inflammation-induced depression. We tested the hypothesis that BDNF deficient mice are vulnerable to the induction of depressive-like behavior following peripheral immune challenge. BDNF heterozygous (BDNF+/-) or wild-type (BDNF+/+) littermate mice were injected intraperitoneally (i.p.) with endotoxin (lipopolysaccharide, LPS) to trigger an acute pro-inflammatory response. After resolution of the acute sickness response, central expression of inflammatory genes, kynurenine metabolites, and depressive-like behaviors across multiple dimensions (symptoms) were measured. BDNF+/- mice displayed an exaggerated neuroinflammatory response following peripheral immune challenge. Pro-inflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) were overexpressed in BDNF+/- mice relative to BDNF+/+ littermate control mice. While behavioral despair and anxiety-like behavior was not different between genotypes, LPS-induced anhedonia-like behavior was significantly more pronounced in BDNF+/- mice relative to BDNF+/+ mice. The kynurenine pathway mediates the many depressive-like behavioral effects of peripheral LPS, and similar to pro-inflammatory cytokine gene expression, indoleamine 2,3-dioxygenase (IDO) expression and kynurenine metabolism was exaggerated in BDNF+/- mice. Genetic BDNF deficiency results in a dysregulated neuroinflammatory and metabolic response to peripheral immune challenge and in a specific vulnerability to the development of inflammation-induced anhedonia.

Prevalence and risk factors of moderate to severe obstructive sleep apnea syndrome in major depression: a observational and retrospective study on 703 subjects

BackgroundSeveral studies have investigated the prevalence and risk factors of depression in subjects with obstructive sleep apnea syndrome. However, few studies have investigated the prevalence and risk factors for obstructive sleep apnea syndrome in major depression. The aim of this study was to examine the prevalence and risk factors of moderate to severe obstructive sleep apnea syndrome in a large sample of individuals with major depression.MethodsData from 703 individuals with major depression recruited from the research database of the sleep laboratory of the Erasme Hospital were analysed. An apnea-hypopnea index of ≥15 events per hour was used as cut-off score for moderate to severe obstructive sleep apnea syndrome. Logistic regression analyses were conducted to examine clinical and demographic risk factors of moderate to severe obstructive sleep apnea syndrome in major depression.ResultsThe prevalence of moderate to severe obstructive sleep apnea syndrome in major depression is 13.94%. Multivariate logistic regression analysis revealed that male gender, snoring, excessive daytime sleepiness, lower insomnia complaint, presence of metabolic syndrome, age ≥ 50 years, BMI >30 kg/m2, ferritin >300 μg/L, CRP >7 mg/L and duration of sleep ≥8 h were significant risk factors of moderate to severe obstructive sleep apnea syndrome in major depression.ConclusionModerate to severe obstructive sleep apnea syndrome is a common pathology in major depression. The identification of these different risk factors advances a new perspective for more effective screening of moderate to severe obstructive sleep apnea syndrome in major depression.

Microglial Dysregulation in Psychiatric Disease

Microglia, the brain's resident immune cells, are phagocytes of the macrophage lineage that have a key role in responding to inflammation and immune challenge in the brain. More recently, they have been shown to have a number of important roles beyond immune surveillance and response, including synaptic pruning during development and the support of adult neurogenesis. Microglial abnormalities have been found in several neuropsychiatric conditions, though in most cases it remains unclear whether these are causative or are a reaction to some other underlying pathophysiology. Here we summarize postmortem, animal, neuroimaging, and other evidence for microglial pathology in major depression, schizophrenia, autism, obsessive-compulsive disorder, and Tourette syndrome. We identify gaps in the existing literature and important areas for future research. If microglial pathology proves to be an important causative factor in these or other neuropsychiatric diseases, modulators of microglial function may represent a novel therapeutic strategy.

Brain-Derived Neurotrophic Factor Signaling and Subgenual Anterior Cingulate Cortex Dysfunction in Major Depressive Disorder

The subgenual anterior cingulate cortex is implicated in the pathology and treatment response of major depressive disorder. Low levels of brain-derived neurotrophic factor (BDNF) and reduced markers for GABA function, including in the amygdala, are reported in major depression, but their contribution to subgenual anterior cingulate cortex dysfunction is not known. Using polymerase chain reaction, we first assessed the degree to which BDNF controls mRNA expression (defined as BDNF dependency) of 15 genes relating to GABA and neuropeptide functions in the cingulate cortex of mice with reduced BDNF function (BDNF-heterozygous [Bdnf(+/-)] mice and BDNF exon-IV knockout [Bdnf(KIV)] mice). Gene expression was then quantified in the subgenual anterior cingulate cortex of 51 postmortem subjects with major depressive disorder and comparison subjects (total subjects, N=102; 49% were women) and compared with previous amygdala results. Based on the results in Bdnf(+/-) and Bdnf(KIV) mice, genes were sorted into high, intermediate, and no BDNF dependency sets. In postmortem human subjects with major depression, BDNF receptor (TRKB) expression, but not BDNF, was reduced. Postmortem depressed subjects exhibited down-regulation in genes with high and intermediate BDNF dependency, including markers of dendritic targeting interneurons (SST, NPY, and CORT) and a GABA synthesizing enzyme (GAD2). Changes extended to BDNF-independent genes (PVALB and GAD1). Changes were greater in men (potentially because of low baseline expression in women), displayed notable differences from prior amygdala results, and were not explained by demographic or clinical factors other than sex. These parallel human/mouse analyses provide direct (low TRKB) and indirect (low expression of BDNF-dependent genes) evidence in support of decreased BDNF signaling in the subgenual anterior cingulate cortex in individuals with major depressive disorder, implicate dendritic targeting GABA neurons and GABA synthesis, and, together, suggest a common BDNF-/GABA-related pathology in major depression with sex- and brain region-specific features.

Aberrant functional connectivity of cortico-basal ganglia circuits in major depression

There is considerable evidence of functional abnormalities of the cortico-basal ganglia circuitry in affective disorders. However, it has been unknown whether this represented primary pathology within these circuits or altered activation as a result of aberrant input from other brain regions. The aim of this study was to test the hypothesis that cortico-basal ganglia circuit dysfunction represents primary pathology in unipolar depression. Eighteen male subjects with recurrent unipolar depression and eighteen controls without psychiatric illness were studied using functional MRI and functional connectivity analyses. All unipolar subjects were unmedicated and without current psychiatric comorbidity. Compared to controls, unipolar subjects exhibited altered connectivity between bilateral subcortical components of the circuitry (putamen–thalamus) and left hemisphere input and output components. Results provided evidence that functional abnormalities of these circuits represent primary pathology. Further, we found that age of onset but not duration of illness impacts circuit function. These findings suggest that the cortico-basal ganglia circuitry is likely one of several loci of primary pathology in major depression. Additionally, early age of onset is associated with greater circuit abnormality and as such may impact clinical characteristics and/or treatment response through a mechanism of decreasing functional connectivity of some circuit segments. Finally, altered cortico-basal ganglia circuit connectivity with cortical regions (anterior cingulate, inferior frontal gyrus and sensorimotor) may contribute to the emotional dysregulation, impaired emotional recognition and psychomotor symptoms associated with unipolar illness.

A Molecular Signature of Depression in the Amygdala

Major depressive disorder is a heterogeneous illness with a mostly uncharacterized pathology. Recent gene array attempts to identify the molecular underpinnings of the illness in human postmortem subjects have not yielded a consensus. The authors hypothesized that controlling several sources of clinical and technical variability and supporting their analysis with array results from a parallel study in the unpredictable chronic mild stress (UCMS) rodent model of depression would facilitate identification of the molecular pathology of major depression. Large-scale gene expression was monitored in postmortem tissue from the anterior cingulate cortex and amygdala in paired male subjects with familial major depression and matched control subjects without major depression (N=14-16 pairs). Area dissections and analytical approaches were optimized. Results from the major depression group were compared with those from the UCMS study and confirmed by quantitative polymerase chain reaction and Western blot. Gene coexpression network analysis was performed on transcripts with conserved major depression-UCMS effects. Significant and bidirectional predictions of altered gene expression were identified in amygdala between major depression and the UCMS model of depression. These effects were detected at the group level and also identified a subgroup of depressed subjects with a more homogeneous molecular pathology. This phylogenetically conserved "molecular signature" of major depression was reversed by antidepressants in mice, identified two distinct oligodendrocyte and neuronal phenotypes, and participated in highly cohesive and interactive gene coexpression networks. These studies demonstrate that the biological liability to major depression is reflected in a persistent molecular pathology that affects the amygdala, and support the hypothesis of maladaptive changes in this brain region as a putative primary pathology in major depression.

Serum markers support disease-specific glial pathology in major depression

Background Recently, it was shown by histopathological studies that mood disorders are characterized by disease-specific glial pathology. Methods To validate this hypothesis in vivo we measured weekly and simultaneously serum levels of the neuronal marker neuron-specific enolase and S100B, a protein expressed in astro- and oligodendroglia in the human brain, in 10 patients with major depressive disorder and 10 age- and gender-matched control subjects. Furthermore, we conducted a systematic, quantitative meta-analysis of all published studies on S100B involving 193 patients suffering from mood disorders and 132 healthy control subjects by calculating effect sizes. Results S100B was elevated at admission and discharge in our patients with major depression compared with control subjects, whereas there were no significant differences for neuron-specific enolase. During treatment S100B decreased slightly, although this effect was not significant. It had no significant impact on neuron-specific enolase. The meta-analysis revealed that serum levels of S100B are consistently elevated in mood disorders during acute major depressive or manic episodes. Additionally, it demonstrated that serum S100B decreases during antidepressive treatment reliably if clinical improvement is sufficient. Limitations As the study measured only serum S100B, future (cell culture) studies have to elucidate molecular mechanisms of this protein in mood disorders. Moreover, results have to be replicated in a larger patient group. Conclusions S100B may represent a biomarker for mood disorders, particularly major depression, and their treatment. Together with unaltered levels of neuron-specific enolase, our results support in vivo the histopathologically generated hypothesis of disease-specific glial pathology in mood disorders.

Histopathology of the prefrontal cortex in major depression: what does it tell us about dysfunctional monoaminergic circuits?

This chapter discusses the prefrontal cell pathology in major depression as it relates to biochemical and structural changes detected in studies of the serotonergic and noradrenergic neurons located in the brainstem. Information pertaining to both current and lifetime psychiatric symptoms was gathered using the schedule for affective disorders and schizophrenia. State-of-the-art morphometric and stereological methods were used to assess neuronal and glial cell densities, cell body size and cortical thickness in each of the three prefrontal regions. The validity of studies described is underscored by the fact that the tissues from the prefrontal cortex and brainstem nuclei were examined in the same depressives and control subjects. The cellular changes described in these postmortem studies indicate that both types of brain cells, neurons and glia, are involved in the cortical pathology of major depression. It remains to be determined whether the morphometric changes detected postmortem in subjects with major depressive disorder are trait or state dependent, and whether antidepressant medications have an effect on cell morphology. In the present study, cell pathology was detected even in those subjects who were not taking antidepressant medications; however, further behavioral and morphometric experiments on animals treated with antidepressant medications will shed more light on this issue.

Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression

Background: This report provides histopathological evidence to support prior neuroimaging findings of decreased volume and altered metabolism in the frontal cortex in major depressive disorder. Methods: Computer-assisted three-dimensional cell counting was used to reveal abnormal cytoarchitecture in left rostral and caudal orbitofrontal and dorsolateral prefrontal cortical regions in subjects with major depression as compared to psychiatrically normal controls. Results: Depressed subjects had decreases in cortical thickness, neuronal sizes, and neuronal and glial densities in the upper (II–IV) cortical layers of the rostral orbitofrontal region. In the caudal orbitofrontal cortex in depressed subjects, there were prominent reductions in glial densities in the lower (V–VI) cortical layers that were accompanied by small but significant decreases in neuronal sizes. In the dorsolateral prefrontal cortex of depressed subjects marked reductions in the density and size of neurons and glial cells were found in both supra- and infragranular layers. Conclusions: These results reveal that major depression can be distinguished by specific histopathology of both neurons and glial cells in the prefrontal cortex. Our data will contribute to the interpretation of neuroimaging findings and identification of dysfunctional neuronal circuits in major depression.

Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression

Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression