RESUMO
Depressive symptoms are highly prevalent and heterogeneous in women. Different brain structures might be associated with depressive symptoms and body composition in women with obesity/overweight and normal-/underweight, although the data is limited. The analysis included 265 women from Bialystok PLUS population study, untreated with antidepressive or antipsychotic medications. The subjects underwent brain magnetic resonance imaging and body composition analysis. Beck Depression Inventory (BDI) score was inversely associated with nucleus accumbens volume (ß = -0.217, p = 0.008) in women with BMI ≥ 25 kg/m2, but with insula volume (ß = -0.147, p = 0.027) in women with BMI < 25 kg/m2 after adjustment for age and estimated intracranial volume (eTIV). In women with BMI ≥ 25 kg/m2, nucleus accumbens volume was inversely associated with the percentage of visceral fat and BDI score (ß = -0.236, p = 0.012, ß = -0.192, p = 0.017) after adjustment for age and eTIV. In women with BMI < 25 kg/m2, insula volume was positively associated with total fat-free mass and negatively with the BDI score (ß = 0.142, p = 0.030, ß = -0.137, p = 0.037) after adjustment for age and eTIV. Depressive symptoms might be associated with nucleus accumbens volume in overweight/obese women, while in normal-/ underweight women-with alterations in insula volume.
Assuntos
Composição Corporal , Encéfalo , Depressão , Imageamento por Ressonância Magnética , Obesidade , Sobrepeso , Humanos , Feminino , Depressão/diagnóstico por imagem , Depressão/patologia , Obesidade/patologia , Adulto , Pessoa de Meia-Idade , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Magreza , Índice de Massa Corporal , Tamanho do Órgão , Núcleo Accumbens/diagnóstico por imagem , Núcleo Accumbens/patologiaRESUMO
BACKGROUND: Depression is a chronic psychiatric disease of multifactorial etiology, and its pathophysiology is not fully understood. Stress and other chronic inflammatory pathologies are shared risk factors for psychiatric diseases, and comorbidities are features of major depression. Epidemiological evidence suggests that periodontitis, as a source of low-grade chronic systemic inflammation, may be associated with depression, but the underlying mechanisms are not well understood. METHODS: Periodontitis (P) was induced in Wistar: Han rats through oral gavage with the pathogenic bacteria Porphyromonas gingivalis and Fusobacterium nucleatum for 12 weeks, followed by 3 weeks of chronic mild stress (CMS) to induce depressive-like behavior. The following four groups were established (n = 12 rats/group): periodontitis and CMS (P + CMS+), periodontitis without CMS, CMS without periodontitis, and control. The morphology and inflammatory phenotype of microglia in the frontal cortex (FC) were studied using immunofluorescence and bioinformatics tools. The endocannabinoid (EC) signaling and proteins related to synaptic plasticity were analyzed in FC samples using biochemical and immunohistochemical techniques. RESULTS: Ultrastructural and fractal analyses of FC revealed a significant increase in the complexity and heterogeneity of Iba1 + parenchymal microglia in the combined experimental model (P + CMS+) and increased expression of the proinflammatory marker inducible nitric oxide synthase (iNOS), while there were no changes in the expression of cannabinoid receptor 2 (CB2). In the FC protein extracts of the P + CMS + animals, there was a decrease in the levels of the EC metabolic enzymes N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), diacylglycerol lipase (DAGL), and monoacylglycerol lipase (MAGL) compared to those in the controls, which extended to protein expression in neurons and in FC extracts of cannabinoid receptor 1 (CB1) and to the intracellular signaling molecules phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2). The protein levels of brain-derived neurotrophic factor (BDNF) and synaptophysin were also lower in P + CMS + animals than in controls. CONCLUSIONS: The combined effects on microglial morphology and inflammatory phenotype, the EC signaling, and proteins related to synaptic plasticity in P + CMS + animals may represent relevant mechanisms explaining the association between periodontitis and depression. These findings highlight potential therapeutic targets that warrant further investigation.
Assuntos
Depressão , Endocanabinoides , Microglia , Periodontite , Ratos Wistar , Transdução de Sinais , Animais , Ratos , Endocanabinoides/metabolismo , Microglia/metabolismo , Microglia/patologia , Periodontite/patologia , Periodontite/metabolismo , Transdução de Sinais/fisiologia , Depressão/metabolismo , Depressão/patologia , Masculino , Modelos Animais de Doenças , Fenótipo , Inflamação/metabolismo , Inflamação/patologiaRESUMO
Decades of neuroimaging studies have shown modest differences in brain structure and connectivity in depression, hindering mechanistic insights or the identification of risk factors for disease onset1. Furthermore, whereas depression is episodic, few longitudinal neuroimaging studies exist, limiting understanding of mechanisms that drive mood-state transitions. The emerging field of precision functional mapping has used densely sampled longitudinal neuroimaging data to show behaviourally meaningful differences in brain network topography and connectivity between and in healthy individuals2-4, but this approach has not been applied in depression. Here, using precision functional mapping and several samples of deeply sampled individuals, we found that the frontostriatal salience network is expanded nearly twofold in the cortex of most individuals with depression. This effect was replicable in several samples and caused primarily by network border shifts, with three distinct modes of encroachment occurring in different individuals. Salience network expansion was stable over time, unaffected by mood state and detectable in children before the onset of depression later in adolescence. Longitudinal analyses of individuals scanned up to 62 times over 1.5 years identified connectivity changes in frontostriatal circuits that tracked fluctuations in specific symptoms and predicted future anhedonia symptoms. Together, these findings identify a trait-like brain network topology that may confer risk for depression and mood-state-dependent connectivity changes in frontostriatal circuits that predict the emergence and remission of depressive symptoms over time.
Assuntos
Mapeamento Encefálico , Corpo Estriado , Depressão , Lobo Frontal , Rede Nervosa , Vias Neurais , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Afeto/fisiologia , Anedonia/fisiologia , Mapeamento Encefálico/métodos , Mapeamento Encefálico/normas , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/patologia , Corpo Estriado/fisiopatologia , Depressão/diagnóstico por imagem , Depressão/patologia , Depressão/fisiopatologia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/patologia , Lobo Frontal/fisiopatologia , Estudos Longitudinais , Imageamento por Ressonância Magnética , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Vias Neurais/diagnóstico por imagem , Vias Neurais/patologia , Vias Neurais/fisiopatologia , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Steatotic liver disease (SLD) is characterized by excessive accumulation of lipids in the liver. It is associated with elevated risk of hepatic and cardiometabolic diseases, as well as mental disorders such as depression. Previous studies revealed global gray matter reduction in SLD. To investigate a possible shared neurobiology with depression, we examined liver fat-related regional gray matter alterations in SLD and its most significant clinical subgroup metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: We analyzed regional cortical thickness and area obtained from brain MRI in 29,051 participants in UK Biobank. Liver fat amount was computed as proton density fat fraction (PDFF) from liver MRI scans. We examined the relationship between brain structure and PDFF, adjusting for sociodemographic, physical, lifestyle, and environmental factors, as well as alcohol intake and a spectrum of cardiometabolic covariates. Finally, we compared patterns of brain alterations in SLD/MASLD and major depressive disorder (MDD) using previously published results. RESULTS: PDFF-related gray matter alterations were region-specific, involving both increases and decreases in cortical thickness, and increased cortical area. In several regions, PDFF effects on gray matter could also be attributed to cardiometabolic covariates. However, PDFF was consistently associated with lower cortical thickness in middle and superior temporal regions and higher cortical thickness in pericalcarine and right frontal pole regions. PDFF-related alterations for the SLD and the MASLD group correlated with those observed in MDD (Pearson r = 0.45-0.54, p < 0.01). CONCLUSION: These findings suggest the presence of shared biological mechanisms linking MDD to SLD and MASLD. They might explain the well-known elevated risk of depression in these groups and support early lifestyle interventions and treatment of metabolic risk factors for the successful management of the interconnected diseases depression and SLD/MASLD.
Assuntos
Bancos de Espécimes Biológicos , Fígado Gorduroso , Substância Cinzenta , Imageamento por Ressonância Magnética , Humanos , Substância Cinzenta/patologia , Substância Cinzenta/diagnóstico por imagem , Masculino , Feminino , Estudos Transversais , Pessoa de Meia-Idade , Reino Unido/epidemiologia , Estudos de Coortes , Idoso , Fígado Gorduroso/patologia , Fígado Gorduroso/diagnóstico por imagem , Fígado Gorduroso/complicações , Depressão/patologia , Adulto , Transtorno Depressivo Maior/patologia , Transtorno Depressivo Maior/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Biobanco do Reino UnidoRESUMO
Late-life depression (LLD) is both common and disabling and doubles the risk of dementia onset. Apathy might constitute an additional risk of cognitive decline but clear understanding of its pathophysiology is lacking. While white matter (WM) alterations have been assessed using diffusion tensor imaging (DTI), this model cannot accurately represent WM microstructure. We hypothesized that a more complex multi-compartment model would provide new biomarkers of LLD and apathy. Fifty-six individuals (LLD n = 35, 26 females, 75.2 ± 6.4 years, apathy evaluation scale scores (41.8 ± 8.7) and Healthy controls, n = 21, 16 females, 74.7 ± 5.2 years) were included. In this article, a tract-based approach was conducted to investigate novel diffusion model biomarkers of LLD and apathy by interpolating microstructural metrics directly along the fiber bundle. We performed multivariate statistical analysis, combined with principal component analysis for dimensional data reduction. We then tested the utility of our framework by demonstrating classically reported from the literature modifications in LDD while reporting new results of biological-basis of apathy in LLD. Finally, we aimed to investigate the relationship between apathy and microstructure in different fiber bundles. Our study suggests that new fiber bundles, such as the striato-premotor tracts, may be involved in LLD and apathy, which bring new light of apathy mechanisms in major depression. We also identified statistical changes in diffusion MRI metrics in 5 different tracts, previously reported in major cognitive disorders dementia, suggesting that these alterations among these tracts are both involved in motivation and cognition and might explain how apathy is a prodromal phase of degenerative disorders.
Assuntos
Apatia , Encéfalo , Depressão , Imagem de Tensor de Difusão , Substância Branca , Humanos , Feminino , Apatia/fisiologia , Idoso , Masculino , Depressão/diagnóstico por imagem , Depressão/patologia , Depressão/fisiopatologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Substância Branca/fisiopatologia , Imagem de Tensor de Difusão/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/fisiopatologia , Idoso de 80 Anos ou mais , Imagem de Difusão por Ressonância Magnética/métodosRESUMO
BACKGROUND: The hypothalamus is a key brain structure involved in the pathogenesis of depression, and its abnormal activity is considered an important pathological mechanism for the formation of depression. The presence of abnormalities in the white matter integrity of hypothalamic subregions in mild cognitive impairment with depressive symptoms (D-MCI) remains unknown. METHODS: In this study, we used diffusion tensor imaging (DTI) to explore the white matter integrity of hypothalamic subregions in D-MCI. On a 3 T magnetic resonance imaging scanner, we collected DTI data from 63 subjects. The subjects included 20 healthy controls (HC), 23 MCI patients without depression (nD-MCI), and 20 patients with D-MCI. The differences in DTI metrics of hypothalamic subregions of the three groups were compared using analysis of variance and post hoc t-tests. We looked at the relationship between clinical variables and DTI metrics in hypothalamus subregions using Pearson correlation analysis. RESULTS: Compared with nD-MCI and HC groups, D-MCI group showed increased fractional anisotropy (FA) in anterior-inferior hypothalamus. There was a weak negative correlation between FA values in the anterior-inferior hypothalamus and depression scores in D-MCI patients. CONCLUSIONS: Our findings suggest that depressive symptoms in MCI patients are associated with abnormal white matter integrity in the anterior-inferior hypothalamus.
Assuntos
Disfunção Cognitiva , Depressão , Imagem de Tensor de Difusão , Hipotálamo , Substância Branca , Humanos , Masculino , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Feminino , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Idoso , Depressão/diagnóstico por imagem , Depressão/patologia , Hipotálamo/diagnóstico por imagem , Hipotálamo/patologia , Pessoa de Meia-Idade , AnisotropiaRESUMO
As a potential preclinical stage of Alzheimer's dementia, subjective cognitive decline (SCD) reveals a higher risk of future cognitive decline and conversion to dementia. However, it has not been clear whether SCD status increases the clinical progression of older adults in the context of amyloid deposition, cerebrovascular disease (CeVD), and psychiatric symptoms. We identified 99 normal controls (NC), 15 SCD individuals who developed mild cognitive impairment in the next 2 years (P-SCD), and 54 SCD individuals who did not (S-SCD) from ADNI database with both baseline and 2-year follow-up data. Total white matter hyperintensity (WMH), WMH in deep (DWMH) and periventricular (PWMH) regions, and voxel-wise grey matter volumes were compared among groups. Furthermore, using structural equation modelling method, we constructed path models to explore SCD-related brain changes longitudinally and to determine whether baseline SCD status, age, and depressive symptoms affect participants' clinical outcomes. Both SCD groups showed higher baseline amyloid PET SUVR, baseline PWMH volumes, and larger increase of PWMH volumes over time than NC. In contrast, only P-SCD had higher baseline DWMH volumes and larger increase of DWMH volumes over time than NC. No longitudinal differences in grey matter volume and amyloid was observed among NC, S-SCD, and P-SCD. Our path models demonstrated that SCD status contributed to future WMH progression. Further, baseline SCD status increases the risk of future cognitive decline, mediated by PWMH; baseline depressive symptoms directly contribute to clinical outcomes. In conclusion, both S-SCD and P-SCD exhibited more severe CeVD than NC. The CeVD burden increase was more pronounced in P-SCD. In contrast with the direct association of depressive symptoms with dementia severity progression, the effects of SCD status on future cognitive decline may manifest via CeVD pathologies. Our work highlights the importance of multi-modal longitudinal designs in understanding the SCD trajectory heterogeneity, paving the way for stratification and early intervention in the preclinical stage. PRACTITIONER POINTS: Both S-SCD and P-SCD exhibited more severe CeVD at baseline and a larger increase of CeVD burden compared to NC, while the burden was more pronounced in P-SCD. Baseline SCD status increases the risk of future PWMH and DWMH volume accumulation, mediated by baseline PWMH and DWMH volumes, respectively. Baseline SCD status increases the risk of future cognitive decline, mediated by baseline PWMH, while baseline depression status directly contributes to clinical outcome.
Assuntos
Disfunção Cognitiva , Progressão da Doença , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Humanos , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/etiologia , Feminino , Masculino , Idoso , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Estudos Longitudinais , Autoavaliação Diagnóstica , Depressão/diagnóstico por imagem , Depressão/patologiaRESUMO
Some mental health problems such as depression and anxiety are more common in females, while others such as autism and attention deficit/hyperactivity (AD/H) are more common in males. However, the neurobiological origins of these sex differences are poorly understood. Animal studies have shown substantial sex differences in neuronal and glial cell structure, while human brain imaging studies have shown only small differences, which largely reflect overall body and brain size. Advanced diffusion MRI techniques can be used to examine intracellular, extracellular, and free water signal contributions and provide unique insights into microscopic cellular structure. However, the extent to which sex differences exist in these metrics of subcortical gray matter structures implicated in psychiatric disorders is not known. Here, we show large sex-related differences in microstructure in subcortical regions, including the hippocampus, thalamus, and nucleus accumbens in a large sample of young adults. Unlike conventional T1-weighted structural imaging, large sex differences remained after adjustment for age and brain volume. Further, diffusion metrics in the thalamus and amygdala were associated with depression, anxiety, AD/H, and antisocial personality problems. Diffusion MRI may provide mechanistic insights into the origin of sex differences in behavior and mental health over the life course and help to bridge the gap between findings from experimental, epidemiological, and clinical mental health research.
Assuntos
Encéfalo , Caracteres Sexuais , Humanos , Feminino , Masculino , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Saúde Mental , Adulto Jovem , Imagem de Difusão por Ressonância Magnética , Adolescente , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Tálamo/diagnóstico por imagem , Núcleo Accumbens/diagnóstico por imagem , Depressão/diagnóstico por imagem , Depressão/patologia , Ansiedade/diagnóstico por imagemRESUMO
Genetic factors confer risks for depression. Understanding the neural endophenotypes, including brain morphometrics, of genetic predisposition to depression would help in unraveling the pathophysiology of depression. We employed voxel-based morphometry (VBM) to examine how gray matter volumes (GMVs) were correlated with the polygenic risk score (PRS) for depression in 993 young adults of the Human Connectome Project. The phenotype of depression was quantified with a DSM-oriented scale of the Achenbach Adult Self-Report. The PRS for depression was computed for each subject using the Psychiatric Genomics Association Study as the base sample. In multiple regression with age, sex, race, drinking severity, and total intracranial volume as covariates, regional GMVs in positive correlation with the PRS were observed in bilateral hippocampi and right gyrus rectus. Regional GMVs in negative correlation with the PRS were observed in a wide swath of brain regions, including bilateral frontal and temporal lobes, anterior cingulate cortex, thalamus, lingual gyri, cerebellum, and the left postcentral gyrus, cuneus, and parahippocampal gyrus. We also found sex difference in anterior cingulate volumes in manifesting the genetic risk of depression. In addition, the GMV of the right cerebellum crus I partially mediated the link from PRS to depression severity. These findings add to the literature by highlighting 1) a more diverse pattern of the volumetric markers of depression, with most regions showing lower but others higher GMVs in association with the genetic risks of depression, and 2) the cerebellar GMV as a genetically informed neural phenotype of depression, in neurotypical individuals.
Assuntos
Conectoma , Substância Cinzenta , Imageamento por Ressonância Magnética , Herança Multifatorial , Humanos , Masculino , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Herança Multifatorial/genética , Adulto Jovem , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Predisposição Genética para Doença , Depressão/genética , Depressão/patologia , Depressão/diagnóstico por imagem , Tamanho do Órgão/genética , AdolescenteRESUMO
Chronic variable mild stress (CVS) in rats is a well-established paradigm for inducing depressive-like behaviors and has been utilized extensively to explore potential therapeutic interventions for depression. While the behavioral and neurobiological effects of CVS have been extensively studied, its impact on myocardial function remains largely unexplored. To induce the CVS model, rats were exposed to various stressors over 40 days. Behavioral assessments confirmed depressive-like behavior. Biochemical analyses revealed alterations in myocardial metabolism, including changes in NAD+ and NADP+, and NADPH concentrations. Free amino acid analysis indicated disturbances in myocardial amino acid metabolism. Evaluation of oxidative DNA damage demonstrated an increased number of abasic sites in the DNA of rats exposed to CVS. Molecular analysis showed significant changes in gene expression associated with glucose metabolism, oxidative stress, and cardiac remodeling pathways. Histological staining revealed minor morphological changes in the myocardium of CVS-exposed rats, including increased acidophilicity of cells, collagen deposition surrounding blood vessels, and glycogen accumulation. This study provides novel insights into the impact of chronic stress on myocardial function and metabolism, highlighting potential mechanisms linking depression and cardiovascular diseases. Understanding these mechanisms may aid in the development of targeted therapeutic strategies to mitigate the adverse cardiovascular effects of depression.
Assuntos
Miocárdio , Estresse Oxidativo , Estresse Psicológico , Animais , Ratos , Miocárdio/metabolismo , Miocárdio/patologia , Masculino , Estresse Psicológico/metabolismo , Depressão/metabolismo , Depressão/patologia , Modelos Animais de Doenças , Dano ao DNA , Adaptação Fisiológica , NAD/metabolismo , Glucose/metabolismoRESUMO
Depression is a neurodevelopmental disorder that exhibits progressive gray matter volume (GMV) atrophy. Research indicates that brain development is influential in depression-induced GMV alterations. However, the interaction between depression and age of onset is not well understood by the underlying molecular and neuropathological mechanisms. Thus, 152 first-episode depression individuals and matched 130 healthy controls (HCs) were recruited to undergo T1-weighted high-resolution magnetic resonance imaging for this study. By two-way ANOVA, age and diagnosis were used as factors when analyzing the interaction of GMV in the participants. Then, spatial correlations between neurotransmitter maps and factor-related volume maps are established. Results illustrate a pronounced antagonistic interaction between depression and age of onset in the right insula, superior temporal gyrus, anterior cingulate gyrus, and orbitofrontal gyrus. Depression-caused reductions in GMV are mainly distributed in thalamic-limbic-cortical regions, regardless of age. For the main effect of age, adults exhibit brain atrophy in frontal, cerebellum, parietal, and temporal lobe structures. Cross-modal correlations showed that GMV changes in the interactive regions were linked with the serotonergic system and dopaminergic systems. Summarily, our results reveal the interaction between depression and age of onset in neurobiological mechanisms, which provide hints for future treatment of different ages of depression.
Assuntos
Idade de Início , Encéfalo , Substância Cinzenta , Imageamento por Ressonância Magnética , Humanos , Masculino , Feminino , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Adulto Jovem , Pessoa de Meia-Idade , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Neuroimagem/métodos , Depressão/diagnóstico por imagem , Depressão/patologia , Imagem Multimodal , Adolescente , Atrofia/patologiaAssuntos
Encéfalo , Depressão , Animais , Camundongos , Depressão/imunologia , Depressão/genética , Depressão/patologia , Encéfalo/imunologia , Encéfalo/metabolismo , HumanosRESUMO
Imaging studies of subthreshold depression (StD) have reported structural and functional abnormalities in a variety of spatially diverse brain regions. However, there is no consensus among different studies. In the present study, we applied a multimodal meta-analytic approach, the Activation Likelihood Estimation (ALE), to test the hypothesis that StD exhibits spatially convergent structural and functional brain abnormalities compared to healthy controls. A total of 31 articles with 25 experiments were included, collectively representing 1001 subjects with StD. We found consistent differences between StD and healthy controls mainly in the left insula across studies with various neuroimaging methods. Further exploratory analyses found structural atrophy and decreased functional activities in the right pallidum and thalamus in StD, and abnormal spontaneous activity converged to the middle frontal gyrus. Coordinate-based meta-analysis found spatially convergent structural and functional impairments in StD. These findings provide novel insights for understanding the neural underpinnings of subthreshold depression and enlighten the potential targets for its early screening and therapeutic interventions in the future.
Assuntos
Depressão , Humanos , Depressão/diagnóstico por imagem , Depressão/fisiopatologia , Depressão/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Encéfalo/patologia , Imageamento por Ressonância Magnética , Neuroimagem/métodosRESUMO
INTRODUCTION: The medial prefrontal cortex (mPFC) forms output pathways through projection neurons, inversely receiving adjacent and long-range inputs from other brain regions. However, how afferent neurons of mPFC are affected by chronic stress needs to be clarified. In this study, the effects of chronic restraint stress (CRS) on the distribution density of mPFC dendrites/dendritic spines and the projections from the cortex and subcortical brain regions to the mPFC were investigated. METHODS: In the present study, C57BL/6â¯J transgenic (Thy1-YFP-H) mice were subjected to CRS to establish an animal model of depression. The infralimbic (IL) of mPFC was selected as the injection site of retrograde AAV using stereotactic technique. The effects of CRS on dendrites/dendritic spines and afferent neurons of the mPFC IL were investigaed by quantitatively assessing the distribution density of green fluorescent (YFP) positive dendrites/dendritic spines and red fluorescent (retrograde AAV recombinant protein) positive neurons, respectively. RESULTS: The results revealed that retrograde tracing virus labeled neurons were widely distributed in ipsilateral and contralateral cingulate cortex (Cg1), second cingulate cortex (Cg2), prelimbic cortex (PrL), infralimbic cortex, medial orbital cortex (MO), and dorsal peduncular cortex (DP). The effects of CRS on the distribution density of mPFC red fluorescence positive neurons exhibited regional differences, ranging from rostral to caudal or from top to bottom. Simultaneously, CRS resulted a decrease in the distribution density of basal, proximal and distal dendrites, as well as an increase in the loss of dendritic spines of the distal dendrites in the IL of mPFC. Furthermore, varying degrees of red retrograde tracing virus fluorescence signals were observed in other cortices, amygdala, hippocampus, septum/basal forebrain, hypothalamus, thalamus, mesencephalon, and brainstem in both ipsilateral and contralateral brain. CRS significantly reduced the distribution density of red fluorescence positive neurons in other cortices, hippocampus, septum/basal forebrain, hypothalamus, and thalamus. Conversely, CRS significantly increased the distribution density of red fluorescence positive neurons in amygdala. CONCLUSION: Our results suggest a possible mechanism that CRS leads to disturbances in synaptic plasticity by affecting multiple inputs to the mPFC, which is characterized by a decrease in the distribution density of dendrites/dendritic spines in the IL of mPFC and a reduction in input neurons of multiple cortices to the IL of mPFC as well as an increase in input neurons of amygdala to the IL of mPFC, ultimately causing depression-like behaviors.
Assuntos
Depressão , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Córtex Pré-Frontal , Restrição Física , Estresse Psicológico , Animais , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/metabolismo , Estresse Psicológico/patologia , Estresse Psicológico/metabolismo , Camundongos , Depressão/patologia , Masculino , Espinhas Dendríticas/patologia , Modelos Animais de Doenças , Vias Aferentes , Dendritos/patologia , Dendritos/metabolismo , Neurônios Aferentes/patologia , Neurônios Aferentes/metabolismo , Encéfalo/patologia , Encéfalo/metabolismoRESUMO
We experimentally demonstrated that chronic social stress during the development of a depression-like state enhances lung metastasis and modifies the expression of many carcinogenesis- and apoptosis-related genes in the hypothalamus of mice, including genes involved in lung cancer pathogenesis in humans. Analysis of the expression of genes encoding the major clinical markers of lung cancer in the hypothalamus of mice with depression-like behavior revealed increased expression of the Eno2 gene encoding neuron-specific enolase, a blood marker of lung cancer progression in humans. It was shown that the expression of this gene in the hypothalamus correlated with the expression of many carcinogenesis- and apoptosis-related genes. The discovered phenomenon may have a fundamental significance and requires further studies.
Assuntos
Biomarcadores Tumorais , Depressão , Hipotálamo , Neoplasias Pulmonares , Fosfopiruvato Hidratase , Animais , Masculino , Camundongos , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinogênese , Depressão/genética , Depressão/metabolismo , Depressão/patologia , Regulação Neoplásica da Expressão Gênica , Hipotálamo/metabolismo , Hipotálamo/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Fosfopiruvato Hidratase/análise , Fosfopiruvato Hidratase/genética , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
The adult brain retains a high repopulation capacity of astrocytes after deletion, and both mature astrocytes in the neocortex and neural stem cells in neurogenic regions possess the potential to generate astrocytes. However, the origin and the repopulation dynamics of the repopulating astrocytes after deletion remain largely unclear. The number of astrocytes is reduced in the medial prefrontal cortex (mPFC) of patients with depression, and selective elimination of mPFC astrocytes is sufficient to induce depression-like behaviors in rodents. However, whether astrocyte repopulation capacity is impaired in depression is unknown. In this study, we used different transgenic mouse lines to genetically label different cell types and demonstrated that in the mPFC of normal adult mice of both sexes, mature astrocytes were a major source of the repopulating astrocytes after acute deletion induced by an astrocyte-specific toxin, L-alpha-aminoadipic acid (L-AAA), and astrocyte regeneration was accomplished within two weeks accompanied by reversal of depression-like behaviors. Furthermore, re-ablation of mPFC astrocytes post repopulation led to reappearance of depression-like behaviors. In adult male mice subjected to 14-day chronic restraint stress, a well-validated mouse model of depression, the number of mPFC astrocytes was reduced; however, the ability of mPFC astrocytes to repopulate after L-AAA-induced deletion was largely unaltered. Our study highlights a potentially beneficial role for repopulating astrocytes in depression and provides novel therapeutic insights into enhancing local mature astrocyte generation in depression.
Assuntos
Astrócitos , Depressão , Camundongos Transgênicos , Córtex Pré-Frontal , Animais , Astrócitos/metabolismo , Córtex Pré-Frontal/metabolismo , Masculino , Depressão/genética , Depressão/patologia , Feminino , Camundongos Endogâmicos C57BL , Camundongos , Modelos Animais de Doenças , Restrição Física , Ácido 2-Aminoadípico , Estresse Psicológico/patologia , Estresse Psicológico/metabolismoRESUMO
BACKGROUND: Depression is reported as a risk factor, prodromal feature and late consequence of Parkinson's disease (PD). We aimed to evaluate the timing, neuroanatomy and prognostic implications of depression in PD. METHODS: We used data from 434 023 participants from UK Biobank with 14.1 years of follow-up. Multivariable regression models established associations of depression with incident PD and regional brain volumes. Cox proportional hazards models assessed prognostic associations of depression in PD with incident dementia and all-cause mortality. RESULTS: Of 2632 individuals with incident PD, 539 (20.5%) were diagnosed with depression at some point. Depression was associated with an increased risk of subsequent PD (risk ratio 1.53, 95% CI 1.37 to 1.72). Among incident PD cases, depression prevalence rose progressively from 10 years pre-PD diagnosis (OR 2.10, 95% CI 1.57 to 2.83) to 10 years postdiagnosis (OR 3.51, 95% CI 1.33 to 9.22). Depression severity in PD was associated with reduced grey matter volume in structures including the thalamus and amygdala. Depression prior to PD diagnosis increased risk of dementia (HR 1.47, 95% CI 1.05 to 2.07) and mortality (HR 1.30, 95% CI 1.07 to 1.58). CONCLUSIONS: This large-scale prospective study demonstrated that depression prevalence increases from 10 years before PD diagnosis and is a marker of cortical and subcortical volume loss. Depression before PD diagnosis signals a worse prognosis in terms of dementia and mortality. This has clinical implications in stratifying people with poorer cognitive and prognostic trajectory in PD.
Assuntos
Demência , Depressão , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/patologia , Masculino , Feminino , Prognóstico , Idoso , Pessoa de Meia-Idade , Depressão/patologia , Demência/patologia , Imageamento por Ressonância Magnética , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Fatores de Risco , Substância Cinzenta/patologia , Substância Cinzenta/diagnóstico por imagem , Modelos de Riscos Proporcionais , Tonsila do Cerebelo/patologiaRESUMO
Type 2 diabetes mellitus (T2DM) patients often suffer from depressive symptoms, which seriously affect cooperation in treatment and nursing. The amygdala plays a significant role in depression. This study aims to explore the microstructural alterations of the amygdala in T2DM and to investigate the relationship between the alterations and depressive symptoms. Fifty T2DM and 50 healthy controls were included. Firstly, the volumes of subcortical regions and subregions of amygdala were calculated by FreeSurfer. Covariance analysis (ANCOVA) was conducted between the two groups with covariates of age, sex, and estimated total intracranial volume to explore the differences in volume of subcortical regions and subregions of amygdala. Furthermore, the structural covariance within the amygdala subregions was performed. Moreover, we investigate the correlation between depressive symptoms and the volume of subcortical regions and amygdala subregions in T2DM. We observed a reduction in the volume of the bilateral cortico-amygdaloid transition area, left basal nucleus, bilateral accessory basal nucleus, left anterior amygdaloid area of amygdala, the left thalamus and left hippocampus in T2DM. T2DM patients showed decreased structural covariance connectivity between left paralaminar nucleus and the right central nucleus. Moreover, there was a negative correlation between self-rating depression scale scores and the volume of the bilateral cortico-amygdaloid transition area in T2DM. This study reveals extensive structural alterations in the amygdala subregions of T2DM patients. The reduction in the volume of the bilateral cortico-amygdaloid transition area may be a promising imaging marker for early recognition of depressive symptoms in T2DM.
Assuntos
Tonsila do Cerebelo , Depressão , Diabetes Mellitus Tipo 2 , Imageamento por Ressonância Magnética , Humanos , Diabetes Mellitus Tipo 2/patologia , Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/diagnóstico por imagem , Masculino , Feminino , Pessoa de Meia-Idade , Depressão/diagnóstico por imagem , Depressão/patologia , Adulto , Idoso , Hipocampo/patologia , Hipocampo/diagnóstico por imagem , Tálamo/diagnóstico por imagem , Tálamo/patologiaRESUMO
Depression is a prevalent and debilitating psychiatric disorder, imposing substantial societal and individual burdens. This study aims to investigate the involvement of ferroptosis and microglial polarization in the pathogenesis of depression, as well as the underlying mechanism. Increased protein arginine methyltransferase 2 (PRMT2) expression was observed in BV2 cells and the hippocampus following lipopolysaccharide (LPS) stimulation. Mechanistically, alkylation repair homolog protein 5 (ALKBH5)-mediated m6A modification enhanced the stability of PRMT2 mRNA. PRMT2 promoted arginine methylation of ß-catenin and induced proteasomal degradation of ß-catenin proteins, resulting in transcriptional inhibition of glutathione peroxidase 4 (GPX4). The upregulation of PRMT2 further accelerated microglia polarization by activating ferroptosis through the ß-catenin-GPX4 axis. Depletion of PRMT2 improved LPS-induced depressive- and anxiety-like behaviors as well as cognitive impairment by inhibiting ferroptosis and M1 polarization of microglia. Our findings underscore the crucial involvement of the ALKBH5-PRMT2-ß-catenin-GPX4 axis in ferroptosis and M1 polarization of microglia, thereby offering novel insights into the pathogenesis interventions for depression.