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1.
J Psychiatr Res ; 137: 383-392, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33765450

RESUMO

he excess availability of glucose and lipids can also have an impact on the dynamics of activation and regulation of peripheral immune cellsWe aimed at understanding the correlations between peripheral metabolic state and immune system during the first year in first-episode psychosis (FEP). Patients with FEP (n = 67) and matched controls (n = 38), aged 18-40 years, were met at baseline, 2 and 12 months. Fasting peripheral blood samples were collected. We applied the NanoString nCounter in-solution hybridization technology to determine gene expression levels of 178 candidate genes reflecting activation of the immune system. Serum triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL) cholesterol and insulin and plasma glucose (fP-Gluc) were measured. We applied Ingenuity Pathway Analysis (IPA) to visualize enrichment of genes to functional classes. Strength of positive or negative regulation of the disease and functional pathways was deduced from IPA activation Z-score at the three evaluation points. We correlated gene expression with plasma glucose, triglycerids and HDL and LDL, and used hierarchical clustering of the pairwise correlations to identify groups of genes with similar correlation patterns with metabolic markers. In patients, initially, genes associated with the innate immune system response pathways were upregulated, which decreased by 12 months. Furthermore, genes associated with apoptosis and T cell death were downregulated, and genes associated with lipid metabolism were increasingly downregulated by 12 months. The immune activation was thus an acute phase during illness onset. At baseline, after controlling for multiple testing, 31/178 genes correlated positively with fasting glucose levels, and 54/178 genes negatively with triglycerides in patients only. The gene clusters showed patterns of correlations with metabolic markers over time. The results suggest a functional link between peripheral immune system and metabolic state in FEP. Metabolic factors may have had an influence on the initial activation of the innate immune system. Future work is necessary to understand the role of metabolic state in the regulation of immune response in the early phases of psychosis.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33175128

RESUMO

BACKGROUND: Shorter leukocyte telomere length (LTL) is associated with aging and dementia. Impact of lifestyle changes on LTL, and relation to cognition and genetic susceptibility for dementia has not been investigated in randomised controlled trials (RCT). METHODS: Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a 2-year RCT enrolling 1260 participants at-risk for dementia from the general population, aged 60-77 years, randomly assigned (1:1) to multidomain lifestyle intervention or control group. Primary outcome was cognitive change (Neuropsychological Test Battery NTB z-score). Relative LTL was measured using quantitative real-time polymerase chain reaction. Trial registration: NCT01041989. RESULTS: This exploratory LTL sub-study included 756 participants (377 intervention, 379 control) with baseline and 24-month LTL measurements. Mean annual LTL change (SD) was -0.016 (0.19) in intervention, and -0.023 (0.17) in control group. Between-group difference was non-significant (unstandardised ß-coefficient 0.007, 95%CI -0.015-0.030). Interaction analyses indicated better LTL maintenance among APOEε4 carriers vs non-carriers: 0.054 (95%CI 0.007-0.102); younger vs older participants: -0.005 (95%CI -0.010 ‒ -0.001); and those with more vs less healthy lifestyle changes: 0.047 (95%CI 0.005-0.089). Cognitive intervention benefits were more pronounced among participants with better LTL maintenance for executive functioning (0.227, 95%CI 0.057-0.396) and long-term memory (0.257, 95%CI 0.024 - 0.489), with a similar trend for NTB total score (0.127, 95%CI -0.011-0.264). CONCLUSION: This is the first large RCT showing that a multidomain lifestyle intervention facilitated LTL maintenance among sub-groups of elderly at-risk for dementia, including APOEε4 carriers. LTL maintenance was associated with more pronounced cognitive intervention benefits.

3.
Genes Brain Behav ; : e12708, 2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33070440

RESUMO

Cryptochrome 2 (Cry2) is a core clock gene important for circadian regulation. It has also been associated with anxiety and depressive-like behaviors in mice, but the previous findings have been conflicting in terms of the direction of the effect. To begin to elucidate the molecular mechanisms of this association, we carried out behavioral testing, PET imaging, and gene expression analysis of Cry2-/- and Cry2+/+ mice. Compared to Cry2+/+ mice, we found that Cry2-/- mice spent less time immobile in the forced swim test, suggesting reduced despair-like behavior. Moreover, Cry2-/- mice had lower saccharin preference, indicative of increased anhedonia. In contrast, we observed no group differences in anxiety-like behavior. The behavioral changes were accompanied by lower metabolic activity of the ventro-medial hypothalamus, suprachiasmatic nuclei, ventral tegmental area, anterior and medial striatum, substantia nigra, and habenula after cold stress as measured by PET imaging with a glucose analog. Although the expression of many depression-associated and metabolic genes was upregulated or downregulated by cold stress, we observed no differences between Cry2-/- and Cry2+/+ mice. These findings are consistent with other studies showing that Cry2 is required for normal emotional behavior. Our findings confirm previous roles of Cry2 in behavior and extend them by showing that the effects on behavior may be mediated by changes in brain metabolism.

4.
eNeuro ; 7(4)2020.
Artigo em Inglês | MEDLINE | ID: mdl-32788298

RESUMO

NETO2 is an auxiliary subunit for kainate-type glutamate receptors that mediate normal cued fear expression and extinction. Since the amygdala is critical for these functions, we asked whether Neto2 -/- mice have compromised amygdala function. We measured the abundance of molecular markers of neuronal maturation and plasticity, parvalbumin-positive (PV+), perineuronal net-positive (PNN+), and double positive (PV+PNN+) cells in the Neto2 -/- amygdala. We found that Neto2 -/- adult, but not postnatal day (P)23, mice had 7.5% reduction in the fraction of PV+PNN+ cells within the total PNN+ population, and 23.1% reduction in PV staining intensity compared with Neto2 +/+ mice, suggesting that PV interneurons in the adult Neto2 -/- amygdala remain in an immature state. An immature PV inhibitory network would be predicted to lead to stronger amygdalar excitation. In the amygdala of adult Neto2 -/- mice, we identified increased glutamatergic and reduced GABAergic transmission using whole-cell patch-clamp recordings. This was accompanied by increased spine density of thin dendrites in the basal amygdala (BA) compared with Neto2 +/+ mice, indicating stronger glutamatergic synapses. Moreover, after fear acquisition Neto2 -/- mice had a higher number of c-Fos-positive cells than Neto2 +/+ mice in the lateral amygdala (LA), BA, and central amygdala (CE). Altogether, our findings indicate that Neto2 is involved in the maturation of the amygdala PV interneuron network. Our data suggest that this defect, together with other processes influencing amygdala principal neurons, contribute to increased amygdalar excitability, higher fear expression, and delayed extinction in cued fear conditioning, phenotypes that are common in fear-related disorders, including the posttraumatic stress disorder (PTSD).

5.
Sci Rep ; 10(1): 13986, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32814800

RESUMO

Telomeres play an important role in maintaining chromosomal integrity. With each cell division, telomeres are shortened and leukocyte telomere length (LTL) has therefore been considered a marker for biological age. LTL is associated with various lifetime stressors and health-related outcomes. Transgenerational effects have been implicated in newborns, with maternal stress, depression, and anxiety predicting shorter telomere length at birth, possibly reflecting the intrauterine growth environment. Previous studies, with relatively small sample sizes, have reported an effect of maternal stress, BMI, and depression during pregnancy on the LTL of newborns. Here, we attempted to replicate previous findings on prenatal stress and newborn LTL in a sample of 1405 infants using a qPCR-based method. In addition, previous research has been expanded by studying the relationship between maternal sleep quality and LTL. Maternal prenatal stress, anxiety, depression, BMI, and self-reported sleep quality were evaluated with self-reported questionnaires. Despite sufficient power to detect similar or even considerably smaller effects than those previously reported in the literature, we were unable to replicate the previous correlation between maternal stress, anxiety, depression, or sleep with LTL. We discuss several possible reasons for the discrepancies between our findings and those previously described.

6.
Transl Psychiatry ; 10(1): 94, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32179746

RESUMO

Several lines of research support immune system dysregulation in psychotic disorders. However, it remains unclear whether the immunological marker alterations are stable and how they associate with brain glial cell function. This longitudinal study aimed at investigating whether peripheral immune functions are altered in the early phases of psychotic disorders, whether the changes are associated with core symptoms, remission, brain glial cell function, and whether they persist in a one-year follow-up. Two independent cohorts comprising in total of 129 first-episode psychosis (FEP) patients and 130 controls were assessed at baseline and at the one-year follow-up. Serum cyto-/chemokines were measured using a 38-plex Luminex assay. The FEP patients showed a marked increase in chemokine CCL22 levels both at baseline (p < 0.0001; Cohen's d = 0.70) and at the 12-month follow-up (p = 0.0007) compared to controls. The group difference remained significant (p = 0.0019) after accounting for relevant covariates including BMI, smoking, and antipsychotic medication. Elevated serum CCL22 levels were significantly associated with hallucinations (ρ = 0.20) and disorganization (ρ = 0.23), and with worse verbal performance (ρ = -0.23). Brain glial cell activity was indexed with positron emission tomography and the translocator protein radiotracer [11C]PBR28 in subgroups of 15 healthy controls and 14 FEP patients with serum CCL22/CCL17 measurements. The distribution volume (VT) of [11C]PBR28 was lower in patients compared to controls (p = 0.026; Cohen's d = 0.94) without regionally specific effects, and was inversely associated with serum CCL22 and CCL17 levels (p = 0.036). Our results do not support the over-active microglia hypothesis of psychosis, but indicate altered CCR4 immune signaling in early psychosis with behavioral correlates possibly mediated through cross-talk between chemokine networks and dysfunctional or a decreased number of glial cells.

7.
Glia ; 68(3): 589-599, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31670864

RESUMO

Alzheimer's disease (AD) is a common dementia affecting a vast number of individuals and significantly impairing quality of life. Despite extensive research in animal models and numerous promising treatment trials, there is still no curative treatment for AD. Astrocytes, the most common cell type of the central nervous system, have been shown to play a role in the major AD pathologies, including accumulation of amyloid plaques, neuroinflammation, and oxidative stress. Here, we show that inflammatory stimulation leads to metabolic activation of human astrocytes and reduces amyloid secretion. On the other hand, the activation of oxidative metabolism leads to increased reactive oxygen species production especially in AD astrocytes. While healthy astrocytes increase glutathione (GSH) release to protect the cells, Presenilin-1-mutated AD patient astrocytes do not. Thus, chronic inflammation is likely to induce oxidative damage in AD astrocytes. Activation of NRF2, the major regulator of cellular antioxidant defenses, encoded by the NFE2L2 gene, poses several beneficial effects on AD astrocytes. We report here that the activation of NRF2 pathway reduces amyloid secretion, normalizes cytokine release, and increases GSH secretion in AD astrocytes. NRF2 induction also activates the metabolism of astrocytes and increases the utilization of glycolysis. Taken together, targeting NRF2 in astrocytes could be a potent therapeutic strategy in AD.


Assuntos
Doença de Alzheimer/metabolismo , Antioxidantes/farmacologia , Astrócitos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Presenilina-1/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Proteínas Amiloidogênicas/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Inflamação/metabolismo , Placa Amiloide/metabolismo
8.
Sci Rep ; 9(1): 19437, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31857655

RESUMO

Pharmacological research in mice and human genetic analyses suggest that the kallikrein-kinin system (KKS) may regulate anxiety. We examined the role of the KKS in anxiety and stress in both species. In human genetic association analysis, variants in genes for the bradykinin precursor (KNG1) and the bradykinin receptors (BDKRB1 and BDKRB2) were associated with anxiety disorders (p < 0.05). In mice, however, neither acute nor chronic stress affected B1 receptor gene or protein expression, and B1 receptor antagonists had no effect on anxiety tests measuring approach-avoidance conflict. We thus focused on the B2 receptor and found that mice injected with the B2 antagonist WIN 64338 had lowered levels of a physiological anxiety measure, the stress-induced hyperthermia (SIH), vs controls. In the brown adipose tissue, a major thermoregulator, WIN 64338 increased expression of the mitochondrial regulator Pgc1a and the bradykinin precursor gene Kng2 was upregulated after cold stress. Our data suggests that the bradykinin system modulates a variety of stress responses through B2 receptor-mediated effects, but systemic antagonists of the B2 receptor were not anxiolytic in mice. Genetic variants in the bradykinin receptor genes may predispose to anxiety disorders in humans by affecting their function.


Assuntos
Transtornos de Ansiedade/metabolismo , Bradicinina/metabolismo , Sistema Calicreína-Cinina/fisiologia , Estresse Psicológico/metabolismo , Adulto , Animais , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/patologia , Antagonistas de Receptor B1 da Bradicinina/administração & dosagem , Antagonistas de Receptor B2 da Bradicinina/administração & dosagem , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Sistema Calicreína-Cinina/efeitos dos fármacos , Cininogênios/genética , Cininogênios/metabolismo , Masculino , Camundongos , Naftalenos/administração & dosagem , Compostos Organofosforados/administração & dosagem , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Polimorfismo de Nucleotídeo Único , Receptor B1 da Bradicinina/genética , Receptor B1 da Bradicinina/metabolismo , Receptor B2 da Bradicinina/genética , Receptor B2 da Bradicinina/metabolismo , Especificidade da Espécie , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/patologia , Regulação para Cima
9.
Mol Psychiatry ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712720

RESUMO

Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.

10.
PLoS Genet ; 15(9): e1008358, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31557158

RESUMO

Stressful life events are major environmental risk factors for anxiety disorders, although not all individuals exposed to stress develop clinical anxiety. The molecular mechanisms underlying the influence of environmental effects on anxiety are largely unknown. To identify biological pathways mediating stress-related anxiety and resilience to it, we used the chronic social defeat stress (CSDS) paradigm in male mice of two inbred strains, C57BL/6NCrl (B6) and DBA/2NCrl (D2), that differ in their susceptibility to stress. Using a multi-omics approach, we identified differential mRNA, miRNA and protein expression changes in the bed nucleus of the stria terminalis (BNST) and blood cells after chronic stress. Integrative gene set enrichment analysis revealed enrichment of mitochondrial-related genes in the BNST and blood of stressed mice. To translate these results to human anxiety, we investigated blood gene expression changes associated with exposure-induced panic attacks. Remarkably, we found reduced expression of mitochondrial-related genes in D2 stress-susceptible mice and in exposure-induced panic attacks in humans, but increased expression of these genes in B6 stress-susceptible mice. Moreover, stress-susceptible vs. stress-resilient B6 mice displayed more mitochondrial cross-sections in the post-synaptic compartment after CSDS. Our findings demonstrate mitochondrial-related alterations in gene expression as an evolutionarily conserved response in stress-related behaviors and validate the use of cross-species approaches in investigating the biological mechanisms underlying anxiety disorders.


Assuntos
Ansiedade/genética , Ansiedade/metabolismo , Estresse Psicológico/metabolismo , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Genômica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , MicroRNAs/genética , Mitocôndrias , Proteômica , RNA Mensageiro/genética , Núcleos Septais/metabolismo , Estresse Psicológico/fisiopatologia , Transcriptoma/genética
11.
JAMA Psychiatry ; 76(9): 924-932, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31116379

RESUMO

Importance: Anxiety and stress-related disorders are among the most common mental disorders. Although family and twin studies indicate that both genetic and environmental factors play an important role underlying their etiology, the genetic underpinnings of anxiety and stress-related disorders are poorly understood. Objectives: To estimate the single-nucleotide polymorphism-based heritability of anxiety and stress-related disorders; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to evaluate the association of psychiatric comorbidities with genetic findings. Design, Setting, Participants: This genome-wide association study included individuals with various anxiety and stress-related diagnoses and controls derived from the population-based Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) study. Lifetime diagnoses of anxiety and stress-related disorders were obtained through the national Danish registers. Genes of interest were further evaluated in mice exposed to chronic social defeat. The study was conducted between June 2016 and November 2018. Main Outcomes and Measures: Diagnoses of a relatively broad diagnostic spectrum of anxiety and stress-related disorders. Results: The study sample included 12 655 individuals with various anxiety and stress-related diagnoses and 19 225 controls. Overall, 17 740 study participants (55.6%) were women. A total of 7308 participants (22.9%) were born between 1981-1985, 8840 (27.7%) between 1986-1990, 8157 (25.6%) between 1991-1995, 5918 (18.6%) between 1996-2000, and 1657 (5.2%) between 2001-2005. Standard association analysis revealed variants in PDE4B to be associated with anxiety and stress-related disorder (rs7528604; P = 5.39 × 10-11; odds ratio = 0.89; 95% CI, 0.86-0.92). A framework of sensitivity analyses adjusting for mental comorbidity supported this result showing consistent association of PDE4B variants with anxiety and stress-related disorder across analytical scenarios. In mouse models, alterations in Pde4b expression were observed in those mice displaying anxiety-like behavior after exposure to chronic stress in the prefrontal cortex (P = .002; t = -3.33) and the hippocampus (P = .001; t = -3.72). We also found a single-nucleotide polymorphism heritability of 28% (standard error = 0.027) and that the genetic signature of anxiety and stress-related overlapped with psychiatric traits, educational outcomes, obesity-related phenotypes, smoking, and reproductive success. Conclusions and Relevance: This study highlights anxiety and stress-related disorders as complex heritable phenotypes with intriguing genetic correlations not only with psychiatric traits, but also with educational outcomes and multiple obesity-related phenotypes. Furthermore, we highlight the candidate gene PDE4B as a robust risk locus pointing to the potential of PDE4B inhibitors in treatment of these disorders.

12.
Mol Psychiatry ; 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138891

RESUMO

We have previously reported a replicable association between variants at the PDE4D gene and familial schizophrenia in a Finnish cohort. In order to identify the potential functional mutations underlying these previous findings, we sequenced 1.5 Mb of the PDE4D genomic locus in 20 families (consisting of 96 individuals and 79 independent chromosomes), followed by two stages of genotyping across 6668 individuals from multiple Finnish cohorts for major mental illnesses. We identified 4570 SNPs across the PDE4D gene, with 380 associated to schizophrenia (p ≤ 0.05). Importantly, two of these variants, rs35278 and rs165940, are located at transcription factor-binding sites, and displayed replicable association in the two-stage enlargement of the familial schizophrenia cohort (combined statistics for rs35278 p = 0.0012; OR = 1.18, 95% CI: 1.06-1.32; and rs165940 p = 0.0016; OR = 1.27, 95% CI: 1.13-1.41). Further analysis using additional cohorts and endophenotypes revealed that rs165940 principally associates within the psychosis (p = 0.025, OR = 1.18, 95% CI: 1.07-1.30) and cognitive domains of major mental illnesses (g-score p = 0.044, ß = -0.033). Specifically, the cognitive domains represented verbal learning and memory (p = 0.0091, ß = -0.044) and verbal working memory (p = 0.0062, ß = -0.036). Moreover, expression data from the GTEx database demonstrated that rs165940 significantly correlates with the mRNA expression levels of PDE4D in the cerebellum (p-value = 0.04; m-value = 0.9), demonstrating a potential functional consequence for this variant. Thus, rs165940 represents the most likely functional variant for major mental illness at the PDE4D locus in the Finnish population, increasing risk broadly to psychotic disorders.

13.
Neuropsychopharmacology ; 44(11): 1855-1866, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30770891

RESUMO

NETO1 and NETO2 are auxiliary subunits of kainate receptors (KARs). They interact with native KAR subunits to modulate multiple aspects of receptor function. Variation in KAR genes has been associated with psychiatric disorders in humans, and in mice, knockouts of the Grik1 gene have increased, while Grik2 and Grik4 knockouts have reduced anxiety-like behavior. To determine whether the NETO proteins regulate anxiety and fear through modulation of KARs, we undertook a comprehensive behavioral analysis of adult Neto1-/- and Neto2-/- mice. We observed no differences in anxiety-like behavior. However, in cued fear conditioning, Neto2-/-, but not Neto1-/- mice, showed higher fear expression and delayed extinction compared to wild type mice. We established, by in situ hybridization, that Neto2 was expressed in both excitatory and inhibitory neurons throughout the fear circuit including the medial prefrontal cortex, amygdala, and hippocampus. Finally, we demonstrated that the relative amount of synaptosomal KAR GLUK2/3 subunit was 20.8% lower in the ventral hippocampus and 36.5% lower in the medial prefrontal cortex in Neto2-/- compared to the Neto2+/+ mice. The GLUK5 subunit abundance was reduced 23.8% in the ventral hippocampus and 16.9% in the amygdala. We conclude that Neto2 regulates fear expression and extinction in mice, and that its absence increases conditionability, a phenotype related to post-traumatic stress disorder and propose that this phenotype is mediated by reduced KAR subunit abundance at synapses of fear-associated brain regions.


Assuntos
Tonsila do Cerebelo/metabolismo , Extinção Psicológica/fisiologia , Medo/fisiologia , Hipocampo/metabolismo , Proteínas de Membrana/genética , Córtex Pré-Frontal/metabolismo , Animais , Condicionamento Clássico/fisiologia , Aprendizagem em Labirinto/fisiologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo , Sinaptossomos/metabolismo
14.
J Psychiatr Res ; 109: 18-26, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30463035

RESUMO

Previous studies suggest immunological alterations in patients with first-episode psychosis (FEP). Some studies show that antipsychotic compounds may cause immunomodulatory effects. To evaluate the immunological changes and the possible immunomodulatory effects in FEP, we recruited patients with FEP (n = 67) and matched controls (n = 38), aged 18-40 years, from the catchment area of the Helsinki University Hospital and the City of Helsinki, Finland. Fasting peripheral blood samples were collected between 8 and 10 a.m. in 10 ml PAXgene tubes. We applied the NanoString nCounter in-solution hybridization technology to determine gene expression levels of 147 candidate genes reflecting activation of the immune system. Cases had higher gene expression levels of BDKRB1 and SPP1/osteopontin compared with controls. Of the individual medications used as monotherapy, risperidone was associated with a statistically significant upregulation of 11 immune system genes, including cytokines and cytokine receptors (SPP1, IL1R1, IL1R2), pattern recognition molecules (TLR1, TLR2 and TLR6, dectin-1/CLEC7A), molecules involved in apoptosis (FAS), and some other molecules with functions in immune activation (BDKRB1, IGF1R, CR1). In conclusion, risperidone possessed strong immunomodulatory properties affecting mainly innate immune response in FEP patients, whereas the observed effects of quetiapine and olanzapine were only marginal. Our results further emphasize the importance of understanding the immunomodulatory mechanisms of antipsychotic treatment, especially in terms of specific compounds, doses and duration of medication in patients with severe mental illness. Future studies should evaluate the response pre- and post-treatment, and the possible role of this inflammatory activation for the progression of psychiatric and metabolic symptoms.


Assuntos
Antipsicóticos/farmacologia , Citocinas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Imunidade Inata/genética , Fatores Imunológicos/farmacologia , Olanzapina/farmacologia , Transtornos Psicóticos/tratamento farmacológico , Fumarato de Quetiapina/farmacologia , Receptores de Citocinas/genética , Risperidona/farmacologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Regulação para Cima , Adulto Jovem
15.
Am J Clin Nutr ; 108(3): 453-475, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535086

RESUMO

Background: Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes. Objective: A collaborative cross-sectional meta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span. Design: Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Study-specific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute [base pairs (bp)] and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories ("young": 18-60 y; "middle": 61-75 y; and "old": >75 y), sex, and ethnicity. Results: Each unit increase in BMI corresponded to a -3.99 bp (95% CI: -5.17, -2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -7.67 bp (95% CI: -10.03, -5.31 bp) difference. Each unit increase in BMI corresponded to a -1.58 × 10(-3) unit T/S ratio (0.16% decrease; 95% CI: -2.14 × 10(-3), -1.01 × 10(-3)) difference in age- and sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -2.58 × 10(-3) unit T/S ratio (0.26% decrease; 95% CI: -3.92 × 10(-3), -1.25 × 10(-3)). The associations were predominantly for the white pooled population. No sex differences were observed. Conclusions: A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL are warranted.


Assuntos
Índice de Massa Corporal , Encurtamento do Telômero/fisiologia , Telômero/ultraestrutura , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Grupos Étnicos , Humanos , Leucócitos/ultraestrutura , Masculino , Pessoa de Meia-Idade , Obesidade/patologia , Fatores Sexuais
16.
eNeuro ; 5(4)2018.
Artigo em Inglês | MEDLINE | ID: mdl-30073192

RESUMO

Anxiety disorders often manifest in genetically susceptible individuals after psychosocial stress, but the mechanisms underlying these gene-environment interactions are largely unknown. We used the chronic social defeat stress (CSDS) mouse model to study resilience and susceptibility to chronic psychosocial stress. We identified a strong genetic background effect in CSDS-induced social avoidance (SA) using four inbred mouse strains: 69% of C57BL/6NCrl (B6), 23% of BALB/cAnNCrl, 19% of 129S2/SvPasCrl, and 5% of DBA/2NCrl (D2) mice were stress resilient. Furthermore, different inbred mouse strains responded differently to stress, suggesting they use distinct coping strategies. To identify biological pathways affected by CSDS, we used RNA-sequencing (RNA-seq) of three brain regions of two strains, B6 and D2: medial prefrontal cortex (mPFC), ventral hippocampus (vHPC), and bed nucleus of the stria terminalis (BNST). We discovered overrepresentation of oligodendrocyte (OLG)-related genes in the differentially expressed gene population. Because OLGs myelinate axons, we measured myelin thickness and found significant region and strain-specific differences. For example, in resilient D2 mice, mPFC axons had thinner myelin than controls, whereas susceptible B6 mice had thinner myelin than controls in the vHPC. Neither myelin-related gene expression in several other regions nor corpus callosum thickness differed between stressed and control animals. Our unbiased gene expression experiment suggests that myelin plasticity is a substantial response to chronic psychosocial stress, varies across brain regions, and is genetically controlled. Identification of genetic regulators of the myelin response will provide mechanistic insight into the molecular basis of stress-related diseases, such as anxiety disorders, a critical step in developing targeted therapy.


Assuntos
Transtornos de Ansiedade/metabolismo , Comportamento Animal/fisiologia , Expressão Gênica/fisiologia , Hipocampo/metabolismo , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Córtex Pré-Frontal/metabolismo , Resiliência Psicológica , Núcleos Septais/metabolismo , Estresse Psicológico/metabolismo , Animais , Transtornos de Ansiedade/etiologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Microscopia Eletrônica de Transmissão , Análise de Sequência de RNA , Estresse Psicológico/complicações
17.
RNA ; 24(5): 643-655, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29445025

RESUMO

Diversity in the structure and expression of microRNAs, important regulators of gene expression, arises from SNPs, duplications followed by divergence, production of isomiRs, and RNA editing. Inbred mouse strains and crosses using them are important reference populations for genetic mapping, and as models of human disease. We determined the nature and extent of interstrain miRNA variation by (i) identifying miRNA SNPs in whole-genome sequence data from 36 strains, and (ii) examining miRNA editing and expression in hippocampus (Hpc) and frontal cortex (FCx) of six strains, to facilitate the study of miRNAs in neurobehavioral phenotypes. miRNA loci were strongly conserved among the 36 strains, but even the highly conserved seed region contained 16 SNPs. In contrast, we identified RNA editing in 58.9% of miRNAs, including 11 consistent editing events in the seed region. We confirmed the functional significance of three conserved edits in the miR-379/410 cluster, demonstrating that edited miRNAs gained novel target mRNAs not recognized by the unedited miRNAs. We found significant interstrain differences in miRNA and isomiR expression: Of 779 miRNAs expressed in Hpc and 719 in FCx, 262 were differentially expressed (190 in Hpc, 126 in FCx, 54 in both). We also identified 32 novel miRNA candidates using miRNA prediction tools. Our studies provide the first comprehensive analysis of SNP, isomiR, and RNA editing variation in miRNA loci across inbred mouse strains, and a detailed catalog of expressed miRNAs in Hpc and FCx in six commonly used strains. These findings will facilitate the molecular analysis of neurological and behavioral phenotypes in this model organism.


Assuntos
Encéfalo/metabolismo , MicroRNAs/genética , Edição de RNA , Animais , Sequência de Bases , Sequência Conservada , Loci Gênicos , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos , MicroRNAs/química , MicroRNAs/metabolismo , Polimorfismo de Nucleotídeo Único , Especificidade da Espécie
18.
Sci Rep ; 7(1): 15061, 2017 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-29118417

RESUMO

Chronic psychosocial stress is a well-established risk factor for neuropsychiatric diseases. Abnormalities in brain activity have been demonstrated in patients with stress-related disorders. Global brain activation patterns during chronic stress exposure are less well understood but may have strong modifying effects on specific brain circuits and thereby influence development of stress-related pathologies. We determined neural activation induced by chronic social defeat stress, a mouse model of psychosocial stress. To assess chronic activation with an unbiased brain-wide focus we used manganese-enhanced magnetic resonance imaging (MEMRI) and immunohistochemical staining of ∆FOSB, a transcription factor induced by repeated neural activity. One week after 10-day social defeat we observed significantly more activation in several brain regions known to regulate depressive and anxiety-like behaviour, including the prefrontal cortex, bed nucleus of stria terminalis, ventral hippocampus and periaqueductal grey in stressed compared to control mice. We further established that the correlation of ∆FOSB positive cells between specific brain regions was altered following chronic social defeat. Chronic activation of these neural circuits may relate to persistent brain activity changes occurring during chronic psychosocial stress exposure, with potential relevance for the development of anxiety and depression in humans.


Assuntos
Transtornos de Ansiedade/fisiopatologia , Encéfalo/fisiopatologia , Comportamento Social , Estresse Psicológico/fisiopatologia , Animais , Transtornos de Ansiedade/diagnóstico por imagem , Transtornos de Ansiedade/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Doença Crônica , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Imuno-Histoquímica , Imagem por Ressonância Magnética/métodos , Masculino , Manganês , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Estresse Psicológico/diagnóstico por imagem , Estresse Psicológico/metabolismo
19.
J Alzheimers Dis ; 59(4): 1459-1470, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28777749

RESUMO

Leukocyte telomere length (LTL) is a biomarker of aging, and it is associated with lifestyle. It is currently unknown whether LTL is associated with the response to lifestyle interventions. The goal is to assess whether baseline LTL modified the cognitive benefits of a 2-year multidomain lifestyle intervention (exploratory analyses). The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was a 2-year randomized controlled trial including 1,260 people at risk of cognitive decline, aged 60-77 years identified from the general population. Participants were randomly assigned to the lifestyle intervention (diet, exercise, cognitive training, and vascular risk management) and control (general health advice) groups. Primary outcome was change in cognition (comprehensive neuropsychological test battery). Secondary outcomes were changes in cognitive domains: memory, executive functioning, and processing speed. 775 participants (392 control, 383 intervention) had baseline LTL (peripheral blood DNA). Mixed effects regression models with maximum likelihood estimation were used to analyze change in cognition as a function of randomization group, time, baseline LTL, and their interaction. Intervention and control groups did not significantly differ at baseline. Shorter LTL was related to less healthy baseline lifestyle. Intervention benefits on executive functioning were more pronounced among those with shorter baseline LTL (p-value for interaction was 0.010 adjusted for age and sex, and 0.007 additionally adjusted for baseline lifestyle factors). The FINGER intervention cognitive benefits were more pronounced with shorter baseline LTL, particularly for executive functioning, indicating that the multidomain lifestyle intervention was especially beneficial among higher-risk individuals.


Assuntos
Doença de Alzheimer/complicações , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/reabilitação , Leucócitos/fisiologia , Estilo de Vida , Telômero/fisiologia , Idoso , Doença de Alzheimer/psicologia , Terapia Cognitivo-Comportamental , Pessoas com Deficiência/reabilitação , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Telômero/patologia
20.
J Affect Disord ; 213: 16-22, 2017 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-28187293

RESUMO

BACKGROUND: Studies have provided evidence that both childhood maltreatment and depressive disorders are associated with shortened telomere lengths. However, as childhood maltreatment is a risk factor for depression, it remains unclear whether this may be driving shortened telomere lengths observed amongst depressed patients. Furthermore, it's unclear if the effects of maltreatment on telomere length shortening are more pervasive amongst depressed patients relative to controls, and consequently whether biological ageing may contribute to depression's pathophysiology. The current study assesses the effects of childhood maltreatment, depression case/control status, and the interactive effect of both childhood maltreatment and depression case/control status on relative telomere length (RTL). METHOD: DNA samples from 80 depressed subjects and 100 control subjects were utilized from a U.K. sample (ages 20-84), with childhood trauma questionnaire data available for all participants. RTL was quantified using quantitative polymerase chain reactions. Univariate linear regression analyses were used to assess the effects of depression status, childhood maltreatment and depression by childhood maltreatment interactions on RTL. The false discovery rate (q<0.05) was used for multiple testing correction. RESULTS: Analysis of depression case/control status showed no significant main effect on RTL. Four subtypes of childhood maltreatment also demonstrated no significant main effect on RTL, however a history of physical neglect did significantly predict shorter RTL in adulthood (F(1, 174)=7.559, p=0.007, q=0.042, Variance Explained=4.2%), which was independent of case/control status. RTL was further predicted by severity of physical neglect, with the greatest differences observed in older maltreated individuals (>50 years old). There were no significant depression case/control status by childhood maltreatment interactions. LIMITATIONS: A relatively small sample limited our power to detect interaction effects, and we were unable to consider depression chronicity or recurrence. CONCLUSION: Shortened RTL was specifically associated with childhood physical neglect, but not the other subtypes of maltreatment or depression case/control status. Our results suggest that the telomere-eroding effects of physical neglect may represent a biological mechanism important in increasing risk for ageing-related disorders. As physical neglect is more frequent amongst depressed cases generally, it may also represent a confounding factor driving previous associations between shorter RTL and depression case status.


Assuntos
Sobreviventes Adultos de Maus-Tratos Infantis , Transtorno Depressivo/patologia , Encurtamento do Telômero , Telômero/ultraestrutura , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Maus-Tratos Infantis , DNA/isolamento & purificação , Depressão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Fatores de Risco , Inquéritos e Questionários , Telômero/genética , Adulto Jovem
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