Effects of Escitalopram on a Rat Model of Persistent Stress-Altered Hedonic Activities: Towards a New Understanding of Stress and Depression.

Chronic mild stress (CMS) paradigm is a model to simulate clinical depression induced by long-term environmental stress. The present study investigated the effects of escitalopram, a specific serotonin reuptake inhibitor (SSRI), on depression-like activities in adult (18 week-old) Sprague-Dawley (SD) rats that underwent a total 8-week CMS. Body weight, locomotor activity and sucrose consumption of the rats were measured under CMS paradigm and following escitalopram treatment. The plasma level of corticosterone was also measured at the end of the experiment. Our results revealed that the CMS program reduced the body weight, but not the locomotor activity of the rats. Adult SD rats consumed less sucrose solution under CMS. However, chronic escitalopram regime (10 mg/kg/day for 4 weeks) appeared not helpful in reversing this CMS effect and, if any, the drug exaggerated anxiety profile of the animals. Unexpectedly, the stressed rats exhibited higher sucrose consumption than non-stressed rats after receiving repeated saline injections. Further, the stressed rats were found to have a higher plasma level of corticosterone after escitalopram treatment. Our results provide an example of the possibility that previously stressed individuals may develop an anti-depression ability that lessens the benefits of intervention with antidepressants. Finally, a separate group of rats that entered the CMS program at 10 week-old were used to examine possible effects of aging to interpret the stress coping ability observed in the 18 week-old rats. The younger rats developed less anti-anhedonia effects under repeated saline injections. The data of the present study provide a different perspective on stress-induced depression and possible interaction with antidepressants.

Amyloid ß peptide-mediated neurotoxicity is attenuated by the proliferating microglia more potently than by the quiescent phenotype.

BACKGROUND: The specific role of microglia on Aß-mediated neurotoxicity is difficult to assign in vivo due to their complicated environment in the brain. Therefore, most of the current microglia-related studies employed the isolated microglia. However, the previous in vitro studies have suggested either beneficial or destructive function in microglia. Therefore, to investigate the phenotypes of the isolated microglia which exert activity of neuroprotective or destructive is required. RESULTS: The present study investigates the phenotypes of isolated microglia on protecting neuron against Aß-mediated neurotoxicity. Primary microglia were isolated from the mixed glia culture, and were further cultured to distinct phenotypes, designated as proliferating amoeboid microglia (PAM) and differentiated process-bearing microglia (DPM). Their inflammatory phenotypes, response to amyloid ß (Aß), and the beneficial or destructive effects on neurons were investigated. DPM may induce both direct neurotoxicity without exogenous stimulation and indirect neurotoxicity after Aß activation. On the other hand, PAM attenuates Aß-mediated neurotoxicity through Aß phagocytosis and/or Aß degradation. CONCLUSIONS: Our results suggest that the proliferating microglia, but not the differentiated microglia, protect neurons against Aß-mediated neurotoxicity. This discovery may be helpful on the therapeutic investigation of Alzheimer's disease.

Blimp-1 Contributes to the Development and Function of Regulatory B Cells.

Regulatory B cells (Bregs) are a B cell subset that plays a suppressive role in immune responses. The CD19+CD1dhiCD5+ Bregs that can execute regulatory functions via secreting IL-10 are defined as B10 cells. Bregs suppress autoimmune and inflammatory diseases, whereas they exacerbate infectious diseases caused by bacteria, viruses, or parasites. Notably, the molecular mechanisms regulating the development and functions of Bregs are still largely unknown. Furthermore, the biological impact of Bregs in fungal infection has not yet been demonstrated. Here, we compared the gene expression profiles of IL-10-producing and -non-producing mouse splenic B cells stimulated with lipopolysaccharide (LPS) or anti-CD40 antibody. Blimp-1, a transcription factor known to be critical for plasma cell differentiation, was found to be enriched in the IL-10-producing B cells. The frequency of Blimp-1+ B10 cells was increased in LPS-treated mice and in isolated B10 cells that were stimulated with LPS. Surprisingly, B cell-specific Blimp-1 knockout (Cko) mice, generated by CD19 promoter driven Cre recombinase-dependent deletion of Prdm1 (gene encoding Blimp-1), showed higher frequencies of B10 cells both in the steady state and following injection with LPS, as compared with control littermates. However, B10 cells lacking Blimp-1 failed to efficiently suppress the proliferation of naïve CD4+ T cells primed with anti-CD3 and anti-CD28 antibodies. B10 cells can be stimulated for further differentiation into plasmablasts, and a subset of plasmablasts express IL-10. We found that B10 cells from Cko mice failed to generate both IL-10-non-producing and IL-10-producing plasmablasts. Mechanistically, we found that Blimp-1 can directly suppress Il-10, whereas, in the presence of activated STAT3, Blimp-1 works together with activated STAT3 to upregulate Il-10. Moreover, we also found that B10 cells improve the clearance of Candida albicans infection but worsen the infection mortality. Notably, a lack of Blimp-1 in B10 cells did not change these effects of adoptively transferred B10 cells on fungal infections. Together, our data show that Blimp-1 regulates the generation, differentiation, and IL-10 production of Bregs.

Tournefolic acid B attenuates amyloid beta protein-mediated toxicity by abrogating the calcium overload in mitochondria and retarding the caspase 8-truncated Bid-cytochrome c pathway in rat cortical neurons.

The effect of tournefolic acid B (TAB) on amyloid beta protein-mediated neurotoxicity and the underlying mechanisms were investigated. Amyloid beta protein 25-35 elicited neuronal death as determined by calcein/ethidium homodimer-1 staining. 10 microM amyloid beta protein 25-35 caused cell death at a level of 41.5+/-3.8% by MTT reduction. 50 microM TAB attenuated the amyloid beta protein 25-35-induced cell death by 49.7+/-11.1%. TAB also abrogated amyloid beta protein-induced activation of caspases 8 and 9 by about 50-60%. Furthermore, TAB significantly diminished the amyloid beta protein 25-35-induced elevation of calcium level in mitochondria, whereas it did not affect the calcium level in cytosol or endoplasmic reticulum. TAB markedly retarded the amyloid beta protein-mediated release of cytochrome c from mitochondria. Amyloid beta protein 25-35 elevated mitochondrial truncated BH3 interacting domain death agonist (tBid) and decreased the level of B-cell leukemia/lymphoma-2alpha (Bcl-2alpha) in mitochondria. Moreover, amyloid beta protein induced a slight up-regulation of Bcl-2 agonist killer 1 (Bak) in cytosol. 50 microM TAB decreased the amyloid beta protein-induced elevation of mitochondrial tBid and the level of Bak, whereas it did not affect the amyloid beta protein-mediated decrease in mitochondrial Bcl-2alpha. Caspase 8 inhibitor significantly inhibited the amyloid beta protein-mediated increase in mitochondrial tBid and the release of cytochrome c. Therefore, TAB blocked the overload of calcium in mitochondria and impaired the amyloid beta protein-mediated activation of the caspase 8-tBid-cytochrome c pathway, thereby conferring its neuroprotective effects on amyloid beta protein-mediated neurotoxicity.

O-GlcNAcylation is required for B cell homeostasis and antibody responses.

O-linked N-acetylglucosamine (O-GlcNAc) transferase (Ogt) catalyzes O-GlcNAc modification. O-GlcNAcylation is increased after cross-linking of the B-cell receptor (BCR), but the physiological function of this reaction is unknown. Here we show that lack of Ogt in B-cell development not only causes severe defects in the activation of BCR signaling, but also perturbs B-cell homeostasis by enhancing apoptosis of mature B cells, partly as a result of impaired response to B-cell activating factor. O-GlcNAcylation of Lyn at serine 19 is crucial for efficient Lyn activation and Syk interaction in BCR-mediated B-cell activation and expansion. Ogt deficiency in germinal center (GC) B cells also results in enhanced apoptosis of GC B cells and memory B cells in an immune response, consequently causing a reduction of antibody levels. Together, these results demonstrate that B cells rely on O-GlcNAcylation to maintain homeostasis, transduce BCR-mediated activation signals and activate humoral immunity.

7,8-Dihydroxyflavone, a Tropomyosin-Kinase Related Receptor B Agonist, Produces Fast-Onset Antidepressant-Like Effects in Rats Exposed to Chronic Mild Stress.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) and its specific receptor, tropomyosin-related kinase (TrkB), play important roles in treating depression. In this experiment, we examined whether 7,8-dihydroxyflavone, a novel potent TrkB agonist, could reverse the behavioral and biochemical abnormalities induced by the chronic mild stress (CMS) paradigm in rats. METHODS: SD rats were exposed to a battery of stressors for 56 days. 7,8-dihydroxyflavone (5 and 20 mg/kg) were administered intraperitoneally during the last 28 days of the CMS paradigm. Rats were tested in sucrose consumption test (SCT), forced-swimming test (FST) and elevated T-maze (ETM). Serum corticosterone levels and hippocampal BDNF levels of the rats were measured. RESULTS: Four-week CMS on the rats induced their depression-like behavior in SCT. The CMS-reduced sucrose consumption was reversed starting from 7 days after the 7,8-dihydroxyflavone (20 mg/kg) treatment and remained across the subsequent treatment regime. 7,8-dihydroxyflavone, when given at 5 mg/kg for 3 weeks, reduced the immobility time in the FST in the CMS-subjected rats. Additionally, the 4-week treatment with 7,8-dihydroxyflavone (20 mg/kg) attenuated the CMS-induced increase in anxiety-like behavior in the ETM. For the CMS-subjected rats, 7,8-dihydroxyflavone treatment dose-dependently reduced their serum corticosterone levels but increased their hippocampal BDNF levels only at 5 mg/kg. CONCLUSION: 7,8-dihydroxyflavone was beneficial for both depression and anxiety-like behaviors, and may exert fast-onset antidepressant effects. This provides a new insight into the pharmacological management of depression.

Effect of Alzheimer's Disease Risk Variant rs3824968 at SORL1 on Regional Gray Matter Volume and Age-Related Interaction in Adult Lifespan.

Sortilin receptor 1 (SORL1) is involved in cellular trafficking of amyloid precursor protein and plays an essential role in amyloid-beta peptide generation in Alzheimer disease (AD). The major A allele in a SORL1 single nucleotide polymorphism (SNP), rs3824968, is associated with an increased AD risk. However, the role of SORL1 rs3824968 in the normal ageing process has rarely been examined in relation to brain structural morphology. This study investigated the association between SORL1 rs3824968 and grey matter (GM) volume in a nondemented Chinese population of 318 adults within a wide age range (21-92 years). Through voxel-based morphometry, we found that participants carrying SORL1 allele A exhibited significantly smaller GM volumes in the right posterior cingulate, left middle occipital, medial frontal, and superior temporal gyri. Considerable interaction between age and SORL1 suggested a detrimental and accelerated ageing effect of allele A on putamen. These findings provide evidence that SORL1 rs3824968 modulates regional GM volume and is associated with brain trajectory during the adult lifespan.

Functional Connectivity Density Mapping of Depressive Symptoms and Loneliness in Non-Demented Elderly Male.

BACKGROUND: Depression and loneliness are prevalent and highly correlated phenomena among the elderly and influence both physical and mental health. Brain functional connectivity changes associated with depressive symptoms and loneliness are not fully understood. METHODS: A cross-sectional functional MRI study was conducted among 85 non-demented male elders. Geriatric depression scale-short form (GDS) and loneliness scale were used to evaluate the severity of depressive symptoms and loneliness, respectively. Whole brain voxel-wise resting-state functional connectivity density (FCD) mapping was performed to delineate short-range FCD (SFCD) and long-range FCD (LFCD). Regional correlations between depressive symptoms or loneliness and SFCD or LFCD were examined using general linear model (GLM), with age incorporated as a covariate and depressive symptoms and loneliness as predictors. RESULTS: Positive correlations between depressive symptoms and LFCD were observed in left rectal gyrus, left superior frontal gyrus, right supraorbital gyrus, and left inferior temporal gyrus. Positive correlations between depressive symptoms and SFCD were observed in left middle frontal gyrus, left superior frontal gyrus, bilateral superior medial frontal gyrus, left inferior temporal gyrus, and left middle occipital region. Positive correlations between SFCD and loneliness were centered over bilateral lingual gyrus. CONCLUSION: Depressive symptoms are associated with FCD changes over frontal and temporal regions, which may involve the cognitive control, affective regulation, and default mode networks. Loneliness is associated with FCD changes in bilateral lingual gyri that are known to be important in social cognition. Depressive symptoms and loneliness may be associated with different brain regions in non-demented elderly male.