Suppression of adult cytogenesis in the rat brain leads to sex-differentiated disruption of the HPA axis activity.

OBJECTIVES: The action of stress hormones, mainly glucocorticoids, starts and coordinates the systemic response to stressful events. The HPA axis activity is predicated on information processing and modulation by upstream centres, such as the hippocampus where adult-born neurons (hABN) have been reported to be an important component in the processing and integration of new information. Still, it remains unclear whether and how hABN regulates HPA axis activity and CORT production, particularly when considering sex differences. MATERIALS AND METHODS: Using both sexes of a transgenic rat model of cytogenesis ablation (GFAP-Tk rat model), we examined the endocrinological and behavioural effects of disrupting the generation of new astrocytes and neurons within the hippocampal dentate gyrus (DG). RESULTS: Our results show that GFAP-Tk male rats present a heightened acute stress response. In contrast, GFAP-Tk female rats have increased corticosterone secretion at nadir, a heightened, yet delayed, response to an acute stress stimulus, accompanied by neuronal hypertrophy in the basal lateral amygdala and increased expression of the glucocorticoid receptors in the ventral DG. CONCLUSIONS: Our results reveal that hABN regulation of the HPA axis response is sex-differentiated.

Cell Cycle Regulation of Hippocampal Progenitor Cells in Experimental Models of Depression and after Treatment with Fluoxetine.

Changes in adult hippocampal cell proliferation and genesis have been largely implicated in depression and antidepressant action, though surprisingly, the underlying cell cycle mechanisms are largely undisclosed. Using both an in vivo unpredictable chronic mild stress (uCMS) rat model of depression and in vitro rat hippocampal-derived neurosphere culture approaches, we aimed to unravel the cell cycle mechanisms regulating hippocampal cell proliferation and genesis in depression and after antidepressant treatment. We show that the hippocampal dentate gyrus (hDG) of uCMS animals have less proliferating cells and a decreased proportion of cells in the G2/M phase, suggesting a G1 phase arrest; this is accompanied by decreased levels of cyclin D1, E, and A expression. Chronic fluoxetine treatment reversed the G1 phase arrest and promoted an up-regulation of cyclin E. In vitro, dexamethasone (DEX) decreased cell proliferation, whereas the administration of serotonin (5-HT) reversed it. DEX also induced a G1-phase arrest and decreased cyclin D1 and D2 expression levels while increasing p27. Additionally, 5-HT treatment could partly reverse the G1-phase arrest and restored cyclin D1 expression. We suggest that the anti-proliferative actions of chronic stress in the hDG result from a glucocorticoid-mediated G1-phase arrest in the progenitor cells that is partly mediated by decreased cyclin D1 expression which may be overcome by antidepressant treatment.

The Association of Metabolic Dysfunction and Mood Across Lifespan Interacts With the Default Mode Network Functional Connectivity.

Background: Numerous studies suggest a relationship between depression and metabolic syndrome, which is likely influenced by age. Interestingly, functional imaging analysis has shown an association between functional connectivity in the default mode network (DMN-FC) and components of metabolic syndrome, which is explored in this study. Methods: From a larger longitudinal cohort study on healthy aging, 943 individuals were extensively characterized for mood and cognition. Among these, 120 individuals who were selected for displaying extreme cognitive performance within the normal range (good and poor performers) were further studied. Here, in a cross-sectional design, using confirmatory factor analysis (CFA), the association between metabolic dysfunction and depressive mood as a function of age and its relationship with DMN-FC was studied. Results: Metabolic dysfunction was modeled as a second-order latent variable using CFA. First-order latent variables were obesity, glucose dysmetabolism, lipids imbalance, and blood pressure. Using multiple linear regression models, this study observed that metabolic dysfunction, glucose dysmetabolism, and lipids imbalance were linearly associated with depressive mood, and the association with obesity was U-shaped. The association of metabolic dysfunction, obesity, and glucose dysmetabolism with depressive mood is positive for the younger individuals in our sample and vanishes with aging. The FC of the right superior temporal gyrus with the DMN correlated with both obesity and depressive mood. In participants with higher obesity scores, FC increased with higher GDS scores, while in those with lower GDS scores, FC decreased. Age and blood pressure were associated with a more complex pattern of association between FC of the right supramarginal gyrus and GDS score. Conclusion: The association of metabolic dysfunction with depressive mood is influenced by age and relates with differential patterns of DMN-FC. The combination of the effects of age, mood, and metabolic dysfunction is likely to explain the heterogeneity of DMN-FC, which deserves further investigation with larger and longitudinal studies.

miR-409 and miR-411 Modulation in the Adult Brain of a Rat Model of Depression and After Fluoxetine Treatment.

Depression is a chronic debilitating disorder predicted to affect around 20% of the world population. Both brain and peripheral changes, including neuroplastic changes have been shown to occur in the brains of depressed individuals and animal models of depression. Over the past few decades, growing evidence has supported the role of miRNAs as regulators of critical aspects of brain plasticity and function, namely in the context of depression. These molecules are not only highly expressed in the brain, but are also relatively stable in bodily fluids, including blood. Previous microarray analysis from our group has disclosed molecular players in the hippocampal dentate gyrus (DG), in the context of depression and antidepressant treatment. Two miRNAs in particular-miR-409-5p and miR-411-5p-were significantly up-regulated in the DG of an unpredictable chronic mild stress (CMS) rat model of depression and reversed by antidepressant treatment. Here, we further analyzed the levels of these miRNAs along the DG longitudinal axis and in other brain regions involved in the pathophysiology of depression, as well as in peripheral blood of CMS-exposed rats and after fluoxetine treatment. The effects of CMS and fluoxetine treatment on miR-409-5p and miR-411-5p levels varied across brain regions, and miR-411-5p was significantly decreased in the blood of fluoxetine-treated rats. Additional bioinformatic analyses revealed target genes and pathways of these miRNAs related to neurotransmitter signaling and neuroplasticity functions; an implication of the two miRNAs in the regulation of the cellular and molecular changes observed in these brain regions in depression is worth further examination.

The moderator effect of age in the association between mood and adiposity in the elderly is specific for the subcutaneous adipose compartment: An MRI study.

The positive association between obesity and depressive mood in young- and middle-age individuals is a phenomenon with major clinical implications in public health. Interestingly, the trend of this association in older individuals is not clear, given the conflicting results of multiple studies. Since aging is accompanied by changes in body fat distribution, we questioned whether age is a modulator of such association. This study explores the role of age in the association between mood and general (body mass index [BMI]) and abdominal adiposity (waist circumference [WC]) in older adults characterizing the different abdominal adipose tissue compartments (subcutaneous adipose tissue [SAT] and visceral adipose tissue [VAT]) with magnetic resonance imaging (MRI) techniques. METHODS: One hundred twenty aged community-dwelling individuals (≥50 y of age) were assessed regarding depressive mood (Geriatric Depression Scale) and adiposity (BMI and WC). From these, 96 were assessed for SAT and VAT using MRI. RESULTS: Using multiple linear regression models, depressive mood was positively associated with BMI, WC, and VAT. Age was a significant moderator of the association between depressive mood and BMI, WC, and SAT: positive in younger participants and null or negative in older participants. On the other hand, higher VAT was significantly associated with a more depressive mood, independently of age. CONCLUSIONS: This study identifies age as a relevant moderator in the association between depressive mood and adiposity in the elderlies. Furthermore, the body fat compartment analysis revealed that the effect of age is specific for the SAT, suggesting its protective role in depressive mood.

Immuno-Golgi as a tool for analyzing neuronal 3D-dendritic structure in phenotypically characterized neurons.

Characterization of neuronal dendritic structure in combination with the determination of specific neuronal phenotype or temporal generation is a challenging task. Here we present a novel method that combines bromodioxyuridine (BrdU) immunohistochemistry with Golgi-impregnation technique; with this simple non-invasive method, we are able to determine the tridimensional structure of dendritic arborization and spine shape of neurons born at a specific time in the hippocampus of adult animals. This analysis is relevant in physiological and pathological conditions in which altered neurogenesis is implicated, such as aging or emotional disorders.