Early-Life Stress Reprograms Stress-Coping Abilities in Male and Female Juvenile Rats.

Prenatal stress (PS) is a major risk factor for the development of emotional disorders in adulthood that may be mediated by an altered hypothalamic-pituitary-adrenal axis response to stress. Although the early onset of stress-related disorders is recognized as a major public health problem, to date, there are relatively few studies that have examined the incidence of early-life stressors in younger individuals. In this study, we assessed PS impact on the stress-coping response of juvenile offspring in behavioral tests and in the induced molecular changes in the hippocampus. Furthermore, we assessed if pregnancy stress could be driving changes in patterns of maternal behavior during early lactation. We found that PS modified stress-coping abilities of both sex offspring. In the hippocampus, PS increased the expression of bdnf-IV and crfr1 and induced sex difference changes on glucocorticoids and BDNF mRNA receptor levels. PS changed the hippocampal epigenetic landscape mainly in male offspring. Stress during pregnancy enhanced pup-directed behavior of stressed dams. Our study indicates that exposure to PS, in addition to enhanced maternal behavior, induces dynamic neurobehavioral variations at juvenile ages of the offspring that should be considered adaptive or maladaptive, depending on the characteristics of the confronting environment. Our present results highlight the importance to further explore risk factors that appear early in life that will be important to allow timely prevention strategies to later vulnerability to stress-related disorders.

The inflammatory response induced by Pseudomonas aeruginosa in macrophages enhances apoptotic cell removal.

Pathogens phagocytosis and the uptake of apoptotic cells (efferocytosis) are essential macrophages tasks, classically considered as mutually exclusive. Macrophages have been observed to polarize into either pro-inflammatory/microbicidal or anti-inflammatory/efferocytic phenotypes. However, macrophage functions have shown to be more complex. Furthermore, little is known about the regulation of efferocytosis under inflammatory conditions. In this study, we elucidate the modulation of the macrophage efferocytic function during an inflammatory stimulus. We find that bone marrow-derived macrophages (BMDM) are very efficient in engulfing both the bacterial pathogen Pseudomonas aeruginosa and apoptotic cells. BMDM showed a high bactericidal capacity unaffected by the concomitant presence of apoptotic material. Plasticity in macrophage programming, in response to changing environmental cues, may modulate efferocytic capability. In this work, we further show that, after phagocyting and processing Pseudomonas aeruginosa, macrophages highly increase their efferocytic capacity without affecting their phagocytic function. Moreover, we demonstrate that Pseudomonas aeruginosa enhances efferocytosis of these phagocytes through the IL-6 signaling pathway. Our results show that the inflammatory response generated by the bacterial processing enhances these macrophages' capacity to control inflammation through an increased efferocytosis.

Age-dependent effects of prenatal stress on the corticolimbic dopaminergic system development in the rat male offspring.

We have previously demonstrated that prenatal stress (PS) exerts an impairment of midbrain dopaminergic (DA) system metabolism especially after puberty, suggesting a particular sensitivity of DA development to variations in gonadal hormonal peaks. Furthermore we demonstrated that PS alters the long term androgens profile of the rat male offspring from prepubertal to adult stages. In this work we evaluated the sexual hormones activational effects on the DA system by analysing PS effects on the dopaminergic D2-like (D2R) and on the gonadal hormones receptor levels on cortical and hippocampal areas of prepubertal and adult male offspring. We further evaluated the dendritic arborization in the same areas by quantifying MAP2 immunoexpresion. Our results show that PS affected oestrogen receptor alpha (ERα) expression: mRNA er1s and ERα protein levels were decreased on prefrontal cortex and hippocampus of adult offspring. Moreover, PS reduced D2R protein levels in hippocampus of prepubertal rats. Morphological studies revealed that prepubertal PS rats presented decreased MAP2 immunoexpression in both areas suggesting that PS reduces the number of dendritic arborizations. Our findings suggest that PS exerts long-term effects on the DA system by altering the normal connectivity in the areas, and by modulating the expression of D2R and ERα in an age-related pattern. Since the developing forebrain DA system was shown to be influenced by androgen exposure, and PS was shown to disrupt perinatal testosterone surges, our results suggest that prenatal insults might be affecting the organizational role of androgens and differentially modulating their activational role on the DA development.

A role for the membrane protein M6 in the Drosophila visual system.

BACKGROUND: Members of the proteolipid protein family, including the four-transmembrane glycoprotein M6a, are involved in neuronal plasticity in mammals. Results from our group previously demonstrated that M6, the only proteolipid protein expressed in Drosophila, localizes to the cell membrane in follicle cells. M6 loss triggers female sterility, which suggests a role for M6 in follicular cell remodeling. These results were the basis of the present study, which focused on the function and requirements of M6 in the fly nervous system. RESULTS: The present study identified two novel, tissue-regulated M6 isoforms with variable N- and C- termini, and showed that M6 is the functional fly ortholog of Gpm6a. In the adult brain, the protein was localized to several neuropils, such as the optic lobe, the central complex, and the mushroom bodies. Interestingly, although reduced M6 levels triggered a mild rough-eye phenotype, hypomorphic M6 mutants exhibited a defective response to light. CONCLUSIONS: Based on its ability to induce filopodium formation we propose that M6 is key in cell remodeling processes underlying visual system function. These results bring further insight into the role of M6/M6a in biological processes involving neuronal plasticity and behavior in flies and mammals.

M6 membrane protein plays an essential role in Drosophila oogenesis.

We had previously shown that the transmembrane glycoprotein M6a, a member of the proteolipid protein (PLP) family, regulates neurite/filopodium outgrowth, hence, M6a might be involved in neuronal remodeling and differentiation. In this work we focused on M6, the only PLP family member present in Drosophila, and ortholog to M6a. Unexpectedly, we found that decreased expression of M6 leads to female sterility. M6 is expressed in the membrane of the follicular epithelium in ovarioles throughout oogenesis. Phenotypes triggered by M6 downregulation in hypomorphic mutants included egg collapse and egg permeability, thus suggesting M6 involvement in eggshell biosynthesis. In addition, RNAi-mediated M6 knockdown targeted specifically to follicle cells induced an arrest of egg chamber development, revealing that M6 is essential in oogenesis. Interestingly, M6-associated phenotypes evidenced abnormal changes of the follicle cell shape and disrupted follicular epithelium in mid- and late-stage egg chambers. Therefore, we propose that M6 plays a role in follicular epithelium maintenance involving membrane cell remodeling during oogenesis in Drosophila.

Inhibitory effect of fluoxetine on lymphoma growth through the modulation of antitumor T-cell response by serotonin-dependent and independent mechanisms.

Fluoxetine, a selective serotonin reuptake inhibitor, is widely used for the treatment of depressive symptoms of cancer patients. However, there are contradictory evidences about its effects on immunity and cancer. Thus, we studied the effects of fluoxetine on tumor growth and on antitumoral T-cell-mediated immunity. In vivo chronic fluoxetine treatment inhibited tumor growth, and increased latency of appearance of solid tumors and survival of mice. Fluoxetine administration also increased mitogen-induced T-cell proliferation and Tumor Necrosis Factor-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) expression, without altering CD4(+)/CD8(+) ratio. In vitro, fluoxetine did not affect tumor cells proliferation, but it exerted a direct effect on T lymphocytes. Both fluoxetine and serotonin stimulated proliferation induced by a suboptimal mitogen concentration but inhibited proliferation at the optimal one. When both drugs were combined the results indicated that the effects of fluoxetine are in part independent of its ability to elevate serotonin extracellular levels. Finally, continue fluoxetine administration in nude mice - devoid of T lymphocytes - did not modify tumor progression, thus supporting the hypothesis of an immuno-modulatory effect of this drug on T cells that drives tumor growth control. These findings indicate, for the first time, that fluoxetine inhibits tumor growth through modulation of T-cell-mediated immunity by the already known serotonin-dependent pathway and by a novel independent mechanism.