SEX-DEPENDENT IMPACT OF MICROBIOTA STATUS ON CEREBRAL μ -OPIOID RECEPTOR DENSITY IN FISCHER RATS.

μ-opioid receptors (MOPr) play a critical role in social play, reward, and pain, in a sex and age-dependent manner. There is evidence to suggest that sex and age differences in brain MOPr density may be responsible for this variability, however, little is known about the factors driving these differences in cerebral MOPr density. Emerging evidence highlights gut microbiota's critical influence and its bidirectional interaction with the brain on neurodevelopment. Therefore, we aimed to determine the impact of gut microbiota on MOPr density in male and female brains at different developmental stages. Quantitative [3 H]DAMGO autoradiographic binding was carried out in the forebrain of male and female conventional (CON), and germ-free (GF) rats at postnatal days (PND) 8, 22, and 116-150. Significant 'microbiota status x sex,' 'age x brain region' interactions, and microbiota status- and age-dependent effects on MOPr binding were uncovered. Microbiota status influenced MOPr levels in males but not females, with higher MOPr levels observed in GF vs. CON rats overall regions and age groups. In contrast, no overall sex differences were observed in GF or CON rats. Interestingly, within-age planned comparison analysis conducted in frontal cortical and brain regions associated with reward revealed that this microbiota effect was restricted only to PND22 rats. Thus, this pilot study uncovers the critical sex-dependent role of gut microbiota in regulating cerebral MOPr density, which is restricted to the sensitive developmental period of weaning. This may have implications in understanding the importance of microbiota during early development on opioid signalling and associated behaviours

FABP7 expression in normal and stab-injured brain cortex and its role in astrocyte proliferation

Reactive gliosis, in which astrocytes as well as other types of glial cells undergo massive proliferation, is a common hallmark of all brain pathologies. Brain-type fatty acid-binding protein (FABP7) is abundantly expressed in neural stem cells and astrocytes of developing brain, suggesting its role in differentiation and/or proliferation of glial cells through regulation of lipid metabolism and/or signaling. However, the role of FABP7 in proliferation of glial cells during reactive gliosis is unknown. In this study, we examined the expression of FABP7 in mouse cortical stab injury model and also the phenotype of FABP7-KO mice in glial cell proliferation. Western blotting showed that FABP7 expression was increased significantly in the injured cortex compared with the contralateral side. By immunohistochemistry, FABP7 was localized to GFAP+ astrocytes (21% of FABP7+ cells) and NG2+ oligodendrocyte progenitor cells (62%) in the normal cortex. In the injured cortex there was no change in the population of FABP7+/NG2+ cells, while there was a significant increase in FABP7+/GFAP+ cells. In the stab-injured cortex of FABP7-KO mice there was decrease in the total number of reactive astrocytes and in the number of BrdU+ astrocytes compared with wild-type mice. Primary cultured astrocytes from FABP7-KO mice also showed a significant decrease in proliferation and omega-3 fatty acid incorporation compared with wild-type astrocytes. Overall, these data suggest that FABP7 is involved in the proliferation of astrocytes by controlling cellular fatty acid homeostasis

Glial plasticity in the dorsal vagal complex in response to western diet in rodents

International audienceGrowing evidence indicates that glial plasticity plays a role in feeding control, by adapting neuronal transmission to metabolic needs. Astroglial morphological changes and microglial activation occurs in response to feeding, in the hypothalamus and in other brain area involved in feeding regulation such as the olfactory bulb. Glial plasticity seems to evolve to glial activation in response to high-fat-high-sugar western diets (WD) consumption generating pro-inflammatory/obesogenic states. There is an abundant glial population in the dorsal vagal complex (DVC), a brainstem area involved in the integration of digestive signals. A thick border of astrocytes delineates the area postrema (AP), a circumventricular organ with permeable blood barrier, from the nucleus of the tractus solitarius (NTS) homing neuronal species involved in satiety, and astrocytes. Microglia are also abundant in the AP and NTS, where pro-inflammatory signals may arrive from the gut in response to dietary load and digestion. However, little isknown about the involvement of these glial populations in the satietogenic signals from the DVC.Our aim was to evaluate astrocytes and microglial changes in response to chronic or repeated episodes of western diet in the DVC of rats or mice.We have analysed the extent of the astrocyte spreading and the number and morphological phenotype of microglia in the AP and NTS by immunohistochemistry, on two rodent models: rats submitted to a high-fat/high-sugar diet (WD), and mice submitted to several 1-week-episodes of WD. Brainstems were taken after killing, fixed in formalin, and cryostat-cut coronal sections were labelled and analysed for astrocytes (GFAP) and microglia (Iba1). We found an increase in the astrocyte spreading (GFAP labelled area and thickness) between the AP and the NTS (but not in the astrocytes within the NTS) after one month of WD in rats as well as in mice after the repeated episodes of WD, as compared to control animals. We did not observe any increase in the microglial number or morphology within the AP in WD fed animals whereas we found an increased number of microglial cells in the NTS of WD fed rats as compared to controls. These glial changes were associated with several digestive markers alteration.These results show morphological changes enlarging the astroglial barrier between the AP and NTS in the DVC of rodents receiving a western diet. This was observed after a chronic exposition in rats or repeated expositions in mice, suggesting a persistence of the influence of the diet on the size of the astroglial barrier. Such an astroglial morphological plasticity in the DVC, between the AP and the NTS, may play a role in the adaptation of the satietogenic activity of the neurons to the type of diet

Effect of dietary n-3 polyunsaturated fatty acids on brain lipid fatty acid composition, learning ability, and memory of senescence-accelerated mouse

Animal studies have shown that a deficiency in brain of the n-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) is associated with memory loss and diminished cognitive function. The senescence-accelerated prone 8 (SAMP8) mouse develops impairments in learning and memory at 8–12 months of age. The effect of diet supplemented with n-3 PUFA on brain phospholipid DHA status, learning, and memory ability in aged SAMP8 mice was investigated. At the age of 10 months, SAMP8 mice were fed either a low-DHA or a high-DHA diet for 8 weeks. In comparison to SAMP8 mice fed the low-DHA diet, those fed a high-DHA diet had improved acquisition and retention in a T-maze foot shock avoidance test and a higher proportion of DHA in hippocampal and amygdala phospholipids. This study demonstrates that, in mature animals, DHA is incorporated into brain phospholipids and that dietary n-3 PUFA is associated with delay in cognitive decline.Anna L. Petursdottir, Susan A. Farr, John E. Morley, William A. Banks and Gudrun V. Skuladotti

The involvement of astrocytes in early-life adversity induced programming of the brain

Early-life adversity (ELA) in the form of stress, inflammation, or malnutrition, can increase the risk of developing psychopathology or cognitive problems in adulthood. The neurobiological substrates underlying this process remain unclear. While neuronal dysfunction and microglial contribution have been studied in this context, only recently the role of astrocytes in early-life programming of the brain has been appreciated. Astrocytes serve many basic roles for brain functioning (e.g., synaptogenesis, glutamate recycling), and are unique in their capacity of sensing and integrating environmental signals, as they are the first cells to encounter signals from the blood, including hormonal changes (e.g., glucocorticoids), immune signals, and nutritional information. Integration of these signals is especially important during early development, and therefore we propose that astrocytes contribute to ELA induced changes in the brain by sensing and integrating environmental signals and by modulating neuronal development and function. Studies in rodents have already shown that ELA can impact astrocytes on the short and long term, however, a critical review of these results is currently lacking. Here, we will discuss the developmental trajectory of astrocytes, their ability to integrate stress, immune, and nutritional signals from the early environment, and we will review how different types of early adversity impact astrocytes