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

Effet des acides gras polyinsatures de la serie n-3 sur la plasticité astrocytaire (rôle dans le fonctionnement de l'horloge circadienne (Etude in vitro et in vivo))

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Omega-3 polyunsaturated fatty acids and chronic stress-induced modulations of glutamatergic neurotransmission in the hippocampus

International audienceChronic stress causes the release of glucocorticoids, which greatly influence cerebral function, especially glutamatergic transmission. These stress-induced changes in neurotransmission could be counteracted by increasing the dietary intake of omega-3 polyunsaturated fatty acids (n-3 PUFAs). Numerous studies have described the capacity of n-3 PUFAs to help protect glutamatergic neurotransmission from damage induced by stress and glucocorticoids, possibly preventing the development of stress-related disorders such as depression or anxiety. The hippocampus contains glucocorticoid receptors and is involved in learning and memory. This makes it particularly sensitive to stress, which alters certain aspects of hippocampal function. In this review, the various ways in which n-3 PUFAs may prevent the harmful effects of chronic stress, particularly the alteration of glutamatergic synapses in the hippocampus, are summarized

Docosahexaenoic acid (DHA) prevents corticosterone-induced changes in astrocyte morphology and function

The many functions of astrocytes, such as glutamate recycling and morphological plasticity, enable them to stabilize synapses environment and protect neurons. Little is known about how they adapt to glucocorticoid-induced stress, and even less about the influence of dietary factors. We previously showed that omega-3 polyunsaturated fatty acids (3PUFA), dietary fats which alleviate stress responses, influence the way astroglia regulate glutamatergic synapses. We have explored the role of docosahexaenoic acid (DHA), the main 3PUFA, in the astroglial responses to corticosterone, the main stress hormone in rodents to determine whether 3PUFA help astrocytes resist stress. Cultured rat astrocytes were enriched in DHA or arachidonic acid (AA, the main 6PUFA) and given 100nM corticosterone for several days. Corticosterone stimulated astrocyte glutamate recycling by increasing glutamate uptake and glutamine synthetase (GS), and altered the astrocyte cytoskeleton. DHA-enriched astrocytes no longer responded to the action of corticosterone on glutamate uptake, had decreased GS, and the cytoskeletal effect of corticosterone was delayed, while AA-enriched cells were unaffected. The DHA-dependent anti-corticosterone effect was related to fewer glucocorticoid receptors, while corticosterone increased DHA incorporation into astrocyte membranes. Thus, DHA helps astrocytes resist the influence of corticosterone, so perhaps promoting a sustainable response by the stressed brain.Acides Gras Poly-Insaturés n-3 et prévention des dommages cérébraux liés au stress et au vieillissement : effets sur la synapse glutamatergique de l'hippocamp

Influence des AGPI n-3 sur l’évolution du phénotype astrocytaire au cours du vieillissement : étude in vivo chez le rat et in vitro sur des cultures d’astrocytes

National audienc

Inhibition of astroglial glutamate transport by polyunsaturated fatty acids: evidence for a signalling role of docosahexaenoic acid

International audienceBrain cells are especially rich in polyunsaturated fatty acids (PUFA), mainly the n-3 PUFA docosahexaenoic acid (DHA) and the n-6 PUFA arachidonic acid (AA). They are released from membranes by PLA2 during neurotransmission, and may regulate glutamate uptake by astroglia, involved in controlling glutamatergic transmission. AA has been shown to inhibit glutamate transport in several model systems, but the contribution of DHA is less clear and has not been evaluated in astrocytes. Because the high DHA content of brain membranes is essential for brain function, we investigated the role of DHA in the regulation of astroglial glutamate transport. We evaluated the actions of DHA and AA using cultured rat astrocytes and suspensions of rat brain membranes (P1 fractions). DHA reduced D-[(3)H]aspartate uptake by cultured astrocytes and cortical membrane suspensions, while AA did not. This also occurred in astrocytes enriched with alpha-tocopherol, indicating that it was not due to peroxidation products. The reduction of d-[(3)H]aspartate uptake by DHA did not involve any change in the concentrations of membrane-associated astroglial glutamate transporters (GLAST and GLT-1), suggesting that DHA reduced the activity of the transporters. In contrast with the inhibition induced by free-DHA, we found no effect of membrane-bound DHA on D-[(3)H]aspartate uptake. Indeed, the uptake was similar in astrocytes with varying amount of DHA in their membrane (induced by long-term supplementation with DHA or AA). Therefore, DHA reduces glutamate uptake through a signal-like effect but not through changes in the PUFA composition of the astrocyte membranes. Also, reactive astrocytes, induced by a medium supplement (G5), were insensitive to DHA. This suggests that DHA regulates synaptic glutamate under basal condition but does not impair glutamate scavenging under reactive conditions. These results indicate that DHA slows astroglial glutamate transport via a specific signal-like effect, and may thus be a physiological synaptic regulator

Le DHA dans la neurotransmission

Long chain polyunsaturated fatty acids (PUFAs), particularly arachidonic acid and docosahexaenoic acid (DHA), are integral components of neural membrane phospholipids. DHA deficiency is associated with behavioural and neurophysiological disorders. A deficiency of DHA markedly affects neurotransmission, membrane-bound proteins, ion channel activities and synaptic plasticity, and the supplementation restores neurotransmission. Although the molecular mechanism of DHA involvement remains unknown, more and more data demonstrate its implication in various cellular activities contributing to regulation of neurotransmission. Since recent studies have provided evidence that n-3 deficiency altered neurogenesis in embryonic brain, the question of lasting effects on neural function can be addressed