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Introduction/Aim: Children with diabetes may display cognitive alterations although vascular disorders have not yet appeared. Glucose level variations together with relative insulin deficiency in treated type-1 diabetes (T1D) were reported to impact brain function indirectly through dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis. We have recently shown that enhancement of glucocorticoid levels in T1D children is not only dependent on their secretion but also on their tissue concentration, which is linked to 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. HPA axis dysfunction and memory alteration were further dissected in a juvenile rat model of diabetes showing that excess 11β-HSD1 activity within hippocampus is associated with hippocampal-dependent memory deficits. Here, to investigate the causal relationships between diabetes, 11β-HSD1 activity and hippocampus-dependent memory deficits, we evaluated the beneficial effect of 11β-HSD1 inhibition on hippocampal-related memory in juvenile diabetic rats. Furthermore, we examined whether diabetes-associated enhancement of hippocampal 11β-HSD1 activity is due to an increase of brain glucose concentration and/or a decrease in insulin signaling.Methods/Results: Diabetes was induced in juvenile rats by daily intraperitoneal injection of streptozotocin for 2 consecutive days. Inhibition of 11β-HSD1 was obtained by administrating the compound UE2316 twice daily by gavage for 3 weeks before assessing hippocampal-dependent object location memory. Hippocampal 11β-HSD1 activity was estimated by the ratio of corticosterone:dehydrocorticosterone measured by mass spectrometry. Regulation of 11β-HSD1 activity in response to changes in glucose or insulin levels was determined ex vivo on acute brain hippocampal slices. The insulin regulation of 11β-HSD1 was further examined in vivo using virally-mediated knock-down of insulin receptor expression specifically in the hippocampus. Our data show that inhibiting 11β-HSD1 activity prevents the hippocampal-related memory deficits of diabetic juvenile rats. A significant increase (nearly 50%) of hippocampal 11β-HSD1 activity was found in slices incubated in high glucose condition (13.9 mM) versus normal glucose condition (2.8 mM) without insulin. However, 11β-HSD1 activity was not affected by variations in the insulin concentration either using the hippocampal slices or after decrease of hippocampal insulin receptor expression.Conclusions: Together these data demonstrate that increase of 11β-HSD1 activity contributes to memory deficits observed in juvenile diabetic rats and that excess of hippocampal 11β-HSD1 activity stems from high glucose levels rather than insulin deficiency. 11β-HSD1 might be a therapeutic target to treat cognitive impairments associated with diabetes.

Microglia constitute the largest population of parenchymal macrophages in the brain and are considered a unique subset of central nervous system glial cells owing to their extra-embryonic origins in the yolk sac. During development, microglial progenitors readily proliferate and eventually colonize the entire brain. In this Review, we highlight the origins of microglial progenitors and their entry routes into the brain and discuss the various molecular and non-molecular determinants of their fate, which may inform their specific functions. Specifically, we explore recently identified mechanisms that regulate microglial colonization of the brain, including the availability of space, and describe how the expansion of highly proliferative microglial progenitors facilitates the occupation of the microglial niche. Finally, we shed light on the factors involved in establishing microglial identity in the brain.The developmental colonization of the brain by microglial progenitors and establishment of microglial cell identity set the stage for microglial function in the adult. Barry-Carroll and Gomez-Nicola describe the mechanisms that regulate the development of microglia, including their origins, infiltration and colonization of the brain, proliferation and fate determination.

The APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD). Here, we show in mice and humans a negative role of microglial APOE4 in the induction of the MGnD response to neurodegeneration. Deletion of microglial APOE4 restores the MGnD phenotype associated with neuroprotection in P301S tau transgenic mice and decreases pathology in APP/PS1 mice. MGnD–astrocyte cross-talk associated with β-amyloid (Aβ) plaque encapsulation and clearance are mediated via LGALS3 signaling following microglial APOE4 deletion. In the brains of AD donors carrying the APOE4 allele, we found a sex-dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, compared to individuals homozygous for the APOE3 allele. Mechanistically, APOE4-mediated induction of ITGB8–transforming growth factor-β (TGFβ) signaling impairs the MGnD response via upregulation of microglial homeostatic checkpoints, including Inpp5d, in mice. Deletion of Inpp5d in microglia restores MGnD–astrocyte cross-talk and facilitates plaque clearance in APP/PS1 mice. We identify the microglial APOE4–ITGB8–TGFβ pathway as a negative regulator of microglial response to AD pathology, and restoring the MGnD phenotype via blocking ITGB8–TGFβ signaling provides a promising therapeutic intervention for AD.

Microglia play a critical role in brain homeostasis and disease progression. In neurodegenerative conditions, microglia acquire the neurodegenerative phenotype (MGnD), whose function is poorly understood. MicroRNA-155 (miR-155), enriched in immune cells, critically regulates MGnD. However, its role in Alzheimer’s disease (AD) pathogenesis remains unclear. Here, we report that microglial deletion of miR-155 induces a pre-MGnD activation state via interferon-γ (IFN-γ) signaling, and blocking IFN-γ signaling attenuates MGnD induction and microglial phagocytosis. Single-cell RNA-sequencing analysis of microglia from an AD mouse model identifies Stat1 and Clec2d as pre-MGnD markers. This phenotypic transition enhances amyloid plaque compaction, reduces dystrophic neurites, attenuates plaque-associated synaptic degradation and improves cognition. Our study demonstrates a miR-155-mediated regulatory mechanism of MGnD and the beneficial role of IFN-γ-responsive pre-MGnD in restricting neurodegenerative pathology and preserving cognitive function in an AD mouse model, highlighting miR-155 and IFN-γ as potential therapeutic targets for AD.

n-3 and n-6 polyunsaturated fatty acids (PUFAs) are essential fatty acids that are provided by dietary intake. Growing evidence suggests that n-3 and n-6 PUFAs are paramount for brain functions. They constitute crucial elements of cellular membranes, especially in the brain. They are the precursors of several metabolites with different effects on inflammation and neuron outgrowth. Overall, long-chain PUFAs accumulate in the offspring brain during the embryonic and post-natal periods. In this review, we discuss how they accumulate in the developing brain, considering the maternal dietary supply, the polymorphisms of genes involved in their metabolism, and the differences linked to gender. We also report the mechanisms linking their bioavailability in the developing brain, their transfer from the mother to the embryo through the placenta, and their role in brain development. In addition, data on the potential role of altered bioavailability of long-chain n-3 PUFAs in the etiologies of neurodevelopmental diseases, such as autism, attention deficit and hyperactivity disorder, and schizophrenia, are reviewed.

Background Facing the diversity of omics data and the difficulty of selecting one result over all those produced by several methods, consensus strategies have the potential to reconcile multiple inputs and to produce robust results. Results Here, we introduce ClustOmics, a generic consensus clustering tool that we use in the context of cancer subtyping. ClustOmics relies on a non-relational graph database, which allows for the simultaneous integration of both multiple omics data and results from various clustering methods. This new tool conciliates input clusterings, regardless of their origin, their number, their size or their shape. ClustOmics implements an intuitive and flexible strategy, based upon the idea of evidence accumulation clustering . ClustOmics computes co-occurrences of pairs of samples in input clusters and uses this score as a similarity measure to reorganize data into consensus clusters. Conclusion We applied ClustOmics to multi-omics disease subtyping on real TCGA cancer data from ten different cancer types. We showed that ClustOmics is robust to heterogeneous qualities of input partitions, smoothing and reconciling preliminary predictions into high-quality consensus clusters, both from a computational and a biological point of view. The comparison to a state-of-the-art consensus-based integration tool, COCA, further corroborated this statement. However, the main interest of ClustOmics is not to compete with other tools, but rather to make profit from their various predictions when no gold-standard metric is available to assess their significance. Availability The ClustOmics source code, released under MIT license, and the results obtained on TCGA cancer data are available on GitHub: https://github.com/galadrielbriere/ClustOmics .

Astrocytes control brain activity via both metabolic processes and gliotransmission, but the physiological links between these functions are scantly known. Here we show that endogenous activation of astrocyte type-1 cannabinoid (CB1) receptors determines a shift of glycolysis towards the lactate-dependent production of D-serine, thereby gating synaptic and cognitive functions in male mice. Mutant mice lacking the CB1 receptor gene in astrocytes (GFAP-CB1-KO) are impaired in novel object recognition (NOR) memory. This phenotype is rescued by the gliotransmitter D-serine, by its precursor L-serine, and also by lactate and 3,5-DHBA, an agonist of the lactate receptor HCAR1. Such lactate-dependent effect is abolished when the astrocyte-specific phosphorylated-pathway (PP), which diverts glycolysis towards L-serine synthesis, is blocked. Consistently, lactate and 3,5-DHBA promoted the co-agonist binding site occupancy of CA1 post-synaptic NMDA receptors in hippocampal slices in a PP-dependent manner. Thus, a tight cross-talk between astrocytic energy metabolism and gliotransmission determines synaptic and cognitive processes.

Type-2 Diabetes (T2D) is characterized by insulin resistance and accompanied by psychiatric comorbidities including major depressive disorders (MDD). Patients with T2D are twice more likely to suffer from MDD and clinical studies have shown that insulin resistance is positively correlated with the severity of depressive symptoms. However, the potential contribution of central insulin signaling in MDD in patients with T2D remains elusive. Here we hypothesized that insulin modulates the serotonergic (5-HT) system to control emotional behavior and that insulin resistance in 5-HT neurons contributes to the development of mood disorders in T2D. Our results show that insulin directly modulates the activity of dorsal raphe (DR) 5-HT neurons to dampen 5-HT neurotransmission through a 5-HT1A receptor-mediated inhibitory feedback. In addition, insulin-induced 5-HT neuromodulation is necessary to promote anxiolytic-like effect in response to intranasal insulin delivery. Interestingly, such an anxiolytic effect of intranasal insulin as well as the response of DR 5-HT neurons to insulin are both blunted in high-fat diet-fed T2D animals. Altogether, these findings point to a novel mechanism by which insulin directly modulates the activity of DR 5-HT neurons to dampen 5-HT neurotransmission and control emotional behaviors, and emphasize the idea that impaired insulin-sensitivity in these neurons is critical for the development of T2D-associated mood disorders. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

Accumulating evidence points to dysregulations of the Nucleus Accumbens (NAc) in eating disorders (ED), however its precise contribution to ED symptomatic dimensions remains unclear. Using chemogenetic manipulations in male mice, we found that activity of dopamine D1 receptor-expressing neurons of the NAc core subregion facilitated effort for a food reward as well as voluntary exercise, but decreased food intake, while D2-expressing neurons have opposite effects. These effects are congruent with D2-neurons being more active than D1-neurons during feeding while it is the opposite during running. Chronic manipulations of each subpopulations had limited effects on energy balance. However, repeated activation of D1-neurons combined with inhibition of D2-neurons biased behavior toward activity-related energy expenditure, whilst the opposite manipulations favored energy intake. Strikingly, concomitant activation of D1-neurons and inhibition of D2-neurons precipitated weight loss in anorexia models. These results suggest that dysregulations of NAc dopaminoceptive neurons might be at the core of EDs.

PUFA of the n-3 and n-6 families are present in high concentration in the brain where they are major components of cell membranes. The main forms found in the brain are DHA (22 :6, n-3) and arachidonic acid (20:4, n-6). In the past century, several studies pinpointed that modifications of n-3 and n-6 PUFA levels in the brain through dietary supply or genetic means are linked to the alterations of synaptic function. Yet, synaptopathies emerge as a common characteristic of neurodevelopmental disorders, neuropsychiatric diseases and some neurodegenerative diseases. Understanding the mechanisms of action underlying the activity of PUFA at the level of synapses is thus of high interest. In this frame, dietary supplementation in PUFA aiming at restoring or promoting the optimal function of synapses appears as a promising strategy to treat synaptopathies. This paper reviews the link between dietary PUFA, synapse formation and the role of PUFA and their metabolites in synaptic functions.