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© 2014 Nature America, Inc. All rights reserved.Neurodegenerative diseases, such as frontotemporal dementia (FTD), are often associated with behavioral deficits, but the underlying anatomical and molecular causes remain poorly understood. Here we show that

The recently identified GGGGCC repeat expansion in the noncoding region of C9ORF72 is the most common pathogenic mutation in patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). We generated a human neuronal model and investi

Treated wastewater and runoff-water is released by the outlet of the sewage treatment plant of Vidy (Lausanne) directly into the Lake of Geneva via a pipe located 300m from the shore. Even if this water is properly treated with modern technologies, we can observe an accumulation of micro pollutants into the sediments, and particularly heavy-metals. The main objective of this project is to investigate how these elevated concentrations of heavy metals affect both abundance and diversity of prokaryotes in the sediments. A special emphasis was given to endospore-forming bacteria, which could use sporulation as a survival strategy to resist in highly contaminated areas. This study could have implications both for understanding the role of endospore-forming bacteria in the environment as well as in terms of improving the bioremediation processes.

Reconstructing functional neuronal circuits is one major challenge of central nervous system repair. Through activation of pro-growth signaling pathways, some neurons achieve long-distance axon regrowth. Yet, functional reconnection has hardly been obtained, as these regenerating axons fail to resume their initial trajectory and reinnervate their proper target. Axon guidance is considered to be active only during development. Here, using the mouse visual system, we show that axon guidance is still active in the adult brain in regenerative conditions. We highlight that regenerating retinal ganglion cell axons avoid one of their primary targets, the suprachiasmatic nucleus (SCN), due to Slit/Robo repulsive signaling. Together with promoting regeneration, silencing Slit/Robo in vivo enables regenerating axons to enter the SCN and form active synapses. The newly formed circuit is associated with neuronal activation and functional recovery. Our results provide evidence that axon guidance mechanisms are required to reconnect regenerating axons to specific brain nuclei., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Animal models, especially rodents, have become instrumental to experimentally investigate the effects of an adverse post-natal environment on the developing brain. For this purpose, maternal separation (MS) paradigms have been widely used in the last decades. Nonetheless, how MS affects maternal behavior and, ultimately, the offspring depend on multiple variables., Methods: To gain further insights into the consequences of MS, we decided to thoroughly measure and compare the effects of short (15 min, 3 times/day) vs. long (3 h, 1 time/day) separation on multiple maternally-associated behaviors and across the entire post-natal period., Results: Compared to unhandled control litters, our results confirmed previous studies and indicated that SMS enhanced the time and variety of maternal care whereas LMS resulted in poor caregiving. We also showed that SMS-accrued caregiving persisted during the whole post-natal period. In contrast, LMS effects on maternal behavior were restricted to the early life (P2-P10). Finally, we also analyzed the behavioral consequences of these different rearing social environments on the offspring. We found that MS has profound effects in social tasks. We showed that affiliative touch, a type of prosocial behavior that provides comfort to others, is particularly sensitive to the modification of maternal caregiving., Discussion: Our results provide further support to the contention that interactions during the early post-natal period critically contribute to emotional processing and brain co-construction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rombaut, Roura-Martinez, Lepolard and Gascon.)

Introduction: Although intensively studied in the last decades, how microRNAs (miRNAs) are expressed across different cell types in the brain remains largely unknown., Materials: To address this issue, we sought to develop optimized fluorescence reporters that could be expressed in precise cellular subsets and used to accurately quantify miR contents in vivo ., Results: Focusing on miR-124, we tested different reporter designs whose efficiency was confirmed in different in vitro settings including cell lines and primary neuronal cultures from different brain structures. Unlike previous reporters, we provide experimental evidence that our optimized designs can faithfully translate miR levels in vitro ., Discussion: Tools developed here would enable assessing miRNA expression at the single cell resolution and are expected to significantly contribute to future miRNA research in vivo ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lepolard, Rombaut, Jaouen, Borges, Caccomo-Garcia, Popa and Gascon.)

Plant cytokinesis, which fundamentally differs from that in animals, requires the outward expansion of a plasma membrane precursor named the cell plate. How the transition from a cell plate to a plasma membrane occurs remains poorly understood. Here, we report that the acquisition of plasma membrane identity occurs through lateral patterning of the phosphatidylinositol 4,5-bisphosphate PI(4,5)P 2 at the newly formed cell plate membrane. There, the phosphoinositide phosphatase SAC9 emerges as a key regulator, colocalizing with and regulating the function of the microtubule-associated protein MAP65-3 at the cell plate leading zone. In sac9-3 mutant, the polar distribution of PI(4,5)P 2 at the cell plate is altered, leading to ectopic recruitment of the cytokinesis apparatus and formation of an additional cell plate insertion site. We propose that at the cell plate, SAC9 drives the depletion of PI(4,5)P 2 , which acts as a polar cue to spatially separate cell plate expansion from the acquisition of plasma membrane identity during final step of cytokinesis.

Background: Psychiatric diseases such as depression and anxiety are multifactorial conditions, highly prevalent in western societies. Human studies have identified a number of high-risk genetic variants for these diseases. Among them, polymorphisms in the promoter region of the serotonin transporter gene (SLC6A4) have attracted much attention. However, due to the paucity of experimental models, molecular alterations induced by these genetic variants and how they correlate to behavioral deficits have not been examined. In this regard, marmosets have emerged as a powerful model in translational neuroscience to investigate molecular underpinnings of complex behaviors., Methods: Here, we took advantage of naturally occurring genetic polymorphisms in marmoset SLC6A4 gene that have been linked to anxiety-like behaviors. Using FACS-sorting, we profiled microRNA contents in different brain regions of genotyped and behaviorally-phenotyped marmosets., Findings: We revealed that marmosets bearing different SLC6A4 variants exhibit distinct microRNAs signatures in a region of the prefrontal cortex whose activity has been consistently altered in patients with depression/anxiety. We also identified Deleted in Colorectal Cancer (DCC), a gene previously linked to these diseases, as a downstream target of the differently expressed microRNAs. Significantly, we showed that levels of both microRNAs and DCC in this region were highly correlated to anxiety-like behaviors., Interpretation: Our findings establish links between genetic variants, molecular modifications in specific cortical regions and complex behavioral responses, providing new insights into gene-behavior relationships underlying human psychopathology., Funding: This work was supported by France National Agency, NRJ Foundation, Celphedia and Fondation de France as well as the Wellcome Trust., Competing Interests: Declaration of interests The authors report no biomedical financial interests or potential conflicts of interest., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)

Striatal cholinergic interneurons (CINs) respond to salient or reward prediction-related stimuli after conditioning with brief pauses in their activity, implicating them in learning and action selection. This pause is lost in animal models of Parkinson's disease. How this signal regulates the striatal network remains an open question. Here, we examine the impact of CIN firing inhibition on glutamatergic transmission between the cortex and the medium spiny neurons expressing dopamine D1 receptor (D1 MSNs). Brief interruption of CIN activity has no effect in control conditions, whereas it increases glutamatergic responses in D1 MSNs after dopamine denervation. This potentiation depends upon M4 muscarinic receptor and protein kinase A. Decreasing CIN firing by optogenetics/chemogenetics in vivo partially rescues long-term potentiation in MSNs and motor learning deficits in parkinsonian mice. Our findings demonstrate that the control exerted by CINs on corticostriatal transmission and striatal-dependent motor-skill learning depends on the integrity of dopaminergic inputs., Competing Interests: Declaration of interests The authors declare no competing financial interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

An extensive body of evidence supports the notion that exposure to an enriched/impoverished environment alters brain functions via epigenetic changes. However, how specific modifications of social environment modulate brain functions remains poorly understood. To address this issue, we investigate the molecular and behavioral consequences of briefly manipulating social settings in young and middle-aged wild-type mice. We observe that, modifications of the social context, only affect the performance in socially related tasks. Social enrichment increases sociability whereas isolation leads to the opposite effect. Our work also pointed out specific miRNA signatures associated to each social environment. These miRNA alterations are reversible and found selectively in the medial prefrontal cortex. Finally, we show that miRNA modifications linked to social enrichment or isolation might target rather different intracellular pathways. Together, these observations suggest that the prefrontal cortex may be a key brain area integrating social information via the modification of precise miRNA networks., Competing Interests: All authors declare having no conflict of interest., (© 2020 The Authors.)

It remains unclear why many patients with depression do not respond to antidepressant treatment. In three cohorts of individuals with depression and treated with serotonin-norepinephrine reuptake inhibitor (N = 424) we show that responders, but not non-responders, display an increase of GPR56 mRNA in the blood. In a small group of subjects we also show that GPR56 is downregulated in the PFC of individuals with depression that died by suicide. In mice, we show that chronic stress-induced Gpr56 downregulation in the blood and prefrontal cortex (PFC), which is accompanied by depression-like behavior, and can be reversed by antidepressant treatment. Gpr56 knockdown in mouse PFC is associated with depressive-like behaviors, executive dysfunction and poor response to antidepressant treatment. GPR56 peptide agonists have antidepressant-like effects and upregulated AKT/GSK3/EIF4 pathways. Our findings uncover a potential role of GPR56 in antidepressant response.

An extensive literature details deterioration of multiple brain functions, especially memory and learning, during aging in humans and in rodents. In contrast, the decline of social functions is less well understood. It is presently not clear whether age-dependent deficits observed in social behavior mainly reflect the disruption of social networks activity or are simply secondary to a more general impairment of cognitive and executive functions in older individuals. To address this issue, we carried out a battery of behavioral tasks exploring different brain functions in young (3 months) and middle-aged wild-type mice (9 months). Consistent with previous reports, our results show no obvious differences between these two groups in most of the domains investigated including learning and memory. Surprisingly, in social tasks, middle-aged animals showed significantly reduced levels of interactions when exposed to a new juvenile mouse. In the absence of overt cognitive decline, our findings suggest that social impairments may precede the disruption of other brain functions and argue for a selective vulnerability of social circuits during aging.

Stimulation of endogenous neurogenesis and recruitment of neural progenitors from the subventricular zone (SVZ) neurogenic site may represent a useful strategy to improve regeneration in the ischemic cortex. Here, we tested whether transgenic overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN), the regulator of matrix metalloproteinases (MMPs) expression, in endogenous neural progenitor cells (NPCs) in the subventricular zone (SVZ) could increase migration towards ischemic injury. For this purpose, we applied a lentivector-mediated gene transfer system. We found that EMMPRIN-transduced progenitors exhibited enhanced MMP-2 activity in vitro and showed improved motility in 3D collagen gel as well as in cortical slices. Using a rat model of neonatal ischemia, we showed that EMMPRIN overexpressing SVZ cells invade the injured cortical tissue more efficiently than controls. Our results suggest that EMMPRIN overexpression could be suitable approach to improve capacities of endogenous or transplanted progenitors to invade the injured cortex., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Intragenic microRNAs (miRNAs), located mostly in the introns of protein-coding genes, are often co-expressed with their host mRNAs. However, their functional interaction in development is largely unknown. Here we show that in Drosophila, miR-92a and miR-92b are embedded in the intron and 3'UTR of jigr1, respectively, and co-expressed with some jigr1 isoforms. miR-92a and miR-92b are highly expressed in neuroblasts of larval brain where Jigr1 expression is low. Genetic deletion of both miR-92a and miR-92b demonstrates an essential cell-autonomous role for these miRNAs in maintaining neuroblast self-renewal through inhibiting premature differentiation. We also show that miR-92a and miR-92b directly target jigr1 in vivo and that some phenotypes due to the absence of these miRNAs are partially rescued by reducing the level of jigr1. These results reveal a novel function of the miR-92 family in Drosophila neuroblasts and provide another example that local negative feedback regulation of host genes by intragenic miRNAs is essential for animal development.

Neurodegenerative diseases, such as frontotemporal dementia (FTD), are often associated with behavioral deficits, but the underlying anatomical and molecular causes remain poorly understood. Here we show that forebrain-specific expression of FTD-associated mutant CHMP2B in mice causes several age-dependent neurodegenerative phenotypes, including social behavioral impairments. The social deficits were accompanied by a change in AMPA receptor (AMPAR) composition, leading to an imbalance between Ca(2+)-permeable and Ca(2+)-impermeable AMPARs. Expression of most AMPAR subunits was regulated by the brain-enriched microRNA miR-124, whose abundance was markedly decreased in the superficial layers of the cerebral cortex of mice expressing the mutant CHMP2B. We found similar changes in miR-124 and AMPAR levels in the frontal cortex and induced pluripotent stem cell-derived neurons from subjects with behavioral variant FTD. Moreover, ectopic miR-124 expression in the medial prefrontal cortex of mutant mice decreased AMPAR levels and partially rescued behavioral deficits. Knockdown of the AMPAR subunit Gria2 also alleviated social impairments. Our results identify a previously undescribed mechanism involving miR-124 and AMPARs in regulating social behavior in FTD and suggest a potential therapeutic avenue.

Increasing evidence suggests that frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) share some clinical, pathological, and molecular features as part of a common neurodegenerative spectrum disorder. In recent years, enormous progress has been made in identifying both pathological proteins and genetic mutations associated with FTD-ALS. However, the molecular pathogenic mechanisms of disease onset and progression remain largely unknown. Recent studies have uncovered unexpected links between FTD-ALS and multiple aspects of RNA metabolism, setting the stage for further understanding of the disorder. Here, the authors will focus on microRNAs and review the emerging roles of these small RNAs in several aspects of FTD-ALS pathogenesis.

The recently identified GGGGCC repeat expansion in the noncoding region of C9ORF72 is the most common pathogenic mutation in patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). We generated a human neuronal model and investigated the pathological phenotypes of human neurons containing GGGGCC repeat expansions. Skin biopsies were obtained from two subjects who had >1,000 GGGGCC repeats in C9ORF72 and their respective fibroblasts were used to generate multiple induced pluripotent stem cell (iPSC) lines. After extensive characterization, two iPSC lines from each subject were selected, differentiated into postmitotic neurons, and compared with control neurons to identify disease-relevant phenotypes. Expanded GGGGCC repeats exhibit instability during reprogramming and neuronal differentiation of iPSCs. RNA foci containing GGGGCC repeats were present in some iPSCs, iPSC-derived human neurons and primary fibroblasts. The percentage of cells with foci and the number of foci per cell appeared to be determined not simply by repeat length but also by other factors. These RNA foci do not seem to sequester several major RNA-binding proteins. Moreover, repeat-associated non-ATG (RAN) translation products were detected in human neurons with GGGGCC repeat expansions and these neurons showed significantly elevated p62 levels and increased sensitivity to cellular stress induced by autophagy inhibitors. Our findings demonstrate that key neuropathological features of FTD/ALS with GGGGCC repeat expansions can be recapitulated in iPSC-derived human neurons and also suggest that compromised autophagy function may represent a novel underlying pathogenic mechanism.

During normal aging or neurodegenerative diseases, neuronal survival and function depend on protein homeostasis, which is regulated by multiple mechanisms, including the microRNA (miRNA) pathway. In different cells types, the absence of Dicer, a key miRNA processing enzyme, leads to neurodegeneration through cell-autonomous and non-cell-autonomous mechanisms. Loss of certain miRNAs also causes neurodegeneration in some model organisms. On the other hand, miRNA expression is misregulated in patients with different neurodegenerative diseases. Thus, the miRNA pathway appears to be essential in the pathogenesis of several age-dependent neurodegenerative conditions; however, our understanding of the underlying mechanism remains rudimentary. The precise causal relationships between specific miRNAs and neurodegeneration in humans need to be further investigated.

The functional significance of microRNA-9 (miR-9) during evolution is evidenced by its conservation at the nucleotide level from flies to humans but not its diverse expression patterns. Recent studies in several model systems reveal that miR-9 can regulate neurogenesis through its actions in neural or non-neural cell lineages. In vertebrates, miR-9 exerts diverse cell-autonomous effects on the proliferation, migration, and differentiation of neural progenitor cells by modulating different mRNA targets. In some developmental contexts, miR-9 suppresses apoptosis and is misregulated in several types of cancer cells, influencing proliferation or metastasis formation. Moreover, downregulation of miR-9 in postmitotic neurons is also implicated in some neurodegenerative diseases. Thus, miR-9 is emerging as an important regulator in development and disease through its ability to modulate different targets in a manner dependent on the developmental stage and the cellular context.

Pain sensation (nociception) is an alarm system aiming to signal the presence of potentially or actually harmful stimuli. In our hazard-rich environment, pain initiates the necessary reactions to prevent or limit tissue damage in response to noxious inputs playing therefore a crucial survival role. Specialized noxious stimuli detectors, called primary nociceptive neurons or nociceptors transduce and convey pain information to the central nervous system. Unlike other sensory systems, pain sensation could be evoked by a vast range of external or internal stimuli. Nearly any of the environmental stimuli could be potentially noxious depending on their nature and/or intensity and/or duration. Early studies at the beginning of the 20th century identified a discrete number of nociceptive neuronal types according to their electrophysiological responses or their degree of myelination. However, the advent of molecular biology techniques revealed an extraordinary diversity among nociceptors. Such heterogeneity likely reflects the evolutionary adaptation required to respond to an extremely variety of circumstances.

Deciphering the precise in vivo function of a particular neuronal subpopulation is one of the most challenging issues in neurobiology. Dorsal root ganglia (DRG) neurons represent a powerful model system to address this fundamental question. These neurons display many morphological, anatomical and few molecular characteristics. With the aim of expanding the molecular description of the primary sensory neurons, we used Affimetrix microarrays to compare global gene expression profiles of DRG of wild type and trkA(trkC/trkC) knock-in mice at birth and identified several hundred potential markers of nociceptive neurons and few markers of proprioceptive neurons. Here, we describe the identification of two members of a family of putative adapter proteins STAC1 and STAC2. We found STAC1 and STAC2 being expressed in a mutually exclusive fashion in adult DRG neurons. STAC1 mainly marks peptidergic nociceptive neurons while STAC2 is expressed in a subset of nonpeptidergic nociceptors, in all trkB+ neurons and in a subpopulation of proprioceptive neurons. Our expression data demonstrate that STAC proteins identify four categories of primary sensory neurons; one class of peptidergic neurons, a subset of nonpeptidergic neurons, all TrkB+neurons and a subset of proprioceptive neurons. Genetic marking of STACs-expressing sensory neurons will lend significant advance into our understanding of DRG neuronal functional diversity., (Copyright © 2010 Elsevier B.V. All rights reserved.)