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Background: Clinical practice guidelines promote bio-psychosocial management of patients suffering from low back pain (LBP). The objective of this study was to examine the current knowledge, attitudes and beliefs of physiotherapists about a guideline-adherent approach to LBP and to assess the ability of physiotherapists to recognise signs of a specific LBP in a clinical vignette. Methods: Physiotherapists were recruited to participate in an online study. They were asked to indicate whether they were familiar with evidence-based guidelines and then to fill in the Health Care Providers’ Pain and Impairment Relationship Scale (HC-PAIRS), Back Pain Attitudes Questionnaire (Back-PAQ), Neurophysiology of Pain Questionnaire (NPQ), as well as questions related to two clinical vignettes. Results: In total, 527 physiotherapists participated in this study. Only 38% reported being familiar with guidelines for the management of LBP. Sixty-three percent of the physiotherapists gave guideline-inconsistent recommendations regarding work. Only half of the physiotherapists recognised the signs of a specific LBP. Conclusions: The high proportion of physiotherapists unfamiliar with guidelines and demonstrating attitudes and beliefs not in line with evidence-based management of LBP is concerning. It is crucial to develop efficient strategies to enhance knowledge of guidelines among physiotherapists and increase their implementation in clinical practice.

The cystine/glutamate antiporter system xc− has been identified as the major source of extracellular glutamate in several brain regions as well as a modulator of neuroinflammation, and genetic deletion of its specific subunit xCT (xCT−/−) is protective in mouse models for age-related neurological disorders. However, the previously observed oxidative shift in the plasma cystine/cysteine ratio of adult xCT−/− mice led to the hypothesis that system xc− deletion would negatively affect life- and healthspan. Still, till now the role of system xc− in physiological aging remains unexplored. We therefore studied the effect of xCT deletion on the aging process of mice, with a particular focus on the immune system, hippocampal function, and cognitive aging. We observed that male xCT−/− mice have an extended lifespan, despite an even more increased plasma cystine/cysteine ratio in aged compared to adult mice. This oxidative shift does not negatively impact the general health status of the mice. On the contrary, the age-related priming of the innate immune system, that manifested as increased LPS-induced cytokine levels and hypothermia in xCT+/+ mice, was attenuated in xCT−/− mice. While this was associated with only a very moderate shift towards a more anti-inflammatory state of the aged hippocampus, we observed changes in the hippocampal metabolome that were associated with a preserved hippocampal function and the retention of hippocampus-dependent memory in male aged xCT−/− mice. Targeting system xc− is thus not only a promising strategy to prevent cognitive decline, but also to promote healthy aging.

Alzheimer's disease is histopathologically well defined by the presence of amyloid deposits and tau-related neurofibrillary tangles in crucial regions of the brain. Interest is growing in revealing and determining possible pathological markers also in the cerebellum as its involvement in cognitive functions is now well supported. Despite the central position of the Purkinje cell in the cerebellum, its electrophysiological behaviour in mouse models of Alzheimer's disease is scarce in the literature. Our first aim was here to focus on the electrophysiological behaviour of the cerebellum in awake mouse model of Alzheimer's disease (APPswe/PSEN1dE9) and the related performance on the water-maze test classically used in behavioural studies. We found prevalent signs of electrophysiological alterations in both Purkinje cells and deep cerebellar nuclei neurons which might explain the behavioural deficits reported during the water-maze test. The alterations of neurons firing were accompanied by a dual (~16 and ~228 Hz) local field potential's oscillation in the Purkinje cell layer of Alzheimer's disease mice which was concomitant to an important increase of both the simple and the complex spikes. In addition, β-amyloid deposits were present in the molecular layer of the cerebellum. These results highlight the importance of the output firing modification of the AD cerebellum that may indirectly impact the activity of its subcortical and cortical targets.

Microglial cells must act as the first line of defense of the central nervous system, but they can be exposed to various mechanical signals that may trigger their activation. While the impact of chemical signaling on brain cells has been studied in detail, our current understanding of the mechanical signaling in microglia is still limited. To address this challenge, we exposed microglial cells to a single mechanical stretch and compared their behavior to chemical activation by lipopolysaccharide treatment. Here we show that stretching microglial cells results in their activation, demonstrating a strong mechanosensitivity. Stretched microglial cells exhibited higher Iba1 protein levels, a denser actin cytoskeleton and migrated more persistently. In contrary to LPS-treated cells, stretched microglia maintain a robust secretory profile of chemokines and cytokines, except for TNF-α, highlighting the relevance of this model. Interestingly, a single stretch injury results in more compacted chromatin and DNA damage, suggesting possible long-term genomic instabilities in stretched microglia. Using neuronal networks in compartmentalized microfluidic chambers, we found that stretched microglial cells exhibit enhanced phagocytic and synaptic stripping activities. Altogether, our results propose that the immune potential of microglial cells can be unlocked by stretching events to maintain brain tissue homeostasis after mechanical injury.

Prdm12 is a conserved epigenetic transcriptional regulator that displays restricted expression in nociceptors of the developing peripheral nervous system. In mice, Prdm12 is required for the development of the entire nociceptive lineage. In humans, PRDM12 mutations cause congenital insensitivity to pain, likely because of the loss of nociceptors. Prdm12 expression is maintained in mature nociceptors suggesting a yet-to-be explored functional role in adults. Using Prdm12 inducible conditional knockout mouse models, we report that in adult nociceptors Prdm12 is no longer required for cell survival but continues to play a role in the transcriptional control of a network of genes, many of them encoding ion channels and receptors. We found that disruption of Prdm12 alters the excitability of dorsal root ganglion neurons in culture. Phenotypically, we observed that mice lacking Prdm12 exhibit normal responses to thermal and mechanical nociceptive stimuli but a reduced response to capsaicin and hypersensitivity to formalin-induced inflammatory pain. Together, our data indicate that Prdm12 regulates pain-related behavior in a complex way by modulating gene expression in adult nociceptors and controlling their excitability. The results encourage further studies to assess the potential of Prdm12 as a target for analgesic development.

Introduction: Low back pain (LBP) is ranked as the first musculoskeletal disorder considering years lived with disability worldwide. Despite numerous guidelines promoting a bio-psycho-social (BPS) approach in the management of patients with LBP, many health care professionals (HCPs) still manage LBP patients mainly from a biomedical point of view. Objective: The purpose of this pilot study was to evaluate the feasibility of implementing an interactive e-learning module on the management of LBP in HCPs. Methods: In total 22 HCPs evaluated the feasibility of the e-learning module with a questionnaire and open questions. Participants filled in the Back Pain Attitude Questionnaire (Back-PAQ) before and after completing the module to evaluate their attitudes and beliefs about LBP. Results: The module was structured and easy to complete (91%) and met the expectations of the participants (86%). A majority agreed that the module improved their knowledge (69%). Some participants (77%) identified specific topics that might be discussed in more detail in the module. HCPs knowledge, beliefs and attitudes about LBP significantly improved following module completion (t = -7.63, P < .001) with a very large effect size (d(s) = -1.63). Conclusion: The module seems promising to change knowledge, attitudes and beliefs of the participants. There is an urgent need to develop and investigate the effect of educational interventions to favor best practice in LBP management and this type of e-learning support could promote the transition from a biomedical to a bio-psycho-social management of LBP in HCPs.

Deformation, compression, or stretching of brain tissues cause diffuse axonal injury (DAI) and induce structural and functional alterations of astrocytes, the most abundant cell type in the brain. To gain further insight into the role of mechanically activated astrocytes on neuronal networks, this study was designed to investigate whether cytokines released by mechanically activated astrocytes can affect the growth and synaptic connections of cortical neuronal networks. Astrocytes were cultivated on elastic membranes and subjected to repetitive mechanical insults, whereas well-defined protein micropatterns were used to form standardized neuronal networks. GFAP staining showed that astrocytes were mechanically activated after two cycles of stretch and mesoscale discovery assays indicated that injured astrocytes released four major cytokines. To understand the role of these cytokines, neuronal networks were cultured with the supernatant of healthy or mechanically activated astrocytes, and the individual contribution of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) was studied. We found that the supernatant of two-cycle stretched astrocytes decreased presynaptic terminals and indicated that TNF-α must be considered a key player of the synaptic loss. Furthermore, our results indicate that cytokines released by injured astrocytes significantly modulate the balance between TNFR1 and TNFR2 receptors by enhancing R2 receptors. We demonstrated that TNF-α is not involved in this process, suggesting a predominant role of other secreted cytokines. Together, these results contribute to a better understanding of the consequences of repetitive astrocyte deformations and highlight the role of inflammatory signaling pathways in synaptic plasticity and modulation of TNFR1 and TNFR2 receptors.

Low back pain (LBP) that radiates to the leg is not always related to a lesion or a disease of the nervous system (neuropathic pain): it might be nociceptive (referred) pain. Unfortunately, patients with low-back related leg pain are often given a variety of diagnoses (e.g. 'sciatica'; 'radicular pain'; pseudoradicular pain"). This terminology causes confusion and challenges clinical reasoning. It is essential for clinicians to understand and recognize predominant pain mechanisms. This paper describes pain mechanisms related to low back-related leg pain and helps differentiate these mechanisms in practice using clinical based scenarios. We illustrate this by using two clinical scenarios including patients with the same symptoms in terms of pain localization (i.e. low-back related leg pain) but with different underlying pain mechanisms (i.e. nociceptive versus neuropathic pain).

Alzheimer’s disease (AD) and related dementia is one of the growing threats to the sustainability of health and care systems in developed countries, and efforts to find therapies have had scant success. The main reasons for this are lack of efficient therapy, which is linked to too late discovery of the disease itself. With this in mind, biomarkers are recognised as an element which can bring a major contribution to research, helping elucidate the disease and the search for treatments. They are also playing an increasing role in early detection and timely diagnosis, which are considered the principal hopes of effective management in the absence of an effective drug. The current arsenal of biomarkers could already, if more widely deployed, provide an effective minimum service to patients and health systems. A concerted action by policy makers and stakeholders could drive progress in access to AD biomarker testing to provide an optimum service in the medium term. This paper discusses how to improve the use of and access to biomarker testing in the detection and diagnosis of AD and other diseases featuring dementia, and how EU healthcare systems could benefit. It outlines the challenges, lists the achievements to date, and highlights the actions needed to allow biomarker testing to deliver more fully on their potential in AD.

The astrocytic cystine/glutamate antiporter system xc− represents an important source of extracellular glutamate in the central nervous system, with potential impact on excitatory neurotransmission. Yet, its function and importance in brain physiology remain incompletely understood. Employing slice electrophysiology and mice with a genetic deletion of the specific subunit of system xc−, xCT (xCT−/− mice), we uncovered decreased neurotransmission at corticostriatal synapses. This effect was partly mitigated by replenishing extracellular glutamate levels, indicating a defect linked with decreased extracellular glutamate availability. We observed no changes in the morphology of striatal medium spiny neurons, the density of dendritic spines, or the density or ultrastructure of corticostriatal synapses, indicating that the observed functional defects are not due to morphological or structural abnormalities. By combining electron microscopy with glutamate immunogold labeling, we identified decreased intracellular glutamate density in presynaptic terminals, presynaptic mitochondria, and in dendritic spines of xCT−/− mice. A proteomic and kinomic screen of the striatum of xCT−/− mice revealed decreased expression of presynaptic proteins and abnormal kinase network signaling, that may contribute to the observed changes in postsynaptic responses. Finally, these corticostriatal deregulations resulted in a behavioral phenotype suggestive of autism spectrum disorder in the xCT−/− mice; in tests sensitive to corticostriatal functioning we recorded increased repetitive digging behavior and decreased sociability. To conclude, our findings show that system xc− plays a previously unrecognized role in regulating corticostriatal neurotransmission and influences social preference and repetitive behavior.

Dataset of a priming visual experiment acquired in the scope ofARC-1923 UMONS3 program. This dataset is linked to the publication "La Fisca et al.,Revealing Biases in BCI Experiments: Can Uncontrolled Covariates Fool You, 2022. Please refer to the publication for citation.

International audience; Attention Deficit Hyperactivity Disorder (ADHD) is the most prevalent neurodevelopmental disorder among children. It affects patients’ lives in many ways: inattention, difficulty with stimuli inhibition or motor function regulation. Different treatments exist today, but these can present side effects or are not effective for all subgroups. Neurofeedback (NF) is an innovative treatment consisting of brain activity display. NF training could consist of a virtual reality (VR) video-game in which the participant’s attention affects the game. Attention being assessed through physiological signals, one of the main steps is to design an estimator for the attention state. We present a novel framework able to record physiological signals in specific attention states and able to estimate the corresponding attention state. We propose a database composed of electroencephalography signals (EEG), and an eye-tracker labelled with a score representing the attention span for 32 healthy participants. Different features are extracted from the signals and machine learning (ML) algorithms are proposed. Our approach exhibits high accuracy for attention estimation, which corroborates a correlation between attention state and physiological signals (i.e. EEG, eye-tracking signals). The dataset has been made publicly available to promote research in the domain and we encourage other scientists to use their own approach for attention estimation

Worldwide, approximately 27 million people are affected by Alzheimer’s disease (AD). AD pathophysiology is believed to be caused by the deposition of the β-amyloid peptide (Aβ). Aβ can reduce long-term potentiation (LTP), a form of synaptic plasticity that is closely associated with learning and memory and involves postsynaptic glutamate receptor phosphorylation and trafficking. Moreover, Aβ seems to be able to reduce glutamatergic transmission by increasing the endocytosis of NMDA receptors. Trace amines (TAs) are biogenic amines that are structurally similar to monoamine neurotransmitters. TAs bind to G protein-coupled receptors, called TAARs (trace amine-associated receptors); the best-studied member of this family, TAAR1, is distributed in the cortical and limbic structures of the CNS. It has been shown that the activation of TAAR1 can rescue glutamatergic hypofunction and that TAAR1 can modulate glutamate NMDA receptor-related functions in the frontal cortex. Several lines of evidence also suggest the pro-cognitive action of TAAR1 agonists in various behavioural experimental protocols. Thus, we studied, in vitro, the role of the TAAR1 agonist RO5256390 on basal cortical glutamatergic transmission and tested its effect on Aβ-induced dysfunction. Furthermore, we investigated, in vivo, the role of TAAR1 in cognitive dysfunction induced by Aβ infusion in Aβ-treated mice. In vitro data showed that Aβ 1–42 significantly decreased NMDA cell surface expression while the TAAR1 agonist RO5256390 promoted their membrane insertion in cortical cells. In vivo, RO5256390 showed a mild pro-cognitive effect, as demonstrated by the better performance in the Y maze test in mice treated with Aβ. Further studies are needed to better understand the interplay between TAAR1/Aβ and glutamatergic signalling, in order to evaluate the eventual beneficial effect in different experimental paradigms and animal models. Taken together, our data indicate that TAAR1 agonism may provide a novel therapeutic approach in the treatments of disorders involving Aβ-induced cognitive impairments, such as AD.

The cystine/glutamate antiporter system x

Extensive research has uncovered diverse forms of synaptic plasticity and an array of molecular signaling mechanisms that act as positive or negative regulators. Specifically, cyclic 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent signaling pathways are crucially implicated in long-lasting synaptic plasticity. In this study, we examine the role of Popeye domain-containing protein 1 (POPDC1) (or blood vessel epicardial substance (BVES)), a cAMP effector protein, in modulating hippocampal synaptic plasticity. Unlike other cAMP effectors, such as protein kinase A (PKA) and exchange factor directly activated by cAMP, POPDC1 is membrane-bound and the sequence of the cAMP-binding cassette differs from canonical cAMP-binding domains, suggesting that POPDC1 may have an unique role in cAMP-mediated signaling. Our results show that Popdc1 is widely expressed in various brain regions including the hippocampus. Acute hippocampal slices from Popdc1 knockout (KO) mice exhibit PKA-dependent enhancement in CA1 long-term potentiation (LTP) in response to weaker stimulation paradigms, which in slices from wild-type mice induce only transient LTP. Loss of POPDC1, while not affecting basal transmission or input-specificity of LTP, results in altered response during high-frequency stimulation. Popdc1 KO mice also show enhanced forskolin-induced potentiation. Overall, these findings reveal POPDC1 as a novel negative regulator of hippocampal synaptic plasticity and, together with recent evidence for its interaction with phosphodiesterases (PDEs), suggest that POPDC1 is involved in modulating activity-dependent local cAMP–PKA–PDE signaling.

While magnesium deficiency is common and its effects well known on the nervous system, very few studies has been dedicated to the efficiency of magnesium replacement treatments on the central nervous system. In this study, the effects of oral administration of magnesium salts of acetyl-taurinate on the central manifestations of magnesium deficiency is described in rats submitted to low-magnesium diet and in a murine model of Alzheimer's disease. We tested the effect of ATA Mg®, a salt combining magnesium and taurine, on the hippocampus, a critical component of cognition. 7-10-month-old rats were submitted to dietary magnesium deprivation for 64 days. The effect of magnesium deficiency was studied in ex vivo hippocampal slices. We showed that long-term potentiation of synaptic transmission in the hippocampus was significantly improved by the oral administration of ATA Mg® at a dose of 50 mg/kg bw/day, which is comparable to the recommended dose in humans. 7-10-months-old transgenic APP/PS1 mice, a model of Alzheimer's disease, received ATA Mg® during 24 days at a dose of 700 mg/kg bw/day which is the dose used in previous studies demonstrating the positive effect of magnesium supplementation. We showed that long-term potentiation was significantly improved in the treated mice. Moreover, the expression of NR2B subunit of NMDA receptors, known to be involved in synaptic plasticity, was significantly increased in the hippocampus. These results demonstrate the ability of ATA Mg® to improve the symptoms related to chronic magnesium deficiency at the level of the hippocampus suggesting its bioavailability and effectiveness in reaching the central nervous system.

BACKGROUND Low back pain (LBP) is ranked as the first musculoskeletal disorder considering years lived with disability worldwide. Despite numerous guidelines promoting a bio-psycho-social (BPS) approach in the management of patients with LBP, many health care professionals (HCPs) still manage LBP patients mainly from a biomedical point of view. This is reflected by overuse of medical imaging and medication, advice to restrict work and activities, and insufficient attention towards psychosocial risk factors during actual consultation, which is all guideline discordant. Implementation strategies designed until now to change HCPs behavior had only limited effects or were not effective at all. OBJECTIVE The purpose of this pilot study was to evaluate the feasibility and effectiveness of implementing an interactive e-learning module on the management of LBP in HCPs. HCPs’ perceptions of their change in knowledge and beliefs about LBP as well as the content, structure, length and access of the module were assessed. METHODS In total 22 HCPs have been recruited. Participants completed and evaluated the e-learning module with an online questionnaire including 20 items based on similar feasibility studies. Likert Scales (n=15) and qualitative open questions (n=5) were both used. Before and after completing the module, participants filled in the Back-PAQ questionnaire to evaluate the potential effect of the module on their attitudes and beliefs about LBP. The Back-PAQ data were analyzed with the paired Student t-test. RESULTS The feasibility of the module was confirmed, it was structured and easy to complete (91%) and met the expectations of the participants (86%). A majority agreed that the module improved their knowledge (69%). According to the HCPs the time to complete the module (36 ± 9.6 minutes) was adequate (91%). Some participants (77%) identified specific topics that might be discussed in more detail in the module. Moreover, HCPs’ knowledge, beliefs and attitudes about LBP significantly improved following module completion (P < .001). CONCLUSIONS The interactive e-learning module seems feasible and effective. Participants were positive regarding the content, they found it sufficient and clear. The module was appealing, structured and easy to complete. Moreover, the module has been effective to change knowledge and beliefs of the participants. Suggestions have been made to improve it in the future.

Traumatic brain injury (TBI) remains one of the leading causes of mortality and morbidity worldwide. Despite its high prevalence and extensive efforts to develop neuroprotective therapies, effective treatments for TBI are still limited. Among important neuronal damages, TBI induces structural and functional alterations of astrocytes, the most abundant cell type in the brain. Injured astrocytes respond in diverse mechanisms that result in reactive astrogliosis and are involved in the physiopathological mechanisms of TBI in an extensive and sophisticated manner. The establishment of effective neuroprotective treatments for TBI requires to better understand the complex biochemical interactions between activated astrocytes and neurons that contribute to the secondary injury. To address this challenge, we studied in vitro the role of mechanically injured astrocytes on the growth and synaptic connections of cortical neuronal networks of controlled architectures grown on well-defined protein micropatterns. Astrocytes were cultivated on elastic membranes and mechanically activated by stretching cycles. The culture media of healthy or activated astrocytes was then introduced on neuronal networks. We analyzed the neuronal viability, the neurite growth and the synaptic density of neuronal networks to understand the role of the inflammatory molecules secreted by mechanically activated astrocytes. Furthermore, we cultivated neuronal networks during 13 days with different doses of TNF-α in order to decipher its individual contribution among the other cytokines. Here we show that the ratio of tubulin to synapsin area was significantly higher in neuronal networks treated with either 4 or 2 doses of TNF-α, suggesting that TNF-α can promote the tubulin polymerization process. Assuming that TNF-α can bind to either TNFR1 or TNFR2 receptors, which lead respectively to the cell survival or the cell apoptosis, we studied the modulation of the both TNF-α receptors in response to the medium of mechanically activated astrocytes and different doses of TNF-α. Our findings indicate that the amount of both receptors increases with the maturation of the network. In addition, we observed a significant modulation of the amount of TNFR1 and TNFR2 in response to the media of injured astrocytes that leads to a large imbalance between both receptors, suggesting an important role for TNFα-signaling in the physiopathological mechanisms of TBI.

Children with Attention Deficit Hyperactivity Disorder (ADHD), present different symptoms binding for everyday life, e.g. difficulty to be focused, impulsiveness, difficulty to regulate motor functions, etc. The most commonly prescribed treatment is the medication that can present side effects. Another solution is behavioural treatment that does not seem to present better results than medication for a higher cost. A novel method with growing interest is the use of neurofeedback (NF) to teach the patient to self-regulate symptoms by herself, through the visualisation of the brain activity in an understandable form. Moreover, virtual reality (VR) is a supportive environment for NF in the context of ADHD. However, before proceeding the NF, it is important to determine the features of the physiological signals corresponding to the symptoms' appearance. We present here a novel framework based on the joint measurement of electroencephalogram (EEG) and sight direction by equipment that can be embedded in VR headset, the goals being to estimate attentional state. In parallel to the signal acquisition, attentional tasks are performed to label the physiological signals. Features have been extracted from the signals and machine learning (ML) models have been applied to retrieve the attentional state. Encouraging results have been provided from the pilot study with the ability to make the right classification in multiple scenarios. Moreover, a dataset with the labelled physiological signals is under development. It will help to have a better understanding of the mechanism behind ADHD symptoms.

International audience; Objective: To investigate the occurrence of olfactory and gustatory dysfunctions in patients with laboratory-confirmed COVID-19 infection. Methods: Patients with laboratory-confirmed COVID-19 infection were recruited from 12 European hospitals. The following epidemiological and clinical outcomes have been studied: age, sex, ethnicity, comorbidities, and general and otolaryngological symptoms. Patients completed olfactory and gustatory questionnaires based on the smell and taste component of the National Health and Nutrition Examination Survey, and the short version of the Questionnaire of Olfactory Disorders-Negative Statements (sQOD-NS). Results: A total of 417 mild-to-moderate COVID-19 patients completed the study (263 females). The most prevalent general symptoms consisted of cough, myalgia, and loss of appetite. Face pain and nasal obstruction were the most disease-related otolaryngological symptoms. 85.6% and 88.0% of patients reported olfactory and gustatory dysfunctions, respectively. There was a significant association between both disorders (p < 0.001). Olfactory dysfunction (OD) appeared before the other symptoms in 11.8% of cases. The sQO-NS scores were significantly lower in patients with anosmia compared with normosmic or hyposmic individuals (p = 0.001). Among the 18.2% of patients without nasal obstruction or rhinorrhea, 79.7% were hyposmic or anosmic. The early olfactory recovery rate was 44.0%. Females were significantly more affected by olfactory and gustatory dysfunctions than males (p = 0.001). Conclusion: Olfactory and gustatory disorders are prevalent symptoms in European COVID-19 patients, who may not have nasal symptoms. The sudden anosmia or ageusia need to be recognized by the international scientific community as important symptoms of the COVID-19 infection.

Graphical abstract, Highlights • The NPs reach the CNS via the blood-brain barrier and cause inflammation and necrotic area in the white matter. • Proliferation of glial cells and neuroblasts is affected in vitro and in vivo. • An oxidative stress was evidenced in vivo in neurons of hippocampus, cerebellum and in subependymal area., Nowadays, nanoparticles (NPs) of titanium dioxide (TiO2) are abundantly produced. TiO2 NPs are present in various food products, in paints, cosmetics, sunscreens and toothpastes. However, the toxicity of TiO2 NPs on the central nervous system has been poorly investigated until now. The aim of this study was to evaluate the toxicity of TiO2 NPs on the central nervous system in vitro and in vivo. In cell cultures derived from embryonic cortical brain of rats, a significant decrease in neuroblasts was observed after 24 to 96 h of incubation with TiO2 NPs (5 to 20 μg/ml). This phenomenon resulted from an inhibition of neuroblast proliferation and a concomitant increase in apoptosis. In the same time, a gliosis, characterized by an increase in proliferation of astrocytes and the hypertrophy of microglial cells, occurred. The phagocytosis of TiO2 NPs by microgliocytes was also observed. In vivo, after intraperitoneal injection, the TiO2 NPs reached the brain through the blood brain barrier and the nanoparticles promoted various histological injuries such as cellular lysis, neuronal apoptosis, and inflammation. A reduction of astrocyte population was observed in some brain area such as plexiform zone, cerebellum and subependymal area. An oxidative stress was also detected by immunohistochemistry in neurons of hippocampus, cerebellum and in subependymal area. In conclusion, our study demonstrated clearly the toxic impact of TiO2 NPs on rat brain and neuronal cells and pointed about not yet referenced toxicity impacts of TiO2 such as the reduction of neuroblast proliferation both in vitro and in vivo.

The cystine/glutamate antiporter system xc-, with xCT as specific subunit, exchanges intracellular glutamate for extracellular cystine. It is highly expressed in the central nervous system, mainly on astrocytes, and has been shown to be the major source of extracellular glutamate in various regions of the brain, such as the striatum and hippocampus. This extrasynaptically released glutamate can affect synaptic neurotransmission. As the physiological function of system xc- in the central nervous system remains poorly understood, we studied how system xc- regulates transmission at corticostriatal synapses, one of the two major types of striatal excitatory synapses. Electrophysiological recordings identified a significant decrease in the amplitude of striatal field excitatory postsynaptic potentials in mice genetically lacking xCT (xCT-/- mice) following stimulation of corticostriatal fibers. Further, using electron microscopy, we observed depletion of glutamate immunogold labeling from corticostriatal terminalsand their corresponding dendritic spines in xCT-/- mice. Genetic deletion of xCT did not, however, affect the morphology of corticostriatal synapses, the density of cortical innervation or the density of dendritic spines in the striatum. Proteomic analysis revealed decreased expression of a wide range of proteins involved in regulating presynaptic neurotransmitter release in the striatum of xCT-/- mice, including synaptophysin, VGLUT1, and members of the synapsin, septin, and syntaxin families. In addition, kinome profiling identified changes in striatal serine/threonine kinase activity, highlighting ERK signaling as a possible node of kinase dysregulation in xCT-/- mice. Finally, we evaluated the effect of the disturbed corticostriatal communication on the behavioral phenotype of the xCT-/- mice. In the marble burying test, a paradigm sensitive to changes in corticostriatal function, we measured a significant increase in repetitive digging behavior in xCT-/- mice. Whereas spontaneous grooming behavior was not affected by genetic deletion of xCT, we have preliminary findings from the reciprocal interaction and three-chamber test, suggesting aberrant social behavior. Together, our results identify system xc- as a modulator of corticostriatal synaptic transmission that may be relevant to neuropsychiatric disorders characterized by corticostriatal dysfunction and repetitive behavior, such as obsessive-compulsive behavior and autism.

Mechanisms driving cognitive improvements following nuclear receptor activation are poorly understood. The peroxisome proliferator–activated nuclear receptor alpha (PPARα) forms heterodimers with the nuclear retinoid X receptor (RXR). We report that PPARα mediates the improvement of hippocampal synaptic plasticity upon RXR activation in a transgenic mouse model with cognitive deficits. This improvement results from an increase in GluA1 subunit expression of the alpha-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, eliciting an AMPA response at the excitatory synapses. Associated with a two times higher PPARα expression in males than in females, we show that male, but not female, PPARα null mutants display impaired hippocampal long-term potentiation. Moreover, PPARα knockdown in the hippocampus of cognition-impaired mice compromises the beneficial effects of RXR activation on synaptic plasticity only in males. Furthermore, selective PPARα activation with pemafibrate improves synaptic plasticity in male cognition-impaired mice, but not in females. We conclude that striking sex differences in hippocampal synaptic plasticity are observed in mice, related to differences in PPARα expression levels., SCOPUS: ar.j, info:eu-repo/semantics/published

System xc-, with xCT as specific subunit, is an astrocytic antiporter that imports cystine in exchange for glutamate. System xc- is enhanced following oxidative stress and inflammation1, both present in the diseased or aged brain2. This upregulation might induce or further drive neurological dysfunction, as it could decrease the threshold for glutamate toxicity (by releasing glutamate)3 and modulate neuroinflammation (by driving the pro-inflammatory microglial phenotype)4, 5. Although inhibition of system xc- has been proposed as a therapeutic strategy for diverse neurological disorders (some age-related), reports on its function in physiological aging are sparse. We first studied the effect of genetic xCT deletion (xCT-/- mice) on life- and health-span. Next, we investigated the effect of aging on hippocampal xCT expression as well as the effect of xCT deletion on hippocampal aging (3-4 month versus 18-19-month old mice). As glutamate released via system xc- into the extrasynaptic space, could modulate synaptic transmission, we hypothesized that absence of system xc- might affect age-induced hippocampal deficits. We therefore compared age-related changes in hippocampal neurotransmission (slice electrophysiology), long-term potentiation (LTP) as well as hippocampus-dependent memory (Barnes maze, novel object location recognition task (NOLR)) between xCT-/- mice and their xCT+/+ littermates. xCT-/- mice have an increased life-span without deterioration of health-span, compared to xCT+/+ mice. Next, although no age-induced changes in xCT protein expression were seen in the brain of xCT+/+ mice (C57BL/6J background; 3-4 month versus 20-24-month old mice), xCT mRNA was significantly increased in hippocampus of 13-month old compared to 9-month old SAMP8 mice (model for accelerated aging). Aging prolongs the learning phase in the Barnes maze task for both genotypes. However, contrary to aged xCT+/+ mice and comparable to adult mice, the majority of aged xCT-/- mice use the hippocampus-dependent direct search strategy in the Barnes maze set-up at the end of the 5-day training session and they preserve this memory till 5 days after the last training session. In the NOLR, loss of system xc- induces impairment of spatial memory in adult mice. However, whereas aging negatively affects performance in the NOLR task in xCT+/+ mice, this was not the case for xCT-/- littermates and aged xCT-/- mice even perform better compared to adult xCT-/- mice. These data suggest that the hippocampal aging process is fundamentally different in mice lacking system xc-. In line with our behavioral data, basal hippocampal neurotransmission is indeed reduced in adult xCT-/- mice, while the age-related decrease in basal synaptic transmission as well as the age-induced changes in LTP that are observed in xCT+/+ mice, are prevented in the absence of system xc-. To conclude, our results demonstrate that absence of system xc- increases life-span and confers protection against age-related hippocampal dysfunction. Indeed, while system xc- seems to be important for hippocampal function in adult animals, it can become harmful during the aging process, thereby contributing to age-related memory decline.

Microglia designate the innate immune cells of the central nervous system (CNS). Their morphology is closely related to their function, from the highly ramified resting phenotype in the healthy brain to the amoeboid-like morphology of the activated typical state of pathological conditions. Indeed, microglial cells act as resident macrophages of the brain in order to respond to injury or pathogens. Recent studies have underlined the function of microglia in physiological conditions, especially via the secretion of several cytokines which have an important impact on synaptic plasticity and cognition. We will discuss the origin, the discovery, and the different activation states of microglia. We will also review the current knowledge about the functions of microglia during CNS development, immune surveillance and their implication in neuronal networks and synaptic plasticity in both physiological and pathological conditions. Microglia could represent a genuine potential therapeutic target in the context of neuroimmune diseases.