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State-of-the-Art review.; International audience; Maintaining energy balance is essential for survival and health. This physiological function is controlled by the brain, which adapts food intake to energy needs. Indeed, the brain constantly receives a multitude of biological signals that are derived from digested foods, or that originate from the gastrointestinal tract, energy stores (liver and adipose tissues), and from other metabolically active organs (muscles). These signals, which include circulating nutrients, hormones, and neuronal inputs from the periphery, collectively provide information on the overall energy status of the body. In the brain, several neuronal populations can specifically detect these signals. Nutrient-sensing neurons are found in discrete brain areas and are highly enriched in the hypothalamus. In turn, specialized brain circuits coordinate homeostatic responses acting mainly on appetite, peripheral metabolism, activity and arousal. Accumulating evidence shows that hypothalamic microglial cells located at the vicinity of these circuits can influence the brain control of energy balance. However, microglial cells could have opposite effects on energy balance, i.e., homeostatic or detrimental, and the conditions for this shift are not totally understood yet. One hypothesis relies on the extent of microglial activation, and nutritional lipids can considerably change it.

The piriform cortex is a unique structure receiving direct afferences from the olfactory bulb, which undergoes partial neuronal renewal and may confer significant plasticity to the olfactory system. In the piriform cortex, the expression levels of parvalbumin (PV) and perineural net (PNN) extracellular matrix are low but increase more slowly and later than in other cortical regions. This raises the hypothesis of a critical period of long-lasting plasticity. To analyze the role of OTX2 in piriform cortex PV cell maturation, we developed viral approaches specifically targeting these cells. Expression of an anti-OTX2 antibody (scFv) secreted by PV cells sequesters OTX2 in the extracellular medium, delays PV cell maturation and induces disassembly of their PNNs. Conversely, over-expression of OTX2 in PV cells accelerates their maturation and increases PNN assembly. Concomitant with changes in OTX2 levels are changes in the expression of enzymes controlling matrix catabolism and the sulfation patterns of chondroitin sulfate proteoglycans (CSPGs). We demonstrate that affecting OTX2 accumulation in PV cells modulates the maturation state of these cells and regulates olfactory memory. Prior to specific internalization by PV cells, OTX2 preferentially binds to type-E CSPGs within the PNNs of PV cells. Chondroitin sulfate glycosaminoglycans (GAGs) could serve as antagonists of OTX2, but their extraction, purification or chemical synthesis remains difficult. Our strategy was to establish a library of GAG peptide mimics and to validate their activity in vivo. In the adult mouse brain, the GAG mimic (EC'AC')6 diffuses significantly, is stable and strongly destabilizes PNN. It interferes with OTX2 and SEMA-3A signaling, breaks the positive feedback loop between OTX2 and PNNs, and reverses PV cell maturation. In the visual cortex, OTX2 blockade by (EC'AC')6 reopens a functional plasticity window in adult mice, demonstrating the therapeutic potential of GAG mimics. These two projects contribute to a better understanding of the non-autonomous activity of OTX2 in the control of plasticity in the piriform and visual cortices. They have allowed the development of tools that precisely neutralize OTX2. Extending these GAG mimic libraries to other proteins should contribute to a better understanding of other signaling mechanisms involving GAGs in the central nervous system., Le cortex piriforme est une structure singulière recevant des afférences directes du bulbe olfactif. Son renouvellement neuronal partiel pourrait conférer un état de plasticité important au système olfactif. Dans le cortex piriforme, les niveaux d’expression de parvalbumine (PV) et des réseaux matriciels périneuronaux (PNN) sont faibles mais augmentent plus lentement et tardivement que dans d’autres régions corticales. Cela soulève l’hypothèse d’une période critique de plasticité de longue durée. Pour analyser le rôle d’OTX2 dans cette maturation tardive du cortex piriforme, nous avons développé des approches virales ciblant spécifiquement les cellules PV du cortex piriforme. L’expression d’un anticorps anti-OTX2 (scFv) secrété par les cellules PV séquestre OTX2 dans le milieu extracellulaire, retarde la maturation des cellules PV et induit le désassemblage de leur PNN. À l’inverse, l’introduction d’OTX2 dans les cellules PV accélère leur maturation et l’accumulation des PNN. Les enzymes contrôlant le catabolisme de la matrice et la sulfatation des chondroïtines sont des cibles directes ou indirectes d’OTX2. Nous démontrons que jouer sur l’accumulation d’OTX2 dans les cellules PV module l’état de maturation de ces cellules et régule la mémoire olfactive. Avant internalisation spécifique par les cellules PV, OTX2 reconnaît préférentiellement les chondroïtines sulfates de type D/E des glycosaminoglycanes (GAG) dans les PNN des cellules PV. Ces sucres pourraient servir d’antagonistes d’OTX2, mais leur extraction, purification ou synthèse chimique reste difficiles. Notre stratégie a consisté à établir une bibliothèque de mimes peptidiques de GAG, puis de valider leur activité in vivo. Dans le cerveau de souris adulte, les peptides (EC'AC')6 diffusent, sont stables et déstabilisent fortement les PNN. Ils interfèrent avec la signalisation OTX2 et SEMA-3A, rompent la boucle de rétrocontrôle positive entre OTX2 et les PNN, déstabilisant ainsi la maturation des cellules PV. Dans le cortex visuel, le blocage d’OTX2 par les peptides (EC'AC')6 rouvre une fenêtre de plasticité chez les souris adultes, démontrant alors le potentiel thérapeutique des mimes de GAG. Ces deux projets contribuent à une meilleure compréhension de l’activité non-autonome d’OTX2 dans le contrôle de la plasticité des cortex piriforme et visuel. Ils ont permis le développement d’outils neutralisant OTX2 avec précision. Élargir ces banques de mimes, à d’autres protéines, devrait contribuer à mieux comprendre d'autres mécanismes de signalisation autour des GAG.

(1) Background: Despite the improvement of the in-hospital survival rate after aborted sudden cardiac death (SCD), cerebral anoxia may have severe neurologic consequences and may impair long-term outcome and quality of life of surviving patients. The aim of this study was to assess neurological outcomes at one year after resuscitated cardiac arrest; (2) Methods: This prospective, observational, and multicentre study included patients >18 yo admitted in the catheterisation laboratory for coronary angiography after aborted SCD between 1 May 2018 and 31 May 2020. Only patients who were discharged alive from hospital were evaluated. The primary endpoint was survival without neurological sequelae at one-year follow-up defined by a cerebral performance category (CPC) of one or two. Secondary end points included all-cause mortality, New York Heart Association (NYHA) functional class, neurologic evaluation at discharge, three-month and one-year follow-up using the CPC scale, and quality of life at 1 year using the Quality of Life after Brain Injury (QOLIBRI) questionnaire; (3) Results: Among 143 patients admitted for SCD within the study period, 61 (42.7%) were discharged alive from hospital, among whom 55 (90.1%) completed the one-year follow-up. No flow and low flow times were 1.9 ± 2.4 min and 16.5 ± 10.4 min, respectively. For 93.4% of the surviving patients, an initial shockable rhythm (n = 57) was observed and acute coronary syndrome was diagnosed in 75.4% of them (n = 46). At 1 year, survival rate without neurologic sequelae was 87.2% (n = 48). Patients with poor outcome were older (69.3 vs. 57.4 yo; p = 0.04) and had lower body mass index (22.4 vs. 26.7; p = 0.013) and a lower initial Left Ventricle Ejection Fraction (LVEF) (32.1% vs. 40.3%; p = 0.046). During follow-up, neurological status improved in 36.8% of patients presenting sequelae at discharge, and overall quality of life was satisfying for 66.7% of patients according to the QOLIBRI questionnaire; (4) Conclusions: Among patients admitted to the catheterisation laboratory for aborted SCD, mainly related to Acute Coronary Syndrom (ACS), less than a half of them were alive at discharge. However, the one-year survival rate without neurological sequelae was high and overall quality of life was good.

International audience; Abstract Brain administration of human platelet lysates (HPL) is an emerging biotherapy of neurodegenerative and traumatic diseases of the central nervous system (CNS). HPLs being prepared from pooled platelet concentrates (PCs) increasing viral risks, manufacturing processes should incorporate robust virus-reduction treatments. We evaluated a 19±2-nm virus removal nanofiltration process using hydrophilic regenerated cellulose hollow fibers on the properties of a neuroprotective heat-treated HPL (HPPL). Spiking experiments demonstrated >5.30 log removal of 20~22-nm non-enveloped minute virus of mice-mock particles using an immuno-quantitative polymerase chain reaction assay. The nanofiltered HPPL (NHPPL) contained a range of neurotrophic factors like HPPL. There was >2 log removal of extracellular vesicles (EVs), associated with decreased expression of pro-thrombogenic phosphatidylserine and procoagulant activity. LC-MS/MS proteomics showed that ca. 80% of HPPL proteins, including neurotrophins, cytokines, and antioxidants, were still found in NHPPL, whereas proteins associated with some infections and cancer-associated pathways, pro-coagulation and EVs, were removed. NHPPL maintained intact neuroprotective activity in LUHMES dopaminergic neuron model of Parkinson’s disease (PD), stimulated the differentiation of SH-SY5Y neuronal cells and showed preserved anti-inflammatory function upon intranasal administration in a mouse model of traumatic brain injury (TBI). Therefore, nanofiltration of HPL is feasible, lowers the viral, prothrombotic and procoagulant risks, and preserves the neuroprotective and anti-inflammatory properties in neuronal pre-clinical of PD and TBI.

International audience

International audience; Intracellular membrane protein trafficking is crucial for both normal cellular physiology and cell-cell communication. The conventional secretory route follows transport from the Endoplasmic reticulum (ER) to the plasma membrane via the Golgi apparatus. Alternative modes of secretion which can bypass the need for passage through the Golgi apparatus have been collectively termed as Unconventional protein secretion (UPS). UPS can comprise of cargo without a signal peptide or proteins which escape the Golgi in spite of entering the ER. UPS has been classified further depending on the mode of transport. Type I and Type II unconventional secretion are non-vesicular and non-SNARE protein dependent whereas Type III and Type IV dependent on vesicles and on SNARE proteins. In this review, we focus on the Type III UPS which involves the import of cytoplasmic proteins in membrane carriers of autophagosomal/endosomal origin and release in the extracellular space following SNARE-dependent intracellular membrane fusion. We discuss the role of vesicular SNAREs with a strong focus on VAMP7, a vesicular SNARE involved in exosome, lysosome and autophagy mediated secretion. We further extend our discussion to the role of unconventional secretion in health and disease with emphasis on cancer and neurodegeneration.

International audience; Mechanical ventilation is a highly utilized life-saving tool, particularly in the current era. The use of EEG in a brain–ventilator interface (BVI) to detect respiratory discomfort (due to sub-optimal ventilator settings) would improve treatment in mechanically ventilated patients. This concept been realized via development of an EEG covariance-based classifier that detects respiratory-related cortical activity associated with respiratory discomfort. The aim of this study was to determine if head movement, detected by an accelerometer, can detect and/or improve detection of respiratory-related cortical activity compared to EEG alone. In 25 healthy participants, EEG and acceleration of the head were recorded during loaded and quiet breathing in the seated and lying postures. Detection of respiratory-related cortical activity using an EEG covariance-based classifier was improved by inclusion of data from an Accelerometer-based classifier, i.e. classifier ‘Fusion’. In addition, ‘smoothed’ data over 50s, rather than one 5s window of EEG/Accelerometer signals, improved detection. Waveform averages of EEG and head acceleration showed the incidence of pre-inspiratory potentials did not differ between loaded and quiet breathing, but head movement was greater in loaded breathing. This study confirms that compared to event-related analysis with >5 minutes signal acquisition, an EEG-based classifier is a clinically valuable tool with rapid processing, detection times and accuracy. Data smoothing would introduce a small delay (< 1 minute) but improves detection results. As head acceleration improved detection compared to EEG alone, the number of EEG signals required to detect respiratory discomfort with future BVIs could be reduced if head acceleration is included.

International audience; BACKGROUND AND OBJECTIVE: We recently showed that perinatal exposure to diets with unbalanced n-6:n-3 polyunsaturated fatty acid (PUFA) ratios affects the olfactory mucosa (OM) fatty acid composition. To assess the repercussions of these modifications, we investigated the impact of diets unbalanced in n-3 PUFAs on the molecular composition and functionality of the OM in young mice. METHODS: After mating, female mice were fed diets either deficient in α-linolenic acid (LOW diet) or supplemented with n-3 long-chain PUFAs (HIGH diet) during the perinatal period. Weaned male offspring were then fed ad libitum with the same experimental diets for 5 weeks. At 8 weeks of age, olfactory behavior tests were performed in young mice. The fatty acid composition of OM and olfactory cilia, as well as the expression of genes involved in different cellular pathways, were analyzed. The electroolfactograms induced by odorant stimuli were recorded to assess the impact of diets on OM functionality. RESULTS AND CONCLUSION: Both diets significantly modified the fatty acid profiles of OM and olfactory cilia in young mice. They also induced changes in the expression of genes involved in olfactory signaling and in olfactory neuron maturation. The electroolfactogram amplitudes were reduced in mice fed the LOW diet. Nevertheless, the LOW diet and the HIGH diet did not affect mouse olfactory behavior. Our study demonstrated that consumption of diets deficient in or supplemented with n-3 PUFAs during the perinatal and postweaning periods caused significant changes in young mouse OM. However, these modifications did not impair their olfactory capacities.

Cocaine induces many supranormal changes in neuronal activity in the brain, notably in learning- and reward-related regions, in comparison to nondrug rewards - a difference that is thought to contribute to its relatively high addictive potential. However, when facing a choice between cocaine and a nondrug reward (e.g., water sweetened with saccharin), most rats do not choose cocaine, as one would expect from the extent and magnitude of its global activation of the brain, but instead choose the nondrug option. We recently showed that cocaine, though larger in magnitude, is also an inherently more delayed reward than sweet water, thereby explaining why it has less value during choice and why rats opt for the more immediate nondrug option. Here we used a large-scale fos brain mapping approach to measure brain responses to each option in saccharin-preferring rats, with the hope to identify brain regions whose activity may explain the preference for the nondrug option. In total, fos expression was measured in 142 brain levels corresponding to 52 brain subregions and composing 5 brain macrosystems. Overall, our findings confirm in rats with a preference for saccharin that cocaine induces more global brain activation than the preferred nondrug option does. Only very few brain regions were uniquely activated by saccharin. They included regions involved in taste processing (i.e., anterior gustatory cortex) and also regions involved in processing reward delay and intertemporal choice (i.e., some components of the septohippocampal system and its connections with the lateral habenula).

International audience; Brain anomalies are frequently found in early psychoses. Although they may remain undetected for many years, their interpretation is critical for differential diagnosis. In secondary psychoses, their identification may allow specific management. They may also shed light on various pathophysiological aspects of primary psychoses. Here we reviewed cases of secondary psychoses associated with brain anomalies, reported over a 20-year period in adolescents and young adults aged 13 to 30 years old. We considered age at first psychotic symptoms, relevant medical history, the nature of psychiatric symptoms, clinical red flags, the nature of the brain anomaly reported, and the underlying disease. We discuss the relevance of each brain area in light of normal brain function, recent case-control studies, and postulated pathophysiology. We show that anomalies in all regions, whether diffuse, multifocal, or highly localized, may lead to psychosis, without necessarily being associated with non-psychiatric symptoms. This underlines the interest of neuroimaging in the initial workup, and supports the hypothesis of psychosis as a global network dysfunction that involves many different regions.

International audience; Glycogen storage disease type 1a (GSD Ia) is an inborn error of carbohydrate metabolism. Despite severe hyperlipidemia, GSD Ia patients show limited atherogenesis compared to age-and-gender matched controls. Employing a GSD Ia mouse model that resembles the severe hyperlipidemia in patients, we here found increased atherogenesis in GSD Ia. These data provide a rationale for investigating atherogenesis in GSD Ia in a larger patient cohort.

International audience; Background: Bipolar disorder (BD) is a severe chronic psychiatric disorder affecting 0.5 to 1% of the population worldwide. To date, most studies have estimated the cost of BD via information sourced from insurance claims with limited information on clinical characteristics and course of BD. The aims of this study are (i) to estimate the direct healthcare cost associated with BD and to identify contributing factors and (ii) to study the evolution of cost during a two-year follow-up period.Method: We analyzed a sample of 1116 individuals with BD included in the Advanced Centers of Expertise in Bipolar Disorder cohort. We estimated the direct healthcare cost per year and per patient, and we identified the clinical features of patients with BD associated with higher direct healthcare costs. In a subsample of patients followed up for two years centers of expertise for BD, we studied the evolution of direct healthcare cost.Results: The average cost of bipolar disorder was € 6910 per year and per patient. Clinical features of BD, sociodemographic characteristics, and associated addiction were associated with higher direct healthcare costs. In the subsample of patients followed-up for two years, direct healthcare cost dropped by more than 50%, strongly suggesting the beneficial effect of specialized care organization.Limitation: We did not estimate indirect healthcare and intangible costs.Conclusion: Our study investigates the cost of BD and its evolution in a deeply phenotyped longitudinal sample. Cost-utility and cost-effectiveness analyses are required to inform resource allocation decisions and to promote innovative healthcare organizations.

The vestibular system in the inner ear plays a central role in sensorimotor control by informing the brain about the orientation and linear acceleration of the head. In the present work we studied the zebrafish larva response to different vestibular stimulus, to characterize the vestibulospinal reflexes and the underlying neural substrates. In the first part of the thesis we described the tail movements elicited by vestibular stimulation, finding that larvae use their tail to compensate imbalance. Next, we characterized different neural populations that are active during sinusoidal-roll stimulation. Despite the fact that vestibular cues are central for locomotion and postural control, most neurophysiological experiments are performed using head-fixed configurations depriving animals of vestibular inputs. To overcome this limitation, we decorated the utricular otolith of the vestibular system with paramagnetic nanoparticles. This procedure effectively endowed the animal with magneto-sensitive capacities: applied magnetic field gradients induced forces on the otoliths resulting in robust behavioral responses comparable to that evoked by rotating the animal by up to 20°. We recorded the whole-brain neuronal response to this fictive vestibular stimulation using light-sheet functional imaging. Experiments performed in unilaterally injected fish revealed the activation of a commissural inhibition between the brain hemispheres. This magnetic-based stimulation technique opens new perspectives to functionally dissect the neural circuits underlying vestibular processing and to develop multisensory virtual environments including vestibular feedback., Le système vestibulaire de l'oreille interne joue un rôle central dans le contrôle sensorimoteur en informant le cerveau de l'orientation et de l'accélération linéaire de la tête. Dans ce travail, nous avons étudié la réponse des larves de poisson zèbre à différents stimuli vestibulaires, afin de caractériser les réflexes vestibulospinaux et les substrats neuraux sous-jacents. D'abord, nous avons décrit les mouvements de la queue provoqués par la stimulation vestibulaire, en constatant que les larves utilisent leur queue pour compenser le déséquilibre. Ensuite, nous avons caractérisé les différentes populations neuronales qui sont actives pendant la stimulation sinusoïdale de la queue. Bien que les signaux vestibulaires soient essentiels à la locomotion et au contrôle postural, la plupart des expériences neurophysiologiques sont réalisées dans des configurations où la tête est fixée, ce qui prive les animaux des signaux vestibulaires. Pour surmonter cette limitation, nous avons utilisé nanoparticules paramagnétiques pour stimuler les système vestibulaire. Nous avons enregistré la réponse neurale de l'ensemble du cerveau à cette stimulation vestibulaire fictive en utilisant l'imagerie fonctionnelle par nappe à lumière. Les expériences réalisées chez des poissons injectés unilatéralement ont révélé l'activation d'une inhibition commissurale entre les hémisphères cérébraux. Cette technique de stimulation magnétique ouvre de nouvelles perspectives pour disséquer fonctionnellement les circuits neuronaux qui sous-tendent le traitement vestibulaire et pour développer des environnements virtuels multisensoriels incluant un retour vestibulaire.

International audience; The relationship between posttraumatic stress disorder (PTSD) and focal epilepsy is poorly understood. It has been hypothesized that there is a complex and reciprocal potential reinforcement of the symptoms of each condition. In this study, we investigated whether there are PTSD-specific brain changes in temporal lobe epilepsy (TLE). Brain fluorodeoxyglucose positron emission tomography (PET) metabolism was compared between controls and two groups of TLE patients: one group of 15 patients fulfilling the criteria for a potential diagnosis of PTSD (TLE-PTSD+), another group of 24 patients without a diagnosis of PTSD (TLE-PTSD-), and a group of 30 healthy control participants. We compared the differences in brain PET metabolism among these three groups, and we studied their correlations with interictal and peri-ictal scales of PTSD symptoms. TLE-PTSD+ patients showed more significant hypometabolism involving right temporal and right orbitofrontal cortex in comparison to TLE-PTSD- patients and healthy subjects. Moreover, degree of reduced metabolism in these brain areas correlated with interictal and peri-ictal PTSD questionnaire scores. PTSD in temporal epilepsy is associated with specific changes in neural networks, affecting limbic and paralimbic structures. This illustrates the close intertwining of epileptogenic and psychogenic processes in these patients

In recent years, variants in the catalytic and regulatory subunits of the kinase CK2 have been found to underlie two different, yet symptomatically overlapping neurodevelopmental disorders, termed Okur-Chung neurodevelopmental syndrome (OCNDS) and Poirier-Bienvenu neurodevelopmental syndrome (POBINDS). Both conditions are predominantly caused by de novo missense or nonsense mono-allelic variants. They are characterized by a generalized developmental delay, intellectual disability, behavioral problems (hyperactivity, repetitive movements and social interaction deficits), hypotonia, motricity and verbalization deficits. One of the main features of POBINDS is epilepsies, which are present with much lower prevalence in patients with OCNDS. While a role for CK2 in brain functioning and development is well acknowledged, these findings for the first time clearly link CK2 to defined brain disorders. Our review will bring together patient data for both syndromes, aiming to link symptoms with genotypes, and to rationalize the symptoms through known cellular functions of CK2 that have been identified in preclinical and biochemical contexts. We will also compare the symptomatology and elaborate the specificities that distinguish the two syndromes.

International audience; Awake surgery for brain gliomas improves resection while minimizing morbidity. Although intraoperative mapping was originally used to preserve motor and language functions, the considerable increase of life expectancy, especially in low-grade glioma, resulted in the need to enhance patients' long-term quality of life. If the main goal of awake surgery is to resume normal familial and socio-professional activities, preventing hemiparesis and aphasia is not sufficient: cognitive and emotional functions must be considered. To monitor higher-order functions, e.g., executive control, semantics or mentalizing, further tasks were implemented into the operating theater. Beyond this more accurate investigation of function-specific neural networks, a better exploration of the inter-system communication is required. Advances in brain connectomics led to a meta-network perspective of neural processing, which emphasizes the pivotal role of the dynamic interplay between functional circuits to allow complex and flexible, goal-directed behaviors. Constant multi-tasking with time constraint in awake patients may be proposed during intraoperative mapping, since it provides a mirror of the (dys)synchronization within and across neural networks and it improves the sensitivity of behavioral monitoring by increasing cognitive demand throughout the resection. Electrical mapping may hamper the patient to perform several tasks simultaneously whereas he/she is still capable to achieve each task in isolation. Unveiling the meta-network organization during awake mapping by using a more ecological multi-demand testing, more representative of the real-life conditions, constitutes a reliable way to tailor the surgical onco-functional balance based upon the expectations of each patient, enabling him/her to resume an active life with long-lasting projects.

In the human, the folding of the brain takes place mostly in utero, during the last trimester of pregnancy, resulting in a convoluted cortical surface at term, displaying furrows (sulci) and crests (gyri), whose patterns remain relatively stable throughout life. The same global folding organization is found between individuals, allowing to identify and compare matching sulci, while the more refined individual folding pattern is unique. The variability of sulcal folding pattern and its relations to functional specialization (both in health and pathology) are increasingly investigated in the mature brain, while studies in the developing brain are still scarce because of the many challenges of early-life neuroimaging. During my PhD, I have investigated the dynamics of folding pattern based on longitudinally acquired magnetic resonance imaging (MRI) images from a cohort of extremely preterm infants, imaged once around the equivalent of 7 months of pregnancy, and once at term-equivalent age (TEA). I have adapted a pipeline established for adult sulcal shape characterization to the context of developing folds and applied it to four sulcal objects: the central sulcus, the sylvian fissure, and the perisylvian region and the inferior frontal region (these last two were only investigated at TEA because of their late appearance in the brain).Throughout my works, I have described the shape variability observed in the central sulcus and the sylvian fissure at both ages. This led me to observe a consistent encoding of pattern between both ages, suggesting an early expression of sulcal shape features. I have incidentally tested if the central sulcus’s shape was able to predict later motor outcome: even though it did not achieve significant results, it still seemed to suggest some functional relevance in sulcal signatures. My observations on the central sulcus and sylvian fissure were concordant with the state of the art and detailed additional pattern specificities and the chronology of shape encoding. My focus in and around the sylvian fissure additionally led me to hypothesize a different dynamic in opercularization (the process leading to the burial of the insular cortex under the frontal, parietal and temporal lobes) from that in sulcation (the process leading to the formation of sulci): opercularization seemed to show an advance in the left hemisphere while sulcation has previously been reported to show an advance in the right hemisphere. Moreover, I have captured hemispheric asymmetries and detailed their shape characteristics in each fold-related object or region considered. These studies have therefore contributed to shedding more light on early-life asymmetries., which could be linked to the functional lateralization of the brain regarding handedness or language perception.In order to complement my contributions, additional investigations should be led in different directions, including the description of pattern variability and its links with brain function in later developmental stages in the child and the adult, the quantification of prematurity-induced sulcal alterations, and the further investigation of the relation between opercularization and sulcation processes, which might interact together during development., Chez l’homme, le cerveau se plisse principalement in utero, pendant le troisième trimestre de grossesse : la surface du cortex au moment de la naissance à terme présente alors des creux (sillons) et des bosses (gyri) dont la forme reste relativement stable au cours de la vie. Les motifs de plissement du cerveau, bien qu'uniques à chaque individu, présentent une organisation globalement cohérente au sein de l'espèce, permettant d'identifier et de comparer les sillons entre individus. La variabilité en forme des sillons et ses relations avec la spécialisation fonctionnelle (que le contexte soit pathologique ou non) sont de plus en plus étudiées dans le cerveau mature, mais les études dans le cerveau en développement restent rares à cause de nombreuses difficultés soulevées par la neuro-imagerie du tout-petit.Pendant mon doctorat, j’ai étudié les dynamiques de forme du plissement cortical sur la base de données d’imagerie par résonance magnétique (IRM) acquises longitudinalement dans une cohorte de nouveau-nés extrêmement prématurés, imagés vers l’âge équivalent à 7 mois de grossesse et à l’âge équivalent de la naissance à terme. J’ai adapté une méthode établie pour le cerveau adulte de caractérisation de la forme des sillons au contexte complexe du développement, et je l’ai appliquée à quatre régions corticales distinctes : le sillon central, la scissure sylvienne, et les régions périsylvienne et frontale inférieure, ces deux dernières n’ayant été explorées qu’à l’âge équivalent du terme du fait de leur apparition tardive dans le cerveau.À travers mes travaux, j’ai tout d’abord décrit la variabilité en forme du sillon central et de la scissure sylvienne. Ceci m’a amenée à découvrir que la forme de ces plis est cohérente entre les deux âges, ce qui suggère un encodage précoce. J’ai par ailleurs évalué si la forme du sillon central permettait de prédire le devenir moteur des sujets : faute d’être significative,elle a néanmoins suggéré la pertinence fonctionnelle de certaines signatures sulcales.Tout en étant concordantes avec l’état de l’art, mes observations sur le sillon central et la scissure sylvienne ont permis de détailler les motifs spécifiques et la chronologie d’encodage de leur forme précoce. En ciblant la scissure sylvienne et ses régions environnantes, j’ai émis l’hypothèse de dynamiques différentes entre l’opercularisation (processus menant au recouvrement du lobe insulaire par les lobes frontaux, pariétaux et temporaux) et la sulcation (processus menant à la formation des sillons) : mes observations ont alors suggéré une avance de l’hémisphère gauche dans le cadre de l’opercularisation, contre une avance de l’hémisphère droit pour la sulcation.Par ailleurs, j’ai capturé des asymétries conséquentes entre hémisphères cérébraux, en détaillant les caractéristiques de formes dans chacun des objets sulcaux considérés : ces travaux ont ainsi contribué à une meilleure compréhension des asymétries précoces qui pourraient être liées au développement de la latéralisation fonctionnelle du cerveau en liens avec la latéralité manuelle ou la perception du langage.De manière à compléter mes contributions, différentes directions devraient être explorées, dont la description de la variabilité des motifs des sillons et leurs relations avec le fonctionnement cérébral à des stades plus tardifs de développement de l’enfant et dans le cerveau de l’adulte, la quantification des altérations de plissement liées à la prématurité, et l’investigation plus approfondie des rapports entre opercularisation et sulcation, qui pourraient interagir ensemble au cours du développement.

International audience; We previously linked TSHZ3 haploinsufficiency to autism spectrum disorder (ASD) and showed that embryonic or postnatal Tshz3 deletion in mice results in behavioral traits relevant to the two core domains of ASD, namely social interaction deficits and repetitive behaviors. Here, we provide evidence that cortical projection neurons (CPNs) and striatal cholinergic interneurons (SCINs) are two main and complementary players in the TSHZ3-linked ASD syndrome. In the cerebral cortex, TSHZ3 is expressed in CPNs and in a proportion of GABAergic interneurons, but not in cholinergic interneurons or glial cells. In the striatum, TSHZ3 is expressed in all SCINs, while its expression is absent or partial in the other main brain cholinergic systems. We then characterized two new conditional knockout (cKO) models generated by crossing Tshz3 flox/flox with Emx1-Cre (Emx1-cKO) or Chat-Cre (Chat-cKO) mice to decipher the respective role of CPNs and SCINs. Emx1-cKO mice show altered excitatory synaptic transmission onto CPNs and impaired plasticity at corticostriatal synapses, with neither cortical neuron loss nor abnormal layer distribution. These animals present social interaction deficits but no repetitive patterns of behavior. Chat-cKO mice exhibit no loss of SCINs but changes in the electrophysiological properties of these interneurons, associated with repetitive patterns of behavior without social interaction deficits. Therefore, dysfunction in either CPNs or SCINs segregates with a distinct ASD behavioral trait. These findings provide novel insights onto the implication of the corticostriatal circuitry in ASD by revealing an unexpected neuronal dichotomy in the biological background of the two core behavioral domains of this disorder.

International audience; Increasing loss of structure and function of neurons and decline in cognitive function is commonly seen during the progression of neurologic diseases, although the causes and initial symptoms of individual diseases are distinct. This observation suggests a convergence of common degenerative features. In myotonic dystrophy type 1 (DM1), the expression of expanded CUG RNA induces neurotransmission dysfunction before axon and dendrite degeneration and reduced MBNL2 expression associated with aberrant alternative splicing. The role of loss of function of MBNL2 in the pathogenesis of neurodegeneration and the causal mechanism of neurodegeneration-reduced expression of MBNL2 remain elusive. Here, we show that increased MBNL2 expression is associated with neuronal maturation and required for neuronal morphogenesis and the fetal to adult developmental transition of RNA processing. Neurodegenerative conditions including NMDA receptor (NMDAR)-mediated excitotoxicity and dysregulated calcium homeostasis triggered nuclear translocation of calpain-2, thus resulting in MBNL2 degradation and reversal of MBNL2-regulated RNA processing to developmental patterns. Nuclear expression of calpain-2 resembled its developmental pattern and was associated with MBNL2 degradation. Knock-down of calpain-2 expression or inhibition of calpain-2 nuclear translocation prevented neurodegeneration-reduced MBNL2 expression and dysregulated RNA processing. Increased calpain-2 nuclear translocation associated with reduced MBNL2 expression and aberrant RNA processing occurred in models for DM1 and Alzheimer's disease (AD) including EpA960/CaMKII-Cre mice of either sex and female APP/PS1 and THY-Tau22 mice. Our results identify a regulatory mechanism for MBNL2 downregulation and suggest that calpain-2-mediated MBNL2 degradation accompanied by re-induction of a developmental RNA processing program may be a converging pathway to neurodegeneration.SIGNIFICANCE STATEMENTNeurologic diseases share many features during disease progression, such as cognitive decline and brain atrophy, which suggests a common pathway for developing degenerative features. Here, we show that the neurodegenerative conditions glutamate-induced excitotoxicity and dysregulated calcium homeostasis induced translocation of the cysteine protease calpain-2 into the nucleus, resulting in MBNL2 degradation and reversal of MBNL2-regulated RNA processing to an embryonic pattern. Knock-down or inhibition of nuclear translocation of calpain-2 prevented MBNL2 degradation and maintained MBNL2-regulated RNA processing in the adult pattern. Models of myotonic dystrophy and Alzheimer's disease (AD) also showed calpain-2-mediated MBNL2 degradation and a developmental RNA processing program. Our studies suggest MBNL2 function disrupted by calpain-2 as a common pathway, thus providing an alternative therapeutic strategy for neurodegeneration.

The activation of the transient receptor potential (TRP) channels expressed by sensory neurons is essential to the transduction of thermal and mechanical sensory information. In the setting of chronic inflammatory conditions, the activation of the melastatin family member 8 (TRPM8), the TRP vanilloid 1 (TRPV1), and the TRP ankyrin 1 (TRPA1) is correlated with pain hypersensitivity reactions. Monoterpenes, among which pulegone and menthol, a major class of phytocompounds present in essential oils of medicinal plants, are known modulators of those TRP channels activity. In the present review, we correlate the monoterpene content of plants with their historical therapeutic properties. We then describe how monoterpenes exert their anti-inflammatory and antihyperalgesia effects through modulation of TRP channels activity. Finally, we discuss the importance and the potential of characterizing new plant extracts and reassessing studied plant extracts for the development of ethnopharmacology-based innovative treatments for chronic pain. This review suggests that monoterpene solutions, based on composition from traditional healing herbs, offer an interesting avenue for the development of new phytotherapeutic treatments to alleviate chronic inflammatory pain conditions.

Adaptation to our social environment requires learning how to avoid potentially harmful situations, such as encounters with aggressive individuals. Threatening facial expressions can evoke automatic stimulus-driven reactions, but whether their aversive motivational value suffices to drive instrumental active avoidance remains unclear. When asked to freely choose between different action alternatives, participants spontaneously—without instruction or monetary reward—developed a preference for choices that maximized the probability of avoiding angry individuals (sitting away from them in a waiting room). Most participants showed clear behavioral signs of instrumental learning, even in the absence of an explicit avoidance strategy. Inter-individual variability in learning depended on participants’ subjective evaluations and sensitivity to threat approach feedback. Counterfactual learning best accounted for avoidance behaviors, especially in participants who developed an explicit avoidance strategy. Our results demonstrate that implicit defensive behaviors in social contexts are likely the product of several learning processes, including instrumental learning.

In this review article, we present the major insights from and challenges faced in the acquisition, analysis and modeling of astrocyte calcium activity, aiming at bridging the gap between those fields to crack the complex astrocyte “Calcium Code”. We then propose strategies to reinforce interdisciplinary collaborative projects to unravel astrocyte function in health and disease.

Social behavior is a basic domain affected by several neurodevelopmental disorders, including ASD and a heterogeneous set of neuropsychiatric disorders. The SCRIB gene that codes for the polarity protein SCRIBBLE has been identified as a risk gene for spina bifida, the most common type of neural tube defect, found at high frequencies in autistic patients, as well as other congenital anomalies. The deletions and mutations of the 8q24.3 region encompassing SCRIB are also associated with multisyndromic and rare disorders. Nonetheless, the potential link between SCRIB and relevant social phenotypes has not been fully investigated. Hence, we show that Scribcrc/+ mice, carrying a mutated version of Scrib, displayed reduced social motivation behavior and social habituation, while other behavioral domains were unaltered. Social deficits were associated with the upregulation of ERK phosphorylation, together with increased c-Fos activity. Importantly, the social alterations were rescued by both direct and indirect pERK inhibition. These results support a link between polarity genes, social behaviors and hippocampal functionality and suggest a role for SCRIB in the etiopathology of neurodevelopmental disorders. Furthermore, our data demonstrate the crucial role of the MAPK/ERK signaling pathway in underlying social motivation behavior, thus supporting its relevance as a therapeutic target.

Microcircuits in the neocortex are functionally organized along layers and columns, which are the fundamental modules of cortical information processing. While the function of cortical microcircuits has focused on neuronal elements, much less is known about the functional organization of astrocytes and their bidirectional interaction with neurons. Here, we show that Cannabinoid type 1 receptor (CB1R)-mediated astrocyte activation by neuron-released endocannabinoids elevate astrocyte Ca2+ levels, stimulate ATP/adenosine release as gliotransmitters, and transiently depress synaptic transmission in layer 5 pyramidal neurons at relatively distant synapses (˃20 μm) from the stimulated neuron. This astrocyte-mediated heteroneuronal synaptic depression occurred between pyramidal neurons within a cortical column and was absent in neurons belonging to adjacent cortical columns. Moreover, this form of heteroneuronal synaptic depression occurs between neurons located in particular layers, following a specific connectivity pattern that depends on a layer-specific neuron-to-astrocyte signaling. These results unravel the existence of astrocyte-mediated nonsynaptic communication between cortical neurons and that this communication is column- and layer-specific, which adds further complexity to the intercellular signaling processes in the neocortex.

BackgroundEEG is a common tool for monitoring anaesthetic depth but is rarely reused at large for biomedical research. This study sets out to explore repurposing of EEG during anaesthesia to learn biomarkers of brain ageing in the absence of consciousness.MethodsWe focused on brain age estimation as an example. Using machine learning, we reanalysed 4-electrodes EEG of 323 patients under propofol and sevoflurane. We included spatio-spectral features from stable anaesthesia for EEG-based age prediction applying recently published reference methods. Anaesthesia was considered stable when 95% of the total power was below a frequency between 8Hz and 13Hz.ResultsWe considered moderate-risk patients (ASA ConclusionsEEG from general anaesthesia may enable state-of-the-art brain age prediction. Yet, differences between anaesthetic drugs can impact the effectiveness of repurposing EEG from anaesthesia. To unleash the dormant potential of repurposing EEG-monitoring for clinical and health research, in the absence of consciousness, collecting larger datasets with precisely documented drug dosage will be key enabling factors.

Binge drinking (BD) behaviour, defined as repeated episodes of rapid and massive alcohol (ethanol) consumption, is widespread among adolescents and young adults and can lead to long term memory deficits. Nevertheless, the neurobiological mechanisms of ethanol during the initial BD episodes, which may reveal the elementary steps of the response to ethanol, remain unknown. In a first work, our laboratory revealed that two ethanol BD episodes in adolescent rats (EtOH 3g/kg, i.p.; blood ethanol content 2g/L) where sufficient to induce learning deficits after 48h, associated, at the cellular level, with an abolition of long term depression and an increase in long term potentiation - two types of synaptic plasticity that corresponds to the cellular mechanisms of memory - recorded ex vivo in the CA1 area of the hippocampus, and with an increase in the functionality of the GluN2B subunit of the NMDA-type glutamate receptor. The challenge of this thesis was to determine how these effects appeared, by considering the involvement of epigenetic and/or neuroinflammatory mechanisms. By combining behavioral, electrophysiological on hippocampal slices, pharmacological et biochemical approaches, we demonstrate that 48h after ethanol, the expression of type 2 histone deacetylase (HDAC2) is increased in the CA1 area and that the prior administration of sodium butyrate (an HDAC inhibitor) prevents the overall effects of ethanol. Furthermore, our results show a decrease of neuronal TLR4 expression in CA1 48h after the two BD episodes and the administration of anti-inflammatory drugs such as minocycline, indomethacin of the TLR4 antagonist TAK-242 also prevents ethanol induced disturbances. We thus conclude that from the first exposures, BD triggers neuroinflammatory processes that seem to occur early, but also epigenetic processes that may occur later and disrupt synaptic plasticity in the hippocampus and consequently, learning. Blocking the establishment of such processes opens interesting perspectives in the prevention of memory deficits in binge drinkers, Le comportement de binge drinking (BD), défini comme la répétition d'épisodes de consommation rapide et massive d'alcool (éthanol), est très répandu chez les adolescents et jeunes adultes et peut conduire à des déficits de mémoire à long terme. Cependant, les mécanismes neurobiologiques de l'éthanol lors des premiers épisodes de BD, qui pourraient révéler les éléments de base de la réponse à l'alcool, restent méconnus. Dans un premier travail, notre laboratoire avait mis en évidence que deux épisodes de BD chez le rat adolescent (EtOH 3g/kg i.p.; éthanolémie 2g/L) suffisaient à induire des déficits d'apprentissage après 48h, associés sur le plan cellulaire à une abolition de la dépression à long terme et à une augmentation de la potentialisation à long terme – deux types de plasticité qui correspondent aux mécanismes cellulaires de la mémoire – enregistrées ex vivo dans l'aire CA1 de l'hippocampe, et à une augmentation de la fonctionnalité des sous-unités GluN2B du récepteur au glutamate de type NMDA. Tout l'enjeu de ce travail de thèse a été de déterminer comment ces effets apparaissaient, en envisageant l'implication de mécanismes épigénétiques et/ou neuroinflammatoires. En combinant des approches comportementales, électrophysiologiques sur tranches d'hippocampe, pharmacologiques et biochimiques, nous démontrons que 48h après l'éthanol, l'expression de l'histone déacétylase de type 2 (HDAC2) est augmentée dans l'aire CA1 et que l'administration préalable de butyrate de sodium (un inhibiteur des HDAC) prévient l'ensemble des effets de l'éthanol. De plus, nos résultats indiquent une sous-expression neuronale du récepteur TLR4 dans CA1 48h après les deux épisodes de BD et l'administration de substances anti-inflammatoires telles que la minocycline, l'indométhacine ou l'antagoniste du TLR4, le TAK-242, préviennent également les perturbations induites par l'éthanol. Nous concluons ainsi que dès les premières expositions, le BD déclenche des processus neuroinflammatoires qui semblent intervenir précocement, mais également des processus épigénétiques qui interviennent peut-être plus tardivement et qui perturbent la plasticité synaptique dans l'hippocampe et par conséquent, l'apprentissage. Bloquer la mise en place de tels processus ouvre des perspectives intéressantes dans la prévention des déficits mnésiques chez les binge drinkers

International audience; Oligophrenin-1 (OPHN1) is a Rho-GTPase-activating protein (RhoGAP), whose mutations are associated with X-linked intellectual disability (XLID). OPHN1 is enriched at the synapse in both pre- and postsynaptic compartments, where it regulates the RhoA/ROCK/MLC2 signaling pathway, playing a critical role in cytoskeleton remodeling and vesicle recycling. Ophn1 knockout (KO) adult mice display some behavioral deficits in multiple tasks, reminiscent of some symptoms in the human pathology. We also previously reported a reduction in dendritic spine density in the adult hippocampus of KO mice. Yet the nature of the deficits occurring in these mice during postnatal development remains elusive. Here, we show that juvenile KO mice present normal basal synaptic transmission, but altered synaptic plasticity, with a selective impairment in long-term depression, but no change in long-term potentiation. This contrasts with the functional deficits that these mice display at the adult stage, as we found that both basal synaptic transmission and long-term potentiation are reduced at later stages, due to presynaptic alterations. In addition, the number of excitatory synapses in adult is increased, suggesting some unsuccessful compensation. Altogether, these results suggest that OPHN1 function at synapses is differentially affected during maturation of the brain, which provides some therapeutic opportunities for early intervention.

International audience; Due to the pathophysiological complexity of Alzheimer's disease, multitarget approaches able to mitigate several pathogenic mechanisms are of interest. Previous studies have pointed to the neuroprotective potential of Doxycycline (Dox), a safe and inexpensive second-generation tetracycline. Dox has been particularly reported to slow down aggregation of misfolded proteins but also to mitigate neuroinflammatory processes. Here, we have evaluated the pre-clinical potential of Dox in the APP/PS1 mouse model of amyloidogenesis. Dox was provided to APP/PS1 mice from the age of 8 months, when animals already exhibit amyloid pathology and memory deficits. Spatial memory was then evaluated from 9 to 10 months of age. Our data demonstrated that Dox moderately improved the spatial memory of APP/PS1 mice without exerting major effect on amyloid lesions. While Dox did not alleviate overall glial reactivity, we could evidence that it rather enhanced the amyloid-dependent upregulation of several neuroinflammatory markers such as CCL3 and CCL4. Finally, Dox exerted differentially regulated the levels of synaptic proteins in the hippocampus and the cortex of APP/PS1 mice. Overall, these observations support that chronic Dox delivery does not provide major pathophysiological improvements in the APP/PS1 mouse model.

iPSC-derived brain and retinal organoids represent biologically relevant 3D models. A new step in the field of brain and retinal organoids was reached a few months ago with the simultaneous development of brain and eye structures from human iPS cells within the same organoid. Single-cell mRNA sequencing analyses allowed the identification of various ocular and cerebral neuronal populations and electrophysiological recordings confirm the presence of functional and electrically active neurons. The coexistence within the same organoid of different cell types from visual and brain regions and the establishment of connections between these regions raises the intriguing question of its real or potential functionality and its ability to process higher-level visual information. This unique model could also be used to further understand the development of the human visual system and associated developmental diseases., Les organoïdes cérébraux comme les organoïdes rétiniens dérivés de cellules souches de type iPS sont des modèles 3D biologiquement pertinents. Une étude récente du laboratoire de Jay Gopalakrishnan (Université de Düsseldorf) en collaboration avec un groupe de l'Université de Bonn et de l'Institut de la Vision à Paris, a montré la capacité des cellules iPS humaines à développer spontanément des organoïdes cérébraux incluant des structures oculaires rudimentaires bilatérales et symétriques. Cette innovation aboutissant à la formation d’organoïdes toujours plus complexes et proches des organes modélisés constitue une étape majeure pour comprendre comment l'œil humain se développe de concert avec le cerveau pour créer un système visuel fonctionnel.

Cav3.2 T-type calcium channel is a major molecular actor of neuropathic pain in peripheral sensory neurons, but its involvement at the supra-spinal level is almost unknown. In the Anterior Pretectum (APT), a hub of connectivity of the somatosensory system involved in pain perception, we show that Cav3.2 channels are expressed in a sub-population of GABAergic neurons co-expressing parvalbumin (PV). In these PV-expressing neurons, Cav3.2 channels contribute to a high frequency bursting activity, which is increased in the spared nerve injury model of neuropathy. Specific deletion of Cav3.2 channels in APT neurons reduced both the initiation and maintenance of mechanical and cold allodynia. These data are a direct demonstration that centrally expressed Cav3.2 channels also play a fundamental role in pain pathophysiology.

International audience; Radiologically Isolated Syndrome (RIS) is characterized by MRI-typical brain lesions fulfilling the 2009 Okuda criteria, detected in patients without clinical conditions suggestive of MS. Half of all RIS patients convert to MS within 10 years. The individual course of the disease, however, is highly variable with 12% of RIS converting directly to progressive MS. Demographic and imaging markers have been associated with the risk of clinical MS in RIS: male sex, younger age, infra-tentorial, and spinal cord lesions on the index scan and gadolinium-enhancing lesions on index or follow-up scans. Although not considered as a distinct MS phenotype, RIS certainly shares common pathological features with early active and progressive MS. In this review, we specifically focus on biological markers that may help refine the risk stratification of clinical MS and disability for early treatment. Intrathecal B-cell activation with cerebrospinal fluid (CSF) oligoclonal bands, elevated kappa free light chains, and cytokine production is specific to MS, whereas neurofilament light chain (NfL) levels reflect disease activity associated with neuroaxonal injury. Specific microRNA profiles have been identified in RIS converters in both CSF and blood. CSF levels of chitinases and glial acidic fibrillary protein (GFAP) reflecting astrogliosis might help predict the evolution of RIS to progressive MS. Innovative genomic, proteomic, and metabolomic approaches have provided several new candidate biomarkers to be explored in RIS. Leveraging data from randomized controlled trials and large prospective RIS cohorts with extended follow-up to identify, as early as possible, biomarkers for predicting greater disease severity would be invaluable for counseling patients, managing treatment, and monitoring.

International audience; Diffuse low-grade gliomas (LGG) commonly affect young adults and display a slow evolution, with a life expectancy that can surpass 15 years, thanks to multimodal therapeutic management. Therefore, preservation of quality of life (QoL), including sexual health, is mandatory. We systematically searched available medical databases of Pubmed, Cochrane, and Scopus for studies that reported data on sexual activity or dysfunction (SD) in LGG patients. We analyzed results to determine incidence of SD and its association with QoL in this population. Three studies focused on SD incidence in patients presenting specifically LGG, or brain tumors including LGG. They comprised 124 brain tumor patients, including 62 LGG, with SD incidence ranging from 44 to 63%. SD was reported by more than 50% of interrogated women in the three studies. Regarding QoL, two out of the three studies found significant associations between SD and alterations of QoL parameters, particularly in the field of social and functional wellbeing. Finally, we discussed those results regarding methods of evaluation, inherent biases, and therapeutic implications regarding antiseizure medications and also planning of surgery, chemo-, and radiotherapy. Our review showed that SD is highly prevalent but still poorly studied in LGG patients. As those patients are usually young and enjoy an active life, there is a need to assess more systematically the occurrence of SD in clinical routine, in order to adapt cancer treatments accordingly, to manage actively these troubles, and finally to improve patients' QoL in the long run.

International audience; Optimizing reproductive fitness in mammalians requires behavioral adaptations during pregnancy. Maternal preparatory nesting is an essential behavior for the survival of the upcoming litter. Brain-wide immediate early gene mapping in mice evoked by nesting sequences revealed that phases of nest construction strongly activate peptidergic neurons of the Edinger-Westphal nucleus in pregnant mice. Genetic ablation, bidirectional neuromodulation, and in vitro and in vivo activity recordings demonstrated that these neurons are essential to modulate arousal before sleep to promote nesting specifically. We show that these neurons enable the behavioral effects of progesterone on preparatory nesting by modulating a broad network of downstream targets. Our study deciphers the role of midbrain CART+ neurons in behavioral adaptations during pregnancy vital for reproductive fitness.

International audience; The observation that a pathophysiological link might exist between Alzheimer's disease (AD) and epilepsy dates back to the identification of the first cases of the pathology itself and is now strongly supported by an ever-increasing mountain of literature. An overwhelming majority of data suggests not only a higher prevalence of epilepsy in Alzheimer's disease compared to healthy aging, but also that AD patients with a comorbid epileptic syndrome, even subclinical, have a steeper cognitive decline. Moreover, clinical and preclinical investigations have revealed a marked sleep-related increase in the frequency of epileptic activities. This characteristic might provide clues to the pathophysiological pathways underlying this comorbidity. Furthermore, the preferential sleep-related occurrence of epileptic events opens up the possibility that they might hasten cognitive decline by interfering with the delicately orchestrated synchrony of oscillatory activities implicated in sleep-related memory consolidation. Therefore, we scrutinized the literature for mechanisms that might promote sleep-related epileptic activity in AD and, possibly dementia onset in epilepsy, and we also aimed to determine to what degree and through which processes such events might alter the progression of AD. Finally, we discuss the implications for patient care and try to identify a common basis for methodological considerations for future research and clinical practice.

Synaptic plasticity is a biological mechanism, integrating neuronal activity in the evolution of recurrent connections between neurons. Spike-timing dependent plasticity (STDP) represents all plasticity mechanisms that depends on the timings of the pre- and postsynaptic spikes. We have developed a general class of models to reproduce different STDP rules in a stochastic setting, modeling spike trains as point processes. Synaptic plasticity is a slow process, compared to neuronal activity, supporting an analysis of this system using slow-fast theory. Adding regularity hypotheses, we prove a convergence theorem in the slow-fast limit, and apply it to different sets of STDP rules. A theoretical and numerical analysis of the synaptic weight asymptotic behavior is performed and has led us to conclude on the potential impact of each STDP rule on a simple network. At the same time, we also study the influence of anti-Hebbian STDP in networks inspired from the striatum, a subcortical nucleus involved in procedural learning. Finally, experimental results have recently shown that two regions of the dorsal striatum, the dorsolateral (DLS) and the dorsomedial (DMS) striatum display different kinds of STDP. We show that STDP present at DMS synapses leads to a quicker forgetting of learned patterns and consequently to higher flexibility, while STDP at DLS synapses helps maintaining these patterns in memory., La plasticité synaptique est un mécanisme biologique intégrant l'activité neuronale dans l'évolution des connections récurrentes entre différents neurones. La spike-timing dependent plasticity (STDP) représente l'ensemble des mécanismes de plasticité dépendant des instants de potentiels d'action pré- et post-synaptiques. Nous avons développé une classe générale de modèles pour reproduire différentes règles de STDP dans un cadre stochastique, en modélisant notamment les ensembles de potentiels d'action par des processus ponctuels. La plasticité synaptique est un processus lent comparé à l'activité neuronale, justifiant une analyse de ce système avec des arguments de la théorie lent-rapide. En ajoutant des hypothèses de régularité, un théorème de convergence dans la limite lent-rapide est énoncé et appliqué à différentes règles de STDP. Enfin, une analyse théorique et numérique de l'évolution des poids synaptiques nous a amené à conclure sur l'impact de la STDP sur un système neuronal simple. En parallèle, nous avons étudié l'influence de la STDP de type anti-Hebienne dans des réseaux reproduisant certaines propriétés du striatum, un noyau sous-cortical impliqué dans l'apprentissage procédural. Des résultats expérimentaux ont récemment démontré que deux régions du striatum dorsal, le striatum dorsolatéral (DLS) et le striatum dorsomédial (DMS) sont caractérisées par deux types de STDP de polarités différentes. Les conclusions de cette étude mettent en avant que la plasticité présente dans le DMS permet au réseau d'oublier rapidement tous motifs précédemment acquis, alors que la STDP du DLS participe à la maintenance de ces mêmes motifs.

How do children acquire language through unsupervised or noisy supervision? How do their brain process language? We take this perspective to machine learning and robotics, where part of the problem is understanding how language models can perform grounded language acquisition through noisy supervision and discussing how they can account for brain learning dynamics. Most prior works have tracked the co-occurrence between single words and referents to model how infants learn wordreferent mappings. This paper studies cross-situational learning (CSL) with full sentences: we want to understand brain mechanisms that enable children to learn mappings between words and their meanings from full sentences in early language learning. We investigate the CSL task on a few training examples with two sequence-based models: (i) Echo State Networks (ESN) and (ii) Long-Short Term Memory Networks (LSTM). Most importantly, we explore several word representations including One-Hot, GloVe, pretrained BERT, and fine-tuned BERT representations (last layer token representations) to perform the CSL task. We apply our approach to three diverse datasets (two grounded language datasets and a robotic dataset) and observe that (1) One-Hot, GloVe, and pretrained BERT representations are less efficient when compared to representations obtained from fine-tuned BERT. (2) ESN online with final learning (FL) yields superior performance over ESN online continual learning (CL), offline learning, and LSTMs, indicating the more biological plausibility of ESNs and the cognitive process of sentence reading. (2) LSTM with fewer hidden units showcases higher performance for small datasets, but LSTM with more hidden units is Cross-Situational Learning needed to perform reasonably well on larger corpora. (4) ESNs demonstrate better generalization than LSTM models for increasingly large vocabularies. Overall, these models are able to learn from scratch to link complex relations between words and their corresponding meaning concepts, handling polysemous and synonymous words. Moreover, we argue that such models can extend to help current human-robot interaction studies on language grounding and better understand children's developmental language acquisition. We make the code publicly available * .

International audience; Frontotemporal dementia (FTD) is a rare neurodegenerative disease, often of genetic origin, with no effective treatment. There is a substantial pathophysiological overlap with amyotrophic lateral sclerosis (ALS), mutations in the C9orf72 gene being their most common genetic cause. In these disorders, no single biomarker can accurately measure progression, thus it is crucial to combine complementary information from multiple modalities to evaluate new therapeutic interventions. In particular, neuroimaging and transcriptomic (microRNA) data have been shown to have value to track FTD and ALS progression. As these conditions are rare, large samples are not available, hence the need for methods to fuse multimodal data from small samples. In this paper, we propose a method for computing a disease progression score (DPS) from cross-sectional multimodal data, based on variational autoencoders (VAE). We show that unsupervised training leads to the estimation of meaningful latent spaces, where subjects with similar disease states are clustered together and from which a DPS may be inferred. Models were evaluated on 14 patients, 40 presymptomatic mutation carriers and 37 healthy controls from the PREV-DEMALS study. Since there is no ground truth for the DPS, we used the inferred scores to perform pairwise classification as a proxy metric. Presymptomatic subjects and patients were classified with an average area under the ROC curve of 0.83 and 0.94, respectively without and with feature selection. The proposed approach has the potential to leverage cross-sectional multimodal datasets with small sample sizes in order to objectively measure disease progression.

International audience; A 39-year-old man was admitted after 1 week of headaches and cognitive changes. CT scan showed bithalamic hypodensities, corresponding to bithalamic vasogenic oedema. Punctuate hemorrhage was present, with foci of thalamic enhancement. CT angiography raised the suspicion of arteriovenous shunt. Digital subtraction angiography confirmed a medial falcotentorial dural arteriovenous fistula. Complete embolization was performed using liquid embolic agent. Although tentorial dural fistulas have already been described as a cause of bithalamic oedema and subacute dementia, they are not generally included in pathologies implied in this radiologic pattern.

International audience; ObjectiveThe role of ipsilateral motor cortex efferent pathways in the transmission of voluntary command to spinal motor nuclei remains controversial in humans. In healthy subjects, their implication in cortical control is hidden by predominant role of crossed corticospinal tract. However, evidence from electrophysiological and imaging studies suggest that ipsilateral tracts may contribute to functional recovery after unilateral brain damage. This randomized-sham control study aims to explore to what extent ipsilateral tracts from the undamaged hemisphere may strengthen corticospinal control onto spinal motor networks following stroke.MethodsAnodal transcranial direct current stimulation (tDCS) was combined with monosynaptic H-reflex method to evaluate the variations of reciprocal inhibition (RI) in wrist flexors in 21 stroke participants.ResultsAnodal tDCS decreased RI in wrist flexors in stroke participants in both arms. tDCS unmasks an ipsilateral control from the undamaged hemisphere onto spinal motor networks controlling affected arm muscles in stroke participants. In the unaffected (contralateral) arm, effects in stroke participants were opposite to those induced in healthy subjects.ConclusionsStimulation of the undamaged cortex in stroke participants induces modulation of ipsilateral motor networks controlling the hemiparetic side.SignificanceRehabilitation could leverage stimulation of the undamaged hemisphere to enhance motor recovery post stroke.

International audience; Objective: Although epilepsies and neurodegenerative disorders show pathophysiological similarities, their direct functional associations are unclear. Here, we tested the hypothesis that experimental seizures can induce tau hyperphosphorylation and amyloidogenic modifications over time, with intersections with neuroinflammation.Methods: We used a model of mesial temporal lobe epilepsy (MTLE) where unilateral intrahippocampal injection of kainic acid (KA) in C57BL/6 mice elicits epileptogenesis and spontaneous focal seizures. We used a model of generalized status epilepticus (SE) obtained by intraperitoneal KA injection in C57BL/6 mice. We performed analyses and cross-comparisons according to a schedule of 72 h, 1 week, and 8 weeks after KA injection.Results: In experimental MTLE, we show AT100, PHF1, and CP13 tau hyperphosphorylation during epileptogenesis (72 h-1 week) and long-term (8 weeks) during spontaneous seizures in the ipsilateral hippocampi, the epileptogenic zone. These pathological modifications extended to the contralateral hippocampus, a seizure propagating zone with no histological lesion or sclerosis. Two kinases, Cdk5 and GSK3β, implicated in the pathological phosphorylation of tau, were activated. In this MTLE model, the induction of the amyloidogenic pathway (APP, C99, BACE1) was prominent and long-lasting in the epileptogenic zone. These Alzheimer's disease (AD)-relevant markers, established during seizure progression and recurrence, reciprocated an enduring glial (GFAP, Iba1) inflammation and the inadequate activation of the endogenous, anti-inflammatory, glucocorticoid receptor system. By contrast, a generalized SE episode provoked a predominantly transient induction of tau hyperphosphorylation and amyloidogenic markers in the hippocampus, along with resolving inflammation. Finally, we identified overlapping profiles of long-term hippocampal tau hyperphosphorylation by comparing MTLE to J20 mice, the latter a model relevant to AD.Significance: MTLE and a generalized SE prompt persistent and varying tau hyperphosphorylation or amyloidogenic modifications in the hippocampus. In MTLE, an AD-relevant molecular trajectory intertwines with neuroinflammation, spatiotemporally involving epileptogenic and nonlesional seizure propagating zones.

International audience; Objectives: Childhood maltreatment, also referred as childhood trauma, increases the severity of Bipolar Disorders (BD). Childhood maltreatment has been associated with more frequent mood recurrences, however mostly in retrospective studies. Since scarce, further prospective studies are required to identify whether childhood maltreatment may be associated with the time to recurrence in BD.Methods: Individuals with BD (N=2008) were assessed clinically and for childhood maltreatment at baseline, and followed-up for two years. The cumulative probability of mood recurrence over time was estimated with the Turnbull's extension of the Kaplan-Meier analysis for interval-censored data, including childhood maltreatment as a whole, and then maltreatment subtypes as predictors. Analyses were adjusted for potential confounding factors.Results: The median duration of follow-up was 22.3 month (IQR:12.0-24.8). Univariable analyses showed associations between childhood maltreatment, in particular all types of abuses (emotional, physical and sexual) or emotional neglect, and a shorter time to recurrence (all p values

International audience

International audience; Recent evidence suggests that people with schizophrenia are at high risk for severe COVID-19 and should be prioritized for vaccination. However, impaired decision-making capacities could negatively affect the uptake of COVID-19 vaccination in this population. Capacity to consent to COVID-19 vaccination was assessed in 80 outpatients with schizophrenia. Using the MacArthur Competence Assessment Tool for Treatment, 56.3% of the sample were classified as having diminished capacity to consent to the vaccination. Diminished capacity to consent to COVID-19 vaccination was associated with lower vaccination rates, poorer cognition and higher level of psychotic symptoms. Developing interventions for enhancing informed consent for vaccination is urgent within this population.

International audience; Clinical research on the beneficial effects induced by slow-paced breathing has been increasingly extended in the past twenty years. Improvements in cardiovascular functioning, executive functions, or stress management appear to be among the most prominent observations in these studies. However, the mechanisms underlying these effects are multiple and complex. This review will focus on the importance of reducing breathing rate at the resonant frequency (~ 0.1 Hz), which increases cardiac oscillations, thus reflecting improved vagally-mediated heart rate variability and baroreflex sensitivity. These effects are achieved through temporal coherence of respiratory, blood pressure, and cardiac phases, which are the origin of multiple peripheral benefits. In return, vagal afferents, which send inputs to interoceptive areas, are stimulated for longer and more intensely than when breathing spontaneously. In limbic areas, which may also be stimulated through larger cerebral blood flow oscillations and increases in oxygen delivery, interoceptive activation produces a cascade of neural activations that may be at the origin of the central benefits of deep and slow-paced breathing.

Cancer-related fatigue can continue long after curative cancer treatment. The aim of this study was to investigate sleep and rest–activity cycles in fatigued and non-fatigued cancer survivors. We hypothesized that sleep and rest–activity cycles would be more disturbed in people experiencing clinically-relevant fatigue, and that objective measures of sleep would be associated with the severity of fatigue in cancer survivors. Cancer survivors (n = 87) completed a 14-day wrist actigraphy measurement to estimate their sleep and rest–activity cycles. Fatigue was measured using the Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-F). Participants were dichotomised into two groups using a previously validated score (fatigued n = 51 and non-fatigued n = 36). The participant’s perception of sleep was measured using the Insomnia Severity Index (ISI). FACIT-F score was correlated with wake after sleep onset (r = −0.28, p = 0.010), sleep efficiency (r = 0.26, p = 0.016), sleep onset latency (r = −0.31, p = 0.044) and Insomnia Severity Index (ISI) score (r = −0.56, p &lt, 0.001). The relative amplitude of the rest–activity cycles was lower in the fatigued vs. the non-fatigued group (p = 0.017, d = 0.58). After treatment for cancer, the severity of cancer-related fatigue is correlated with specific objective measures of sleep, and there is evidence of rest–activity cycle disruption in people experiencing clinically-relevant fatigue.

Summary Bipolar disorder (BD) is characterized by cyclical mood shifts. Studies indicate that BD patients have a peripheral pro-inflammatory state and alterations in glial populations in the brain. We utilized an in vitro model to study inflammation-related phenotypes of astrocytes derived from induced pluripotent stem cells (iPSCs) generated from BD patients and healthy controls. BD astrocytes showed changes in transcriptome and induced a reduction in neuronal activity when co-cultured with neurons. IL-1β-stimulated BD astrocytes displayed a unique inflammatory gene expression signature and increased secretion of IL-6. Conditioned medium from stimulated BD astrocytes reduced neuronal activity, and this effect was partially blocked by IL-6 inactivating antibody. Our results suggest that BD astrocytes are functionally less supportive of neuronal excitability and this effect is partially mediated by IL-6. We confirmed higher IL-6 in blood in a distinct cohort of BD patients, highlighting the potential role of astrocyte-mediated inflammatory signaling in BD neuropathology., Highlights • Bipolar disorder astrocytes are functionally less supportive of neuronal activity • Bipolar disorder astrocytes response to IL-1β is transcriptionally distinct • IL-6 secretion in bipolar disorder astrocytes reduces neuronal activity • Bipolar disorder patients show higher circulating levels of IL-6 in blood, In this article, Gage and collaborators show that astrocytes differentiated from induced pluripotent stem cells generated from bipolar disorder patients are functionally less supportive of neuronal activity. Bipolar disorder astrocytes' response to pro-inflammatory cytokines is characterized by a unique transcriptional response and increased IL-6 secretion that directly and negatively impacted on neuronal activity. Increased peripheral IL-6 was confirmed in a distinct clinical cohort highlighting the potential role of astrocyte-mediated inflammatory signaling in the neuropathology of bipolar disorder.

The enteric nervous system plays a critical role in the regulation of gastrointestinal tract functions and is often referred to as the 'second brain' because it shares many features with the central nervous system. These similarities include among others a large panel of neurotransmitters, a large population of glial cells and a susceptibility to neurodegeneration. This close homology between the central and enteric nervous systems suggests that a disease process affecting the central nervous system could also involve its enteric counterpart. This was already documented in Parkinson's disease, the most common synucleinopathy, in which alpha-synuclein deposits are reported in the enteric nervous system in the vast majority of patients. Tau is another key protein involved in neurodegenerative disorders of the brain. Whether changes in tau also occur in the enteric nervous system during gut or brain disorders has just begun to be explored. The scope of the present article is therefore to review existing studies on the expression and phosphorylation pattern of tau in the enteric nervous system under physiological and pathological conditions and to discuss the possible occurrence of 'enteric tauopathies'.

International audience; Aims: The objective of this study was to elucidate the early white matter changes in CADASIL small vessel disease.Methods: We used high-pressure freezing and freeze substitution (HPF/FS) in combination with high-resolution electron microscopy (EM), immunohistochemistry and confocal microscopy of brain specimens from control and CADASIL (TgNotch3R169C ) mice aged 4-15 months to study white matter lesions in the corpus callosum.Results: We first optimised the HPF/FS protocol in which samples were chemically prefixed, frozen in a sample carrier filled with 20% polyvinylpyrrolidone and freeze-substituted in a cocktail of tannic acid, osmium tetroxide and uranyl acetate dissolved in acetone. EM analysis showed that CADASIL mice exhibit significant splitting of myelin layers and enlargement of the inner tongue of small calibre axons from the age of 6 months, then vesiculation of the inner tongue and myelin sheath thinning at 15 months of age. Immunohistochemistry revealed an increased number of oligodendrocyte precursor cells, although only in older mice, but no reduction in the number of mature oligodendrocytes at any age. The number of Iba1 positive microglial cells was increased in older but not in younger CADASIL mice, but the number of activated microglial cells (Iba1 and CD68 positive) was unchanged at any age.Conclusion: We conclude that early WM lesions in CADASIL affect first and foremost the myelin sheath and the inner tongue, suggestive of a primary myelin injury. We propose that those defects are consistent with a hypoxic/ischaemic mechanism.

BACKGROUND: Neurocognitively impaired patients with brain tumour are presumed to have reduced cognitive awareness preventing them from adequately valuing and reporting their own functioning, for instance, when providing patient-reported outcomes (PROs) such as health-related quality of life instruments. In this cross-sectional study, we aimed at assessing the concordance of neurocognitive complaints (NCCs) and objective neurocognitive functioning (NCF) as a measure of cognitive awareness.METHODS: NCF was assessed using an internationally accepted clinical trial battery. NCC was assessed using the cognitive functioning questionnaire from the Medical Outcome Study (MOS) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire cognitive functioning subscale. Patients were divided in cognitively impaired and unimpaired groups, based on their NCF performance. Pearson's correlation coefficients between NCF and NCCs were calculated. The same procedure was used to evaluate the correlation of NCF and QLQ-C30 CF subscale.RESULTS: Data from EORTC trials 26091 and 26101 were pooled into a data set of 546 patients. Twenty percent of patients could be characterised as unimpaired (109) and 80% as impaired (437). Impaired patients reported more cognitive complaints on the MOS scale than unimpaired patients. Correlations between NCF and NCCs were weak but significant for impaired patients and non-significant for unimpaired ones. Similar results were found for the correlation between NCF test performance and the QLQ-C30 CF subscale.CONCLUSION: Correlations between NCF test scores and complaints were weak but suggesting that neurocognitive impairment in patients with HGG does not preclude cognitive awareness. However, considering the findings of this study, we would suggest not to use PROs as a surrogate of performance-based neurocognitive evaluation.

Preclinical studies have shown that mesenchymal stem cells have a positive effect in perinatal brain injury models. The mechanisms that cause these neurotherapeutic effects are not entirely intelligible. Mitochondrial damage, inflammation, and reactive oxygen species are considered to be critically involved in the development of injury. Mesenchymal stem cells have immunomodulatory action and exert mitoprotective effects which attenuate production of reactive oxygen species and promote restoration of tissue function and metabolism after perinatal insults. This review summarizes the present state, the underlying causes, challenges and possibilities for effective clinical translation of mesenchymal stem cell therapy., Mesenchymal stem cells have a positive effect in perinatal brain injury models. Mitochondrial damage, inflammation, and reactive oxygen species are critically involved in the development of injury. Mesenchymal stem cells have immunomodulatory action and exert mitoprotective effects which attenuate production of reactive oxygen species and promote restoration of tissue function and metabolism after perinatal insults. This review summarizes the present state, the underlying causes, challenges and possibilities for effective clinical translation of mesenchymal stem cell therapy. The image illustrates transfer of mitochondria from mesenchymal stem cells to damaged neurons and inflamed microglia via tunneling nanotubes.