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International audience; In the adult brain, both neurons and oligodendrocytes can be generated from neural stem cells located within the Sub-Ventricular Zone (SVZ). Physiological signals regulating neuronal versus glial fate are largely unknown. Here we report that a thyroid hormone (T 3)-free window, with or without a demyelinating insult, provides a favorable environment for SVZ-derived oligodendrocyte progenitor generation. After demyelination, oligodendrocytes derived from these newly-formed progenitors provide functional remyelination, restoring normal conduction. The cellular basis for neuronal versus glial determination in progenitors involves asymmetric partitioning of EGFR and TRa1, expression of which favor glio-and neuro-genesis, respectively. Moreover, EGFR + oligodendrocyte progenitors, but not neuroblasts, express high levels of a T 3-inactivating deiodinase, Dio3. Thus, TRa absence with high levels of Dio3 provides double-pronged blockage of T 3 action during glial lineage commitment. These findings not only transform our understanding of how T 3 orchestrates adult brain lineage decisions, but also provide potential insight into demyelinating disorders.

The great demand for long-wavelength and high signal-to-noise Ca2+ indicators has led us to develop CaRuby-Nano, a new functionalizable red calcium indicator with nanomolar affinity for use in cell biology and neuroscience research. In addition, we generated CaRuby-Nano dextran conjugates and an AM-ester variant for bulk loading of tissue. We tested the new indicator using in vitro and in vivo experiments demonstrating the high sensitivity of CaRuby-Nano as well as its power in dual color imaging experiments. DOI: http://dx.doi.org/10.7554/eLife.05808.001, eLife digest The movement of calcium ions within cells controls many vital biological processes, ranging from cell growth to muscle contraction and brain activity. These calcium signals are triggered by stimuli, such as nerve impulses, which drive calcium entry into cells or release calcium from internal stores. These changes in calcium levels can span several orders of magnitude, and can be either localized to very small parts of the cell or span the entire cell. Scientists have developed numerous indicators or ‘probes’ that can detect even very low levels of calcium. One common method uses proteins that fluoresce when viewed under a fluorescence microscope each time the protein senses increases of calcium. Most of these probes fluoresce green, and so to view a second signal that occurs in the cell at the same time it's easier to use a probe that fluoresces with a different color, such as red. However, the red-shifted probes that are currently available either produce unreliable results because they tend to leak through cell membranes, or are not very sensitive to calcium ions. New types of red-shifted probes are therefore urgently needed. In 2012, researchers developed a family of red fluorescent probes known as Calcium Ruby (CaRuby for short) that were more versatile than earlier red probes. Now, Collot, Wilms et al.—including several of the researchers involved in the 2012 research—have enhanced the properties of CaRuby by modifying the chemical structure of the probes. This increased the ability of CaRuby to bind calcium ions, making it more sensitive to small calcium changes. Testing the usefulness of the newly developed probes—called CaRuby Nano—in mouse nerve cells revealed the probes are highly sensitive and can even detect the calcium signal resulting from a single nerve impulse. Collot, Wilms et al. then went on to demonstrate that CaRuby-Nano can be used alongside a green-fluorescing probe to record two signals at the same time. In one experiment, the release of chemical messengers known as neurotransmitters was stimulated, which caused calcium ions to flow into the observed nerve cells. The researchers succeeded in simultaneously detecting a green signal indicating an increase in neurotransmitter levels and a red signal produced by the corresponding release of calcium. Such dual-color imaging was not possible with previous probes. Finally, it was shown that CaRuby-Nano can also be used to produce dual-color images of the brain activity of live mice. In summary, these results demonstrate that CaRuby-Nano is a highly sensitive and versatile indicator and can be used together with other probes to observe two simultaneous events in cells. DOI: http://dx.doi.org/10.7554/eLife.05808.002

International audience; Oligodendrocyte precursor cells (OPCs) are a major source of remyelinating oligodendrocytes in demyelinating diseases such as Multiple Sclerosis (MS). While OPCs are innervated by unmyelinated axons in the normal brain, the fate of such synaptic contacts after demyelination is still unclear. By combining electrophysiology and immunostainings in different transgenic mice expressing fluorescent reporters, we studied the synaptic innervation of OPCs in the model of lysolecithin (LPC)-induced demyelination of corpus callosum. Synaptic innervation of reactivated OPCs in the lesion was revealed by the presence of AMPA receptor-mediated synaptic currents, VGluT1+ axon-OPC contacts in 3D confocal reconstructions and synaptic junctions observed by electron microscopy. Moreover, 3D confocal reconstructions of VGluT1 and NG2 immunolabeling showed the existence of glutamatergic axon-OPC contacts in post-mortem MS lesions. Interestingly, patch-clamp recordings in LPC-induced lesions demonstrated a drastic decrease in spontaneous synaptic activity of OPCs early after demyelination that was not caused by an impaired conduction of compound action potentials. A reduction in synaptic connectivity was confirmed by the lack of VGluT1+ axon-OPC contacts in virtually all rapidly proliferating OPCs stained with EdU (50-ethynyl-20-deoxyuridine). At the end of the massive proliferation phase in lesions, the proportion of innervated OPCs rapidly recovers, although the frequency of spontaneous synaptic currents did not reach control levels. In conclusion, our results demonstrate that newly-generated OPCs do not receive synaptic inputs during their active proliferation after demyelination, but gain synapses during the remyelination process. Hence, glutamatergic synaptic inputs may contribute to inhibit OPC proliferation and might have a physiopathological relevance in demyelinating disorders.

International audience; Enhanced neuronal activity in the brain triggers a local increase in blood flow, termed functional hyperemia, via several mechanisms, including calcium (Ca2+) signaling in astrocytes. However, recent in vivo studies have questioned the role of astrocytes in functional hyperemia because of the slow and sparse dynamics of their somatic Ca2+ signals and the absence of glutamate metabotropic receptor 5 in adults. Here, we reexamined their role in neurovascular coupling by selectively expressing a genetically encoded Ca2+ sensor in astrocytes of the olfactory bulb. We show that in anesthetized mice, the physiological activation of olfactory sensory neuron (OSN) terminals reliably triggers Ca2+ increases in astrocyte processes but not in somata. These Ca2+ increases systematically precede the onset of functional hyperemia by 1-2 s, reestablishing astrocytes as potential regulators of neurovascular coupling.

International audience; Mechanotransduction, the conversion of a mechanical stimulus into a biological response, constitutes the basis of a variety of physiological functions such as the senses of touch, balance, proprioception, blood pressure, and hearing. In vertebrates, mechanosensation is mediated by mechanosensory neurons, whose cell bodies are located in trigeminal and dorsal root ganglia. Here, we describe an in vitro model of mechanotransduction that provides an opportunity to explore the properties of mechanosensitive channels in mammalian sensory neurons. The mechano-clamp method allows applying local force on plasma membrane of whole-cell patch-clamped sensory neurons. This technique uses a mechanical probe driven by a computer-assisted piezoelectric microstage to repeatedly stimulate sensory neurons with accurate control of stimulus strength, duration, and speed.

International audience; no abstract

International audience; We report a theoretical study that elaborates the influence of the polarization state of both the pump and the probe pulse in ultrafast coherent vibrational ladder climbing experiments in the mid-infrared. Whereas a subensemble in a randomly oriented sample of molecules is excited by the pump pulse in this multiphoton process, further inhomogeneities such as the spatial profile of the laser beams, the longitudinal attenuation in the sample, and the probe beam polarization have to be taken into account. Analytical expressions for a density function describing the number of molecules that are exposed to an effective pump intensity are introduced, and the variation of the population distribution and the actual transient absorption signal in dependence on the polarization-state combinations for pump and probe pulse are discussed in detail. In simulations on the model system carboxy-hemoglobin, it is demonstrated that the polarization states play important roles both for exciting a certain population distribution and for actually observing it. In particular, it will be discussed under which conditions experimental data indicates a population inversion. Cop. 2011 American Chemical Society.

International audience; PC12 cells are a useful model to study neuronal differentiation, as they can undergo terminal differentiation, typically when treated with nerve growth factor (NGF). In this study we investigated the influence of surface energy distribution on PC12 cell differentiation, by atomic force microscopy (AFM) and immunofluorescence. Glass surfaces were modified by chemisorption: an aminosilane. n-[3-(trimethoxysilyl)propyl]ethylendiamine (C(8)H(22)N(2)O(3)Si; EDA), was grafted by polycondensation. AFM analysis of substrate topography showed the presence of aggregates suggesting that the adsorption is heterogeneous, and generates local gradients in energy of adhesion. PC12 cells cultured on these modified glass surfaces developed neurites in absence of NGF treatment. In contrast, PC12 cells did not grow neurites when cultured in the absence of NGF on a relatively smooth surface such as poly-L-lysine substrate, where amine distribution is rather homogeneous. These results suggest that surface energy distribution, through cell-substrate interactions, triggers mechanisms that will drive PC12 cells to differentiate and to initiate neuritogenesis. We were able to create a controlled physical nano-structuration with local variations in surface energy that allowed the study of these parameters on neuritogenesis. (C) 2009 Elsevier B.V. All rights reserved.

A fluorescence resonance energy transfer pair consisting of a colloidal quantum dot donor and multiple organic fluorophores as acceptors is reported and the photophysics of the system is characterized. Most nanoparticle-based biosensors reported so far use the detection of specific changes of the donor/acceptor distance under the influence of analyte binding. Our nanoparticle design on the other hand leads to sensors that detect spectral changes of the acceptor (under the influence of analyte binding) at fixed donor/acceptor distance by the introduction of the acceptor into the polymer coating. This approach allows for short acceptor-donor separation and thus for high-energy transfer efficiencies. Advantageously, the binding properties of the hydrophilic polymer coating further allows for addition of poly(ethylene glycol) shells for improved colloidal stability.

International audience; To investigate the effect of branching on linear and nonlinear optical properties, a specific series of chromophores, epitome of (multi)branched dipoles, has been thoroughly explored by a combined theoretical and experimental approach. Excited-state structure calculations based on quantum-chemical techniques (time-dependent density functional theory) as well as a Frenkel exciton model nicely complement experimental photoluminescence and one- and two-photon absorption findings and contribute to their interpretation. This allowed us to get a deep insight into the nature of fundamental excited-state dynamics and the nonlinear optical (NLO) response involved. Both experiment and theory reveal that a multidimensional intramolecular charge transfer takes place from the donating moiety to the periphery of the branched molecules upon excitation, while fluorescence stems from an excited state localized on one of the dipolar branches. Branching is also observed to lead to cooperative enhancement of two-photon absorption (TPA) while maintaining high fluorescence quantum yield, thanks to localization of the emitting state. The comparison between results obtained in the Frenkel exciton scheme and ab initio results suggests the coherent coupling between branches as one of the possible mechanisms for the observed enhancement. New strategies for the rational design of NLO molecular assemblies are thus inferred on the basis of the acquired insights.

Two quadripolar dyes have been designed and synthesized that present large cross sections for two-photon excitation and whose fluorescence responds strongly to (de)protonation. These dyes are considered as prototypes of molecular pH probes for multiphoton fluorescence microscopy.

International audience; Novel octupolar fluorophores derived from the symmetrical functionalization of a triphenylamine core with strong acceptor peripheral groups via phenylene-ethynylene linkers have been synthesized and shown to exhibit high fluorescence quantum yields, very large TPA cross-sections in the red-NIR region and suitable photostability.

International audience; A series of structurally-related chromophores of different symmetry (quadrupolar, C 2v , octupolar...) and shape (rod-like, propeller-shaped, Y-shaped, dendritic…) were investigated and compared for optimization of molecular two-photon absorption (TPA). Their design is based on the functionalization of linear or branched conjugated backbones with electron-releasing and/or electron-withdrawing peripheral groups. Their TPA spectra were determined by investigating their two-photon-excited fluorescence properties in the NIR region using pulsed excitation in the femtosecond regime. These studies provide evidence that the charge symmetry plays an important role in determining the TPA magnitude, the quadrupolar chromophore leading to the highest TPA cross-section. However, higher-order charge symmetries and branched-structures provide an interesting route for improvement of the nonlinear absorptivity/transparency range trade-off as well as for TPA spectral broadening in the NIR region.

see also erratum page 9065; International audience; Two new three-branched fluorenylene-vinylene derivatives were synthesized by triple Heck-type or Horner–Wadsworth–Emmons reactions. Their one-photon absorption and fluorescence as well as their two-photon absorption properties are reported. These compounds, which combine very high solubility in organic solvents, high fluorescence quantum yield and giant two-photon absorption cross-sections in the red-NIR region (up to 3660 GM, in the femtosecond regime) are promising candidates for both optical power limiting applications and two-photon laser scanning microscopy.

International audience; P. 9. Préface / Pierre Laporte et François Salin P. 11. Introduction - Le réseau des technologies des lasers femtosecondes. La mission ressources et compétences technologiques du CNRS / Gérard Lelièvre et Catherine Leblanc Communications P.27. Technologie des sources femtosecondes historique et état de l'art / Charles Hirlimann et François Salin P. 47. Applications industrielles et médicales pour les lasers femtosecondes / Jean-Luc Tapie et al... P. 53. Générateurs paramétriques en régime fs / Rysvan Maleck P. 65. Génération et détection d'ondes acoustiques par des impulsions laser femtosecondes / Bernard Perrin P. 91. Impulsions électriques femtosecondes:techniques optoélectroniques et applications / Jean-Louis Coutaz et al. P. 107. Mesure de la phase spectrale d'une impulsion ultra-brève / Christophe Dorrer et Manuel Joffre. P. 123. Caractérisation et contrôle de la phase temporelle des impulsions femtoseconde / Jean-Paul Chambaret et al.. P. 141. Caractérisation et contrôle de la répartition d'énergie et du front d'onde d'impulsions femtosecondes / Gilles Chériaux et al.. P. 157. Méthodes de spectrocopie non-linéaire / Claude Rullière P. 159. Spectroscopie Raman de résonance picoseconde / Guy Buntix et OlivierPoizat P. 183. Artefacts dans une expérience pompe-sonde / Stanislas Pommeret et al.. P. 209. Le Contrôle cohérent / Bertrand Girard et al.. P. 223. Les composants spécifiques à la manipulation d'impulsions femtosecondes / Vincent Baqnoud P. 239. Technologie des lasers de puissance de durée femtoseconde/ Catherine LeBlanc P. 257. Z-scan résolu en temps et autres méthodes de détection liées à des variations d'indice / Jean Etchepare et Olivier Albert P. 269. Technologies de caméra à balayage de fente femtoseconde / Jean-Claude Kieffer P. 281. Fluorescence résolue en temps et molécules d'intérêt biologique / Jean-Claude Brochon. P. 295. Propagation d'impulsions ultracourtes dans les milieux diffusants. Application au diagnostic médical / Sigrid Avrillier et al. P. 311. Applications biologiques de la microscopie nonlinéaire / Jérôme Mertz et al. P. 319. Nouvelles sources lasers femtosecondes / Patrick Georges. P. 335. Lasers femtosecondes appliqués à la métrologie des fréquences / Christian Chardonnet et A. Amy-Klein P. 361. Génération d'Harmoniques et Applications / Pierre Agostini Posters P. 385. Acoustique Picoseconde à longueur d'onde variable / Arnaud Devos P. 389. Étude du panache plasma créé par ablation laser femtoseconde du carbone et dépôt de couches minces de DLC / Florence Garrelie et al. P. 393. Diffusion d'un puise laser court par une particule sphérique / Loïc Méès et al. P. 397. Micro-usinage par impulsions laser ultra-courtes / Emmanuel Baubeau et al. P. 401. Étude par Spectroscopie laser femtoseconde d'une base de l'ADN : la Cytosine en solution aqueuse / Eric Renault et al. P. 405. Systèmes femtosecondes pour l'étude des milieux hétérogènes compartimentés absorbants et diffusants / Stéphane Mottin et Pierre Laporte P. 409. Systèmes femtosecondes pour la mesure intracérébrale de marqueurs fluorescents comme la E-GFP - Stéphane Mottin et al. P. 413. Projet Teramobile: propagation des impulsions terawatt dans l'air et application à la détection par lidar des pollutions atmosphériques / J. Yu et al. P. 417. Liste des participants

International audience; We explored the degree to which the duration of acoustic cues contributes to the respective involvement of the two hemispheres in the perception of speech. To this end, we recorded the reaction time needed to identify monaurally presented natural French plosives with varying VOT values. The results show that a right-ear advantage is significant only when the phonetic boundary is close to the release burst, i.e., when the identification of the two successive acoustical events (the onset of voicing and the release from closure) needed to perceive a phoneme as voiced or voiceless requires rapid information processing. These results are consistent with the recent hypothesis that the left hemisphere is superior in the processing of rapidly changing acoustical information.

Background Neurodegeneration biomarkers are routinely used in the diagnosis of Alzheimer's disease (AD). Objective To evaluate the respective contributions of two neuroimaging biomarkers, structural MRI and 18FDG-PET, in the assessment of neurodegeneration in AD dementia. Methods Patients with mild AD dementia diagnosed based on clinical and cerebrospinal fluid criteria and cognitively healthy subjects, from the Marseille cohort ADAge with cognitive, structural MRI and 18FDG-PET assessments, were included. Extent of atrophy on MRI and of hypometabolism on 18FDG-PET were individually evaluated in each patient using a voxel-based analysis on whole-brain approach and compared to healthy subjects. Patients were divided in distinct groups according to their atrophy extent on the one hand and to their hypometabolism extent on the other, then, to their imaging profile combining the extent of the two biomarkers. Results Fifty-two patients were included. The MMSE score was significantly lower in the "Extensive hypometabolism" group than in the "Limited hypometabolism" group (respectively 19.5/30 versus 23/30). A lower Innotest Amyloid Tau Index was associated with an extensive hypometabolism (p = 0.04). There were more patients with low educational level in the "Extensive atrophy" group, while a higher educational level was more found in the "Limited atrophy" group (p = 0.005). Conclusion 18FDG-PET hypometabolism extent is associated with the pathological processes and clinical severity of AD, while MRI atrophy seems to be influenced by the cognitive reserve. In the context of mild AD dementia, these two biomarkers of neurodegeneration are thus not interchangeable and require to be considered in combination rather than in isolation.

Programmed cell death and early activity contribute to the emergence of functional cortical circuits. While most neuronal populations are scaled-down by death, some subpopulations are entirely eliminated, raising the question of the importance of such demise for cortical wiring. Here, we addressed this issue by focusing on Cajal-Retzius neurons (CRs), key players in cortical development that are eliminated in postnatal mice in part via Bax-dependent apoptosis. Using Bax-conditional mutants and CR hyperpolarization, we show that the survival of electrically active subsets of CRs triggers an increase in both dendrite complexity and spine density of upper layer pyramidal neurons, leading to an excitation/inhibition imbalance. The survival of these CRs is induced by hyperpolarization, highlighting an interplay between early activity and neuronal elimination. Taken together, our study reveals a novel activity-dependent programmed cell death process required for the removal of transient immature neurons and the proper wiring of functional cortical circuits., Agence Nationale de la Recherche ANR-15-CE16-0003-01. Fondation pour la Recherche Medicale Equipe (DEQ20130326521) Equipe (DEQ20150331681). European Commission ERC-2013-CoG-616080. Ministry of Higher Education, Research and Innovation Fellowship. Ministry of Science, Innovation and Universities BFU2015-64432-R.European Commission ERC-2014-CoG-647012. Fondation pour l’Aide a la Recherche sur la Sclerose en Plaques Postdoctoral fellowship.

Neurodegenerative diseases are characterized by oxidative stress associated with mitochondrial damages leading to neuronal cell death. To mitigate these damages and promote neuronal cytoprotection and neurogenesis, endogenous (Neuropeptide: octadecaneuropeptide (ODN)) or exogenous (Polyphenols: resveratrol (RSV) and apigenin (API)) natural neurotrophic factors could be used as therapeutic agents to promote neuronal differentiation of immature and pluripotent stem cells. ODN is a peptide produced by astrocytes and known as a powerful neuroprotective agent. It is therefore of interest of studying its effects on the mobilization of calcium, its ability to protect neuronal cells against apoptosis death caused by hydrogen peroxide (H2O2) and evaluate its ability to stimulate neurogenesis by promoting neuronal differentiation. The effects of polyphenols (RSV, API), major compounds of the Mediterranean diet, on neurogenesis were also evaluated.The cytoprotective and/or differentiating properties of ODN (10-16 -10-8 M) and polyphenols (RSV: 6.25 -50 μM, API: 6.25 -50 μM) were mainly studied on murine N2a neuroblastoma cells but also on other murine (BV-2, C6) and human (SK-N-BE, CCF-STTG1) nerve lines. Cytoprotection was measured by various viability tests (FDA, MTT, DiOC6(3), propidium iodide). Differentiation was morphologically evaluated by the presence of neurites (axons and dendrites) and visualized by different microscopical techniques. Retinoic acid (RA: 6.25-50 μM) was used as a positive inductor of differentiation. The signaling pathways involved in neuronal differentiation have been characterized. We also studied the effect of ODN (10-14 M, 48 h) on the morphology, topography and activity of mitochondria and peroxisome during differentiation. These two organelles are involved in the metabolism of lipids (fatty acids, cholesterol).The results obtained show that ODN is able to promote the survival of N2a cells cultured under the conditions of acute oxidative stress induced by H2O2. In addition, ODN as well as polyphenols (RSV and API), which lack intrinsic cytotoxic effects, stimulate neurite outgrowth, indicating that they exert pro-differentiating neurotrophic effects. This effect of ODN involves activation of its metabotropic receptor associated with intracellular transduction pathways PKA, PKC and MAPK / ERKs. In addition, ODN stimulates the biogenesis of mitochondria and peroxisomes, essential organelles in axonal activity (axonal transport and renewal). The study of signaling pathways demonstrate that the trophic effects of RSV and API involve the activation of PKC, PKA and MAPK / ERK transduction pathways.Based on these results, the ODN release could be an endogenous protective mechanism in response to oxidative attacks and process of neurodegeneration, preventing cell death and promoting neuronal cell differentiation. Our work also highlights for the first time that polyphenols, in addition to their antioxidant activity, stimulate the formation, maturation and elongation of neurites of undifferentiated N2a cells. All of this work indicates that ODN neuropeptide and polyphenols (RSV and API) are potent neurotrophic agents. These molecules and/or their synthetic analogues may have pharmacological interest for treating neurodegenerative diseases by promoting neuroprotection, neuro-repair and neurogenesis., Les maladies neurodégénératives sont caractérisées par un stress oxydatif associé à des dommages mitochondriaux aboutissant à la mort des cellules neuronales. Pour atténuer ces dommages et favoriser la cytoprotection neuronale ainsi que la neurogenèse, des facteurs neurotrophiques naturels de type endogènes (Neuropeptide : octadécaneuropeptide (ODN)) ou exogènes (Polyphénols : resvératrol (RSV) et apigénine (API)) pourraient être utilisés comme agents thérapeutiques permettant de favoriser la différenciation neuronale des cellules souches immatures et pluripotentes. L’ODN est un peptide produit par les astrocytes et connu comme agent neuroprotecteur puissant d’où l’intérêt d’étudier ses effets sur la mobilisation du calcium, sa capacité à protéger les cellules neuronales contre la mort par apoptose générée par le peroxyde d’hydrogène (H2O2) et d’évaluer son pouvoir à stimuler la neurogenèse en favorisant la différenciation neuronale. Les effets des polyphénols (RSV, API), composés majeurs du régime méditerranéen, sur la neurogenèse ont été également évalués.Les propriétés cytoprotectrices et/ou différenciatrices de l’ODN (10-16 -10-8 M) et des polyphénols (RSV : 6.25 -50 µM ; API : 6.25 -50 µM) ont été essentiellement étudiées sur des cellules de neuroblastomes murins N2a mais aussi sur d’autres lignées nerveuses murines (BV-2, C6) et humaines (SK-N-BE ; CCF-STTG1). La cytoprotection a été mesurée par différents tests de viabilité (FDA, MTT, DiOC6(3), iodure de propidium). La différenciation a été évaluée morphologiquement par la présence de neurites (axones et dendrites) visualisés grâce à différentes techniques de microscopie. L’acide rétinoïque (AR : 6.25 -50 µM) a été utilisé comme contrôle positif d’induction de différenciation. Les voies de signalisation impliquées dans la différenciation neuronale ont été caractérisées. Nous avons aussi étudié l’effet de l’ODN (10-14 M, 48 h) sur la morphologie, la topographie et l’activité des mitochondries et des peroxysomes au cours de la différenciation. Ces deux organites sont impliqués dans le métabolisme des lipides (acides gras, cholestérol).Les résultats obtenus montrent que l’ODN est capable de promouvoir la survie des cellules N2a cultivées en condition de stress oxydatif aigue induit par le H2O2. De plus, l’ODN ainsi que les polyphénols RSV et l’API, qui sont dépourvus d’effet cytotoxique intrinsèque stimulent la croissance des neurites indiquant qu’ils exercent des effets neurotrophiques pro-différenciateurs. Cet effet de l’ODN met en jeu l’activation de son récepteur métabotropique associé aux voies de transduction intracellulaire PKA, PKC ainsi que MAPK / ERKs. De plus, l’ODN stimule la biogenèse des mitochondries et des peroxysomes, organites essentiels dans l’activité axonale (transport axonal et renouvellement). L’étude des voies de signalisation démontre que les effets trophiques du RSV et API mettent en jeu l’activation des voies de transduction de la PKC, PKA ainsi que celle des MAPK / ERKs.Sur la base de ces résultats, la libération d’ODN pourrait être un mécanisme endogène de protection en réponse aux attaques oxydatives et au processus de neurodégénérescence, empêchant la mort cellulaire et favorisant la différenciation des cellules neuronales. Nos travaux mettent aussi en évidence pour la première fois que les polyphénols en plus de leur action antioxydante stimulent la formation, la maturation et l’élongation des neurites des cellules N2a non différenciées. L’ensemble de ces travaux indique que le neuropeptide ODN et les polyphénols RSV et API sont de puissants agents neurotrophiques. Ces molécules présentent donc un intérêt pharmacologique en vue de leur utilisation et/ou de leurs analogues synthétiques pour traiter des maladies neurodégénératives en favorisant la neuroprotection, la neuro-réparation et la neurogenèse.

The first wave of oligodendrocyte precursor cells (firstOPCs) and most GABAergic interneurons share common embryonic origins. Cortical firstOPCs are thought to be replaced by other OPC populations shortly after birth, maintaining a consistent OPC density and making postnatal interactions between firstOPCs and ontogenetically-related interneurons unlikely. Challenging these ideas, we show that a cortical firstOPC subpopulation survives and forms functional cell clusters with lineage-related interneurons. Favored by a common embryonic origin, these clusters display unexpected preferential synaptic connectivity and are anatomically maintained after firstOPCs differentiate into myelinating oligodendrocytes. While the concomitant rescue of interneurons and firstOPCs committed to die causes an exacerbated neuronal inhibition, it abolishes interneuron-firstOPC high synaptic connectivity. Further, the number of other oligodendroglia populations increases through a non-cell-autonomous mechanism, impacting myelination. These findings demonstrate unprecedented roles of interneuron and firstOPC apoptosis in regulating lineage-related cell interactions and the homeostatic oligodendroglia density., During cortical development the first wave of oligodendrocyte precursor cells (OPCs) completely disappear by programmed cell death, so that it is presumed that this OPC population does not play a role at postnatal stages. In this study, authors use lineage tracing in different transgenic mice to show that a subpopulation of OPCs from the first wave survives at postnatal stages and display a preferential synaptic connectivity with their ontogenetically-related interneurons compared to other OPCs or interneurons

Monitoring calcium concentration in the cytosol is of main importance as this ion drives many biological cascades within the cell. To this end, molecular calcium probes are widely used. Most of them, especially the red emitting probes, suffer from nonspecific interactions with inner membranes due to the hydrophobic nature of their fluorophore. To circumvent this issue, calcium probes conjugated to dextran can be used to enhance the hydrophilicity and reduce the nonspecific interaction and compartmentalization. However, dextran conjugates also feature important drawbacks including lower affinity, lower dynamic range, and slow diffusion. Herein, we combined the advantage of molecular probes and dextran conjugate without their drawbacks by designing a new red emitting turn-on calcium probe based on PET quenching, Rhod-PEG, in which the rhodamine fluorophore bears four PEG4 units. This modification led to a high affinity calcium probe (Kd = 748 nM) with reduced nonspecific interactions, enhanced photostabilit...

International audience; Astrocyte-derived gliotransmitters glutamate and ATP modulate neuronal activity. It remains unclear, however, how astrocytes control the release and coordinate the actions of these gliotransmitters. Using transgenic expression of the light-sensitive channelrhodopsin 2 (ChR2) in astrocytes, we observed that photostimulation reliably increases action potential firing of hippocampal pyramidal neurons. This excitation relies primarily on a calcium-dependent glutamate release by astrocytes that activates neuronal extra-synaptic NMDA receptors. Remarkably, our results show that ChR2-induced Ca2+ increase and subsequent glutamate release are amplified by ATP/ADP-mediated autocrine activation of P2Y1 receptors on astrocytes. Thus, neuronal excitation is promoted by a synergistic action of glutamatergic and autocrine purinergic signaling in astrocytes. This new mechanism may be particularly relevant for pathological conditions in which ATP extracellular concentration is increased and acts as a major danger signal.

International audience; Cajal-Retzius cells (CRs), the first-born neurons in the developing cerebral cortex, coordinate crucial steps in the construction of functional circuits. CRs are thought to be transient, as they disappear during early postnatal life in both mice and humans, where their abnormal persistence is associated with pathological conditions. Embryonic CRs comprise at least three molecularly and functionally distinct subtypes: septum, ventral pallium/pallial-subpallial boundary (PSB), and hem. However, whether subtype-specific features exist postnatally and through which mechanisms they disappear remain unknown. We report that CR subtypes display unique distributions and dynamics of death in the postnatal mouse cortex. Surprisingly, although all CR subtypes undergo cell death, septum, but not hem, CRs die in a Bax-dependent manner. Bax-inactivated rescued septum-CRs maintain immature electrophysiological properties. These results underlie the existence of an exquisitely refined control of developmental cell death and provide a model to test the effect of maintaining immature circuits in the adult neocortex.

International audience; X-ray observations of the hot gas filling the intra-cluster medium (ICM) provide a wealth of information on the dynamics of clusters of galaxies. The global equilibrium of the ICM is believed to be ensured by non-thermal and thermal pressure support sources, among which gas movements and the dissipation of energy through turbulent motions. Accurate mapping of turbulence using X-ray emission lines is challenging due to the lack of spatially resolved spectroscopy. Only future instruments such as the X-ray Integral Field Unit (X-IFU) on Athena will have the spatial and spectral resolution to quantitatively investigate the ICM turbulence over a broad range of spatial scales. Powerful diagnostics for these studies are line shift and the line broadening maps, and the second-order structure function. When estimating these quantities, instruments will be limited by uncertainties of their measurements, and by the sampling variance (also known as cosmic variance) of the observation. Here, we extend the formalism started in our companion Paper I to include the effect of statistical uncertainties of measurements in the estimation of these line diagnostics, in particular for structure functions. We demonstrate that statistics contribute to the total variance through different terms, which depend on the geometry of the detector, the spatial binning and the nature of the turbulent field. These terms are particularly important when probing the small scales of the turbulence. An application of these equations is performed for the X-IFU, using synthetic turbulent velocity maps of a Coma-like cluster. Results are in excellent agreement with the formulas both for the structure function estimation (≤3%) and its variance (≤10%). The expressions derived here and in Paper I are generic, and ensure an estimation of the total errors in any X-ray measurement of turbulent structure functions. They also open the way for optimisations in the upcoming instrumentation and in observational strategies.

Serotonin (5-HT) takes a key position in regulating vital functions, such as cardio-ventilatory activity, locomotion and behaviour. Selective serotonin reuptake inhibitors (SSRIs) modulate the serotonergic system and thus affect these functions. Rhythmic behaviours, such as cardio-ventilatory activity, are controlled by central pattern generators, which in turn are regulated by 5-HT. In crustaceans, 5-HT also regulates the synthesis and secretion of crustacean hyperglycaemic hormone, a pleiotropic hormone involved in the mobilisation and release of glucose into the haemolymph, thus stimulating the animal’s activity. As a matter of consequence, SSRIs may affect cardio-ventilatory activity. In order to examine how the SSRIs affect fundamental physiological parameters based on rhythmic behaviours in decapods, cardio-respiratory activity in the shore crab Carcinus maenas was assessed after pericardial injection of a single dose of either 0.5 μM, 0.75 μM or 1 μM fluoxetine, respectively. Simultaneous recordings of heart and scaphognathite movements in both brachial chambers were conducted by measuring impedance changes in the respective body compartments. Injection of 5-HT had an immediate effect on cardio-ventilatory activities and strongly upregulated both cardiac and ventilatory activities. Fluoxetine showed similar effects, entailing moderate tachycardia and increased ventilation rates. Compared to 5-HT, these effects were delayed in time and much less pronounced. Metabolism of fluoxetine into the active compound nor-fluoxetine might account for the delayed action, whereas compensatory regulation of cardio-ventilatory frequencies and amplitudes are likely to explain the attenuation of the responses compared to the strong and immediate increase by 5-HT. Overall, the results suggest increased 5-HT levels in invertebrates following fluoxetine exposure, which are able to disturb physiological functions regulated by 5-HT, such as cardiac and respiratory activity.

International audience; Introduction Articular involvement is the most common extraintestinal manifestation associated with inflammatory bowel diseases (IBDs). Manifestations are `paradoxical' when they occur during treatment, notably with anti-tumor necrosis factor (anti-TNF) drugs, which are expected to prevent or treat them. The aim of this study was to assess the frequency, characteristics, and associated factors of paradoxical articular manifestations in patients with IBD treated with anti-TNF. Patients and methods In this prospective single-center study, an examination by a rheumatologist was systematically offered to all patients with IBD treated with infliximab (IFX) to assess the prevalence of articular manifestations and distinguish between those related to treatment and those associated with intestinal disease. Paradoxical manifestations were defined as the occurrence of articular manifestations (excluding induced lupus and hypersensitivity reactions) during anti-TNF therapy in patients with intestinal remission. Measures of biological inflammatory, immunological markers, HLA-B27 allele, IFX trough levels, and anti-IFX antibody (Ab) were performed for all patients. Results Between May 2013 and April 2014, 65 patients with Crohn's disease and 15 with patients ulcerative colitis treated with IFX were included. The median duration of anti-TNF therapy was 66 months [quartile (Q) 1=23 months-Q3=81 months]. Articular manifestations were observed in 50 (62%) patients treated with IFX. Eleven percent (n=9) were considered to be associated with IBD and 16% (n=13) to be associated with anti-TNF therapy. Among articular manifestations associated with anti-TNF therapy, nine (11%) patients were considered paradoxical, two (2%) as drug-induced lupus, and two (2%) as a hypersensitivity reaction. Among the nine patients with paradoxical manifestations, all had Crohn's disease in clinical remission, three patients presented a spondyloarthropathy, and three developed associated paradoxical psoriasis. No patient discontinued anti-TNF because of the articular manifestations. Methotrexate was effective on articular symptoms in two of the three treated patients with paradoxical manifestations. No clinical or biological factors, including IFX trough levels, were associated with the occurrence of paradoxical manifestations. Conclusion Paradoxical articular manifestations in IBD patients treated by anti-TNF are common, affecting more than 10% of patients. These events are generally mild and do not need discontinuation of anti-TNF therapy. Eur J Gastroenterol Hepatol 28:876-881 Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

Microglial cells are a population of specialized macrophages residing in the CNS only. They have long been studied solely under pathological contexts and were thought to be active only upon homeostatic disturbance following a brain lesion. However, over the last decade, they have been increasingly recognized to be essential players in the physiological functioning of the CNS. Specifically, during the CNS formation, microglia has been shown to regulate apoptosis and neuronal survival. They are also able to directly interact with synapses, by eliminating supernumerary and inappropriate connections, by promoting synapse formation or by regulating their activity. However, mechanisms by which microglia influence wiring and functional maturation of cortical are not fully understood. To better assess the role of microglia in cortical development, we used the barrel field as a model of neuronal development and we combined in vivo manipulations together with electrophysiology, optogenetics, pharmacologic and histologic approaches on brain slices of genetically-engineered mice. We first explored the consequences of microglia entry near the terminals of thalamic afferents (center of the barrels) in the primary somatosensory cortex during the first postnatal week on functional properties of thalamocortical synapses and associated disynaptic feedforward inhibition. By selectively depleting microglia at early postnatal days by intracerebral injections of clodronate-encapsulated liposomes, we show that microglia absence during the first postnatal week delays the functional maturation of both monosynaptic thalamocortical synapse and feedforward inhibition of layer 4 principal cells of the barrel cortex (PC) up to the 10th and 12th postnatal days (P10-12). To identify the mechanism underlying this process, we used the CX3CR1+/CreERT2; BDNFlox/lox mouse line allowing the conditional deletion of microglial BDNF during the first postnatal week. Our recordings indicate that the absence of microglial BDNF, as well as early microglia depletion, leads to a deficit in the functional maturation of both monosynaptic excitatory and disynaptic inhibitory thalamocortical connexions between P10-12. We therefore identified a microglial key factor in the maturation of cortical synapses. Our recordings in the young adult suggest that early microglial BDNF deletion has a long-term effect on thalamocortical excitatory synapses. In a second study, we investigated the consequences of microglia dysfunction during embryonic development on cortical networks wiring. Maternal immune activation (MIA) triggered by bacterial lipopolysaccharide (LPS) injection modifies the laminar repartition of parvalbumin-expressing inhibitory interneurons (PV+), key actors in neuropsychiatric disease, in the cortex until P20. Our functional data revealed that these MIA and depletion protocols lead to an increase of layer 4 PC perisomatic inhibition at P20, as well as a horizontal exuberance of cortical inhibition supported by PV+ interneurons. This increased inhibition does not last within development as suggested by our recordings in the adult. On the opposite, it seems that MIA and early microglia depletion result in weaker inhibitory synapses at P60. To conclude, we postulate that microglial cells are the missing link between maternal immune challenge and à higher risk of having neurodevelopmental pathologies like autism or schizophrenia. Our results highlight the crucial role of microglial cells in neuronal network development during perinatal period.; La microglie désigne l'ensemble des macrophages résidents du système nerveux central (SNC). Longtemps considérées comme étant actives uniquement en conditions pathologiques, les cellules microgliales sont pourtant essentielles à l'activité physiologique du SNC. En particulier, pendant la formation du SNC, elles régulent apoptose et survie neuronales, et interagissent directement avec les synapses en les éliminant, en promouvant leur formation ou en régulant leur activité. Toutefois, les mécanismes microgliaux impliqués dans la mise en place et la maturation fonctionnelle des circuits corticaux pendant le développement ne sont pas intégralement élucidés. Afin de mieux comprendre le rôle de la microglie dans le développement cortical, nous avons utilisé le système des champs de tonneaux du cortex somatosensoriel de la souris, et combiné des manipulations in vivo avec des approches électrophysiologiques, optogénétique, pharmacologique et histologique sur tranches de cerveaux de souris génétiquement modifiées. Dans une première étude, nous nous sommes intéressés aux conséquences de l'arrivée de la microglie à proximité des zones de terminaison des fibres thalamiques (les centres des tonneaux) dans le cortex somatosensoriel au cours de la première semaine postnatale sur les propriétés fonctionnelles des synapses thalamocorticales et de l'inhibition disynaptique associée (inhibition antérograde ou feedforward). Nos résultats montrent qu'une déplétion de la microglie pendant la première semaine postnatale entraîne un retard de maturation fonctionnelle de la connexion thalamocorticale excitatrice monosynaptique et de l'inhibition feedforward disynaptique au niveau des cellules principales excitatrices de la couche 4 (CP) entre les 10ème et 12ème jours postnataux (P10-12). Nous avons ensuite testé si le facteur neurotrophique BDNF (brain-derived neurotrophic factor) pouvait être la molécule microgliale impliquée dans la maturation de ces synapses corticales en utilisant une approche transgénique (lignée CX3CR1+/CreERT2;BDNFlox/lox). Nos enregistrements indiquent que l'absence de BDNF microglial entraîne aussi un déficit de maturation fonctionnelle des connexions excitatrices monosynaptiques et inhibitrices disynaptiques thalamocorticales entre P10-12. Nous avons donc identifié un facteur microglial clé dans la maturation des synapses corticales, et nos enregistrements chez le jeune adulte suggèrent que la suppression de BDNF microglial pendant la première semaine postnatale altère la synapse thalamocorticale excitatrice sur le long terme. Dans une deuxième étude, nous avons examiné les conséquences de perturbations de la microglie au cours du développement embryonnaire sur la mise en place des réseaux corticaux. L'induction d'une activation immunitaire maternelle (MIA) par injection de lipopolysaccharide (LPS) bactérien ou la déplétion de la microglie aux stades embryonnaires modifie la répartition laminaire des interneurones inhibiteurs exprimant la parvalbumine (PV+) _cellules responsables de l'inhibition feedforward_ dans le cortex jusqu'à P20. Nos données fonctionnelles ont révélé que ces protocoles de MIA et de déplétion induisent une augmentation de l'inhibition périsomatique des CP à P20, ainsi qu'une exubérance horizontale de l'inhibition soutenue par les interneurones PV+. Cette inhibition exacerbée ne perdure pas et nos enregistrements chez l'adulte indiquent au contraire un affaiblissement des synapses inhibitrices entre les interneurones PV+ et les CP. Nous postulons donc que les cellules microgliales sont le chaînon manquant entre des stimulations immunitaires, telles qu'elles peuvent se produire durant une inflammation pendant la grossesse, et l'augmentation du risque de développer des pathologies neurodéveloppementales. Ainsi, nos résultats mettent en exergue le rôle crucial de la microglie dans le développement des réseaux neuronaux corticaux pendant la période périnatale.

International audience; In the skin, Merkel cells connect with keratinocytes and Ab nerve fibers to form a touch receptor that functions as a slow adapting mechanoreceptor (slow adapting type 1). In human and mouse Merkel cells, we observed an increased concentration of intracellular Ca 2þ ions in response to cold temperature and transient receptor potential melastatine 8 (TRPM8) ion channel agonists. A reduction in the response to cooling and TRPM8 ag-onists occurred after the addition of TRPM8 antagonists, as well as in TRPM8 knockout mice. Cold temperature and TRPM8 agonists also induced a current that was inhibited by a TRPM8 antagonist. Our results indicate that Merkel cells sense cooling through TRPM8 channels. We hypothesized that cooling modulates the slow adapting type 1 receptor response. Cooling mouse skin to 22 C reduced the slow adapting type 1 receptor discharge frequency. Interestingly, we observed no such reduction in TRPM8 knockout mice. Similarly, in human skin, a temperature of 22 C applied to the slow adapting type 1 receptive field reduced the spiking discharge. Altogether, our results indicate that Merkel cells are polymodal sensory cells that respond to mild cold stimuli through the activation of TRPM8 channels. Thermal activation of Merkel cells, and possibly other TRPM8-expressing non-neuronal cells, such as keratinocytes, potentially adapts the discharge of slow adapting type 1 receptors during cooling.

Epilepsy is characterized by unpredictable recurrent seizures resulting from abnormal neuronal excitability. Increasing evidence indicates that aberrant astrocyte signaling to neurons plays an important role in driving the network hyperexcitability, but the underlying mechanism that alters glial signaling in epilepsy remains unknown. Increase in glutamate release by astrocytes participates in the onset and progression of seizures. Epileptic seizures are also accompanied by increase of tumor necrosis factor alpha (TNFα), a cytokine involved in the regulation of astrocyte glutamate release. Here we tested whether TNFα controls abnormal astrocyte glutamate signaling in epilepsy and through which mechanism. Combining Ca2+ imaging, optogenetics, and electrophysiology, we report that TNFα triggers a Ca2+ -dependent glutamate release from astrocytes that boosts excitatory synaptic activity in the hippocampus through a mechanism involving autocrine activation of P2Y1 receptors by astrocyte-derived ATP/ADP. In a mouse model of temporal lobe epilepsy, such TNFα-driven astrocytic purinergic signaling is permanently active, promotes glial glutamate release, and drives abnormal synaptic activity in the hippocampus. Blocking this pathway by inhibiting P2Y1 receptors restores normal excitatory synaptic activity in the inflamed hippocampus. Our findings indicate that targeting the coupling of TNFα with astrocyte purinergic signaling may be a therapeutic strategy for reducing glial glutamate release and normalizing synaptic activity in epilepsy.

© The Author(s) 2018. This article is published with open access. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/., Synaptic dysfunction plays a central role in Alzheimer's disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A2A receptor (A2AR) encoding gene-ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A2AR in age-related conditions. We report, for the first time, a significant overexpression of A2AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A2AR overexpression in rats was sufficient to drive age-like memory impairments in young animals and to uncover a hippocampal LTD-to-LTP shift. This was accompanied by increased NMDA receptor gating, dependent on mGluR5 and linked to enhanced Ca2+ influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon A2AR blockade. This A2AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity., MT-F is an FCT/PhD Fellow (IMM Lisbon BioMed PhD program; SFRH/BD/52228/2013); VLB, DGF and JEC were supported by a fellowship from Fundação para a Ciência e Tecnologia (FCT, Portugal); LVL is an Investigator FCT. TFO is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Goettingen, Germany. RAC is supported by Maratona da Saúde, Santa Casa da Misericórdia and ERDF, through Centro 2020 (project CENTRO-01-0145-FEDER-000008:BrainHealth 2020), and through FCT (projects POCI-01-0145-FEDER-007440 and PTDC/NEU-NMC/4154/2016). DB, VBS, EF, and LB are supported by Région Hauts de France (PARTNAIRR COGNADORA), ANR (ADORATAU and SPREADTAU), LECMA/Alzheimer Forschung Initiative, Programs d’Investissements d’Avenir LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to AD), France Alzheimer/Fondation de France, the FHU VasCog research network (Lille, France), Fondation pour la Recherche Médicale, Fondation Plan Alzheimer, INSERM, CNRS, Université Lille 2, Lille Métropole Communauté Urbaine, FEDER, DN2M, LICEND, and CoEN. LVL and DB are supported by AAP Internationalization, Université de Lille. EF is supported by ANR and Université de Lille. We would like to thank the Lille Neurobank for providing human brain tissues. HM and PAP supported by ATIP/AVENIR program (Center National de la Recherche Scientifique—CNRS), by the Foundation Plan Alzheimer (Senior Innovative Grant 2010) and PP by the Fondation pour la Recherche Médicale (FRM post-doctoral fellowship). Funded by LISBOA-01-0145-FEDER-007391, project co-financed by FEDER, POR Lisboa 2020—Programa Operacional Regional de Lisboa, from PORTUGAL 2020 and by Fundação para a Ciência e a Tecnologia (PTDC/BIM-MEC/47778/2014).

Objective The simultaneous recording of intracerebral EEG (stereotaxic EEG, SEEG) and magnetoencephalography (MEG) is a promising strategy that provides both local and global views on brain pathological activity. Yet, acquiring simultaneous signals poses difficult technical issues that hamper their use in clinical routine. Our objective was thus to develop a set of solutions for recording a high number of SEEG channels while preserving signal quality. Approach We recorded data in a patient with drug resistant epilepsy during presurgical evaluation. We used dedicated insertion screws and optically insulated amplifiers. We recorded 137 SEEG contacts on 10 depth electrodes (5-15 contacts each) and 248 MEG channels (magnetometers). Signal quality was assessed by comparing the distribution of RMS values in different frequency bands to a reference set of MEG acquisitions. Main results The quality of signals was excellent for both MEG and SEEG; for MEG, it was comparable to that of MEG signals without concurrent SEEG. Discharges involving several structures on SEEG were visible on MEG, whereas discharges limited in space were not seen at the surface. Significance SEEG can now be recorded simultaneously with whole-head MEG in routine. This opens new avenues, both methodologically for understanding signals and improving signal processing methods, and clinically for future combined analyses.

International audience; The baroreflex response is an essential component of the cardiovascular regulation that buffers abrupt changes in blood pressure to maintain homeostasis. Urotensin II (UII) and its receptor UT are present in the brain and in peripheral cardiovascular tissues of fish and mammals. Intracerebroventricular (ICV) injection of UII in these vertebrates provokes hypertension and tachycardia, suggesting that the cardio-inhibitory baroreflex response is impaired. Since nothing is known about the effect of UII on the cardiac baroreflex sensitivity (BRS), we decided to clarify the changes in spontaneous BRS using a cross spectral analysis technique of systolic blood pressure (SBP) and R-R interval variabilities after ICV and intra-arterial (IA) injections of trout UII in the unanesthetized trout. We contrasted the effects of UII with those observed for the UII-related peptides (URP), URP1 and URP2. Compared with vehicle-injected trout, ICV injection of UII (5-500 pmol) produced a gradual increase in SBP, a decrease in the R-R interval (reflecting a tachycardia) associated with a dose-dependent reduction of the BRS. The threshold dose for a significant effect on these parameters was 50 pmol (BRS; -55%; 1450 ± 165 ms/kPa vs. 3240 ± 300 ms/kPa; P < 0.05). Only the 500-pmol dose of URP2 caused a significant increase in SBP without changing significantly the R-R interval but reduced the BRS. IA injection of UII (5-500 pmol) caused a dose-dependent elevation of SBP. Contrasting with the ICV effects of UII, the R-R interval increased (reflecting a bradycardia) up to the 50-pmol dose while the BRS remained unchanged (50 pmol; 2530 ± 270 ms/kPa vs. 2600 ± 180 ms/kPa; P < 0.05). Nonetheless, the highest dose of UII reduced the BRS as did the highest dose of URP1. In conclusion, the contrasting effect of low picomolar doses of UII after central and peripheral injection on the BRS suggests that only the central urotensinergic system is involved in the attenuation of the BRS. The limited and quite divergent effects of URP1 and URP2 on the BRS, indicate that the action of UII is specific for this peptide. Further studies are required to elucidate the site(s) and mechanisms of action of UII on the baroreflex pathways. Whether such effects of central UII on the BRS exist in mammals including humans warrants further investigations.

Microglial cells are the resident macrophages of the central nervous system (CNS) and are mainly known for their roles in neuropathologies. However, major recent developments have revealed that these immune cells actively interact with neurons in physiological conditions and can modulate the fate and functions of synapses. Originating from myeloid precursors born in the yolk sac, microglial cells invade the CNS during early embryonic development. As a consequence they can potentially influence neuronal proliferation, migration and differentiation as well as the formation and maturation of neuronal networks, thereby contributing to the entire shaping of the CNS. We review here recent evidence indicating that microglial cells are indeed involved in crucial steps of the CNS development, including neuronal survival and apoptosis, axonal growth, migration of neurons, pruning of supernumerary synapses and functional maturation of developing synapses. We also discuss current hypotheses proposing that diverting microglial cells of their physiological functions, by promoting the expression of an immune phenotype during development, may be central to neurodevelopmental disorders such as autism, schizophrenia and epilepsy.

International audience; We describe a patient with chronic pharmacoresistant epilepsy related to right parietal focal cortical dysplasia (FCD), who became seizure-free following an episode of convulsive status epilepticus (SE). Magnetic resonance imaging (MRI) and fludeoxyglucose positron emission tomography (FDG-PET) were performed before and after SE. Longitudinal MRI scans showed a stable appearance of the FCD with no new signal change. However, diffusion tensor imaging showed altered white matter fiber tract orientation in posterior cortices, especially in proximity to the lesion, at 3 years post-SE. FDG-PET showed more widespread hypometabolism 3 years after SE. The unusual occurrence of spontaneous seizure remission following SE in the context of FCD-related epilepsy, in association with neuroimaging evolution, suggests possible cerebral reorganization triggered by SE as a mechanism in this case.

Summary The etiology of neurodevelopmental disorders is linked to defects in parvalbumin (PV)-expressing cortical interneurons and to prenatal immune challenges. Mouse models of maternal immune activation (MIA) and microglia deficits increase the postnatal density of PV interneurons, raising the question of their functional integration. Here, we show that MIA and embryonic depletion of macrophages including microglia have a two-step impact on PV interneurons wiring onto their excitatory target neurons in the barrel cortex. In adults, both challenges reduced the inhibitory drive from PV interneurons, as reported in neurodevelopmental disorders. In juveniles, however, we found an increased density of PV neurons, an enhanced strength of unitary connections onto excitatory cells, and an aberrant horizontal inhibition with a reduced lateral propagation of sensory inputs in vivo. Our results provide a comprehensive framework for understanding the impact of prenatal immune challenges onto the developmental trajectory of inhibitory circuits that leads to pathological brain wiring., Graphical Abstract, Highlights • In utero immune challenges have a two-step impact on PV neurons in the barrel cortex • A hypo-inhibition by PV interneurons in adult barrels • A higher density of PV interneurons with an enhanced inhibitory drive in juveniles • An impairment of sensory information flow observable in vivo in the juvenile cortex, Thion et al. show that embryonic macrophages and inflammation shape the wiring of inhibitory neurons, in addition to their known roles on excitatory circuits. It highlights that prenatal immune challenges initially trigger hyperinhibition and miswiring, before leading to a reduced inhibitory drive, thereby revealing the importance of examining full developmental trajectories.

Voltage-gated Na + channels (Nav) are the targets of a variety of scorpion toxins. Here, we investigated the effects of Amm VIII, a toxin isolated from the venom of the scorpion Androctonus mauretanicus mauretanicus , on pain-related behaviours in mice. The effects of Amm VIII were compared with the classic scorpion α-toxin AaH II from Androctonus australis . Contrary to AaH II, intraplantar injection of Amm VIII at relatively high concentrations caused little nocifensive behaviours. However, Amm VIII induced rapid mechanical and thermal pain hypersensitivities. We evaluated the toxins’ effects on Nav currents in nociceptive dorsal root ganglion (DRG) neurons and immortalized DRG neuron-derived F11 cells. Amm VIII and AaH II enhanced tetrodotoxin-sensitive (TTX-S) Nav currents in DRG and F11 cells. Both toxins impaired fast inactivation and negatively shifted activation. AaH II was more potent than Amm VIII at modulating TTX-S Nav currents with EC 50 of 5 nM and 1 μM, respectively. AaH II and Amm VIII also impaired fast inactivation of Nav1.7, with EC 50 of 6.8 nM and 1.76 μM, respectively. Neither Nav1.8 nor Nav1.9 was affected by the toxins. AaH II and Amm VIII reduced first spike latency and lowered action potential threshold. Amm VIII was less efficient than AaH II in increasing the gain of the firing frequency-stimulation relationship. In conclusion, our data show that Amm VIII, although less potent than AaH II, acts as a gating-modifier peptide reminiscent of classic α-toxins, and suggest that its hyperalgesic effects can be ascribed to gain-of-function of TTX-S Na + channels in nociceptors.