Interhemispheric coupling between the posterior sylvian regions impacts successful auditory temporal order judgment.

Accurate perception of the temporal order of sensory events is a prerequisite in numerous functions ranging from language comprehension to motor coordination. We investigated the spatio-temporal brain dynamics of auditory temporal order judgment (aTOJ) using electrical neuroimaging analyses of auditory evoked potentials (AEPs) recorded while participants completed a near-threshold task requiring spatial discrimination of left-right and right-left sound sequences. AEPs to sound pairs modulated topographically as a function of aTOJ accuracy over the 39-77ms post-stimulus period, indicating the engagement of distinct configurations of brain networks during early auditory processing stages. Source estimations revealed that accurate and inaccurate performance were linked to bilateral posterior sylvian regions activity (PSR). However, activity within left, but not right, PSR predicted behavioral performance suggesting that left PSR activity during early encoding phases of pairs of auditory spatial stimuli appears critical for the perception of their order of occurrence. Correlation analyses of source estimations further revealed that activity between left and right PSR was significantly correlated in the inaccurate but not accurate condition, indicating that aTOJ accuracy depends on the functional decoupling between homotopic PSR areas. These results support a model of temporal order processing wherein behaviorally relevant temporal information--i.e. a temporal 'stamp'--is extracted within the early stages of cortical processes within left PSR but critically modulated by inputs from right PSR. We discuss our results with regard to current models of temporal of temporal order processing, namely gating and latency mechanisms.

Neurophysiologic and proteomic investigations of experience-dependent plasticity in the somatosensory cortex of the adult mouse following chronic whisker stimulation

RESUME Les follicules des vibrisses des rongeurs sont représentés sous la forme d'une carte topographique dans le cortex à tonneaux. Lorsque un groupe de vibrisses est coupé pendant plusieurs jours chez un rongeur adulte, en laissant les autres vibrisses intactes, le champ réceptif des neurones du cortex à tonneaux est modifié, ce qui démontre que les cartes corticales sont plastiques. Dans notre étude, une expérience sensorielle a été induite chez une souris adulte se comportant librement en stimulant chroniquement une de ses vibrisses pendant 24h. Par une analyse des potentiels de champ locaux, nous démontrons que les caractéristiques spatiotemporelles du flux d'excitation évoqué par la vibrisse principale (VP) dans la colonne corticale correspondante à la vibrisse stimulée n'est pas altéré. Par contre, l'enregistrement des potentiels d'actions d'un total de 1041 neurones à travers le cortex à tonneaux révèlent plusieurs modifications de l'activité neuronale. L'activité spontanée ainsi que la réponse évoquée par la VP sont déprimées dans la colonne corticale stimulée (nombre moyen de potentiels d'action évoqués par la VP diminue de 25 % et 36% dans la couche IV et les couches II&III). La réponse des neurones à la vibrisse stimulée diminue également dans les colonnes corticales adjacentes, «non-stimulées». La dépression de l'activité spontanée et de la réponse à la VP est localisée à la colonne corticale stimulée. Dans le tonneau stimulé, la première partie de la réponse à la VP n'est pas affaiblie, démontrant que la dépression de la réponse n'est pas due à un phénomène de plasticité sous-corticale ou thalamocorticale. La stimulation chronique d'une vibrisse entraîne une augmentation du nombre de synapses GABAergiques dans la couche IV du tonneau correspondant (Knott et al, 2002). Dès lors, nos résultats suggèrent qu'une augmentation de l'inhibition dans le tonneau stimulé serait à l'origine de la diminution des potentiels d'action évoqués par la vibrisse stimulée et en conséquence de l'amplitude du flux d'excitation vers les couches II&III puis vers les colonnes corticales adjacentes. Toutes les réponses des neurones du tonneau stimulé ne sont pas déprimées. Les réponses des neurones à la vibrisse voisine caudale à VP diminuent dans la couche IV (42%) et dans les couches II&III (52%) mais pas les réponses aux 7 autres vibrisses voisines. Les entrées synaptiques en provenance de la vibrisse caudale pourraient avoir été spécifiquement déprimées en raison d'une décorrélation prolongée entre l'activité évoquée dans les chemins sensoriels relatifs à la vibrisse stimulée et à la vibrisse caudale, spécificité qui découlerait du fait que, parmi les vibrisses voisines à la VP, la vibrisse caudale génère les réponses les plus fortes dans la colonne corticale. Quatre jours après l'arrêt de la stimulation, l'activité neuronale n'est plus déprimée; au contraire, nous observons une potentiation des réponses à la VP dans la couche IV de la colonne corticale stimulée. De plus, nous montrons que l'expression des protéines GLT-1 et GLAST, deux transporteurs astrocytaires du glutamate, est augmentée de ~2.5 fois dans la colonne corticale stimulée, indiquant l'existence d'une «plasticité gliale» et suggérant que les cellules gliales participent activement à l'adaptation du cerveau à l'expérience. ABSTRACT In the barrel cortex, mystacial whisker follicles are represented in the form of a topographie map. The selective removal of a set of whiskers while sparing others for several days in an adult rodent alters receptive field of barrel cortex neurons, demonstrating experience-dependent plasticity of cortical maps. Here sensory experience was altered by chronic stimulation of a whisker for a 24h period in a freely behaving adult mouse. By means of an evoked local field potential analysis, we show that chronic stimulation does not alter the flow of excitation evoked by the principal whisker (PW) in the stimulated barrel column. However, the recording of neuronal firing from a total of 1041 single units throughout the barrel cortex reveals several changes in neuronal activity. Immediately after chronic stimulation, spontaneous activity as well as PW-responses are depressed in the stimulated barrel column (mean number of spikes per PW-deflection decreases by 25% and 36% in layer IV and layers II&III, respectively). Neuronal responses towards the chronically stimulated whisker are also significantly depressed in layers II&III of the adjacent "non-stimulated" barrel' columns. The depression of both spontaneous activity and PW-responses are restricted to the stimulated ban-el column. The earliest time epoch of the PW-response in the stimulated barrel is not depressed, demonstrating that the decrease of cortical responses is not due to subcortical or thalamocortical plasticity. The depression of PW-response in the stimulated barrel correlates with an increase in the number of GABAergic synapses in layer IV (Knott et al., 2002). Therefore, our results suggest that an increase in inhibition within the stimulated barrel may reduce its excitatory output and accordingly the flow of excitation towards layers and the subsequent horizontal spread into adjacent barrel columns. Not all responses of neurons in the stimulated barrel are depressed. Neuronal responses towards the caudal in-row whisker decrease by 42% in layer IV and 52% in layers MM but responses to the other 7 immediate surround whiskers (SWs) are not affected. The synaptic inputs from the SW that elicit the strongest responses in the stimulated barrel may have been specifically depressed following a prolonged period of diminished coherence between neuronal activity evoked in the pathways from the chronically stimulated whisker and from its surrounding in-row whisker. Four days after the cessation of the stimulation, depression of neuronal activity is no longer present; on the contrary, we observe a small but significant potentiation of PW-responses in layer IV of the stimulated barrel column. Moreover we show that the expression of astrocytic glutamate transporters GLT-1 and GLAST proteins were both upregulated by ~2.5 fold in the stimulated barrel column, which indicates that glial cells exhibit experience-dependent functional changes and could actively take part in the adaptation of the cerebral cortex to experience.

Emergence of oriented circuits driven by synaptic pruning associated with spike-timing-dependent plasticity (STDP)

ABSTRACT: Massive synaptic pruning following over-growth is a general feature of mammalian brain maturation. Pruning starts near time of birth and is completed by time of sexual maturation. Trigger signals able to induce synaptic pruning could be related to dynamic functions that depend on the timing of action potentials. Spike-timing-dependent synaptic plasticity (STDP) is a change in the synaptic strength based on the ordering of pre- and postsynaptic spikes. The relation between synaptic efficacy and synaptic pruning suggests that the weak synapses may be modified and removed through competitive "learning" rules. This plasticity rule might produce the strengthening of the connections among neurons that belong to cell assemblies characterized by recurrent patterns of firing. Conversely, the connections that are not recurrently activated might decrease in efficiency and eventually be eliminated. The main goal of our study is to determine whether or not, and under which conditions, such cell assemblies may emerge out of a locally connected random network of integrate-and-fire units distributed on a 2D lattice receiving background noise and content-related input organized in both temporal and spatial dimensions. The originality of our study stands on the relatively large size of the network, 10,000 units, the duration of the experiment, 10E6 time units (one time unit corresponding to the duration of a spike), and the application of an original bio-inspired STDP modification rule compatible with hardware implementation. A first batch of experiments was performed to test that the randomly generated connectivity and the STDP-driven pruning did not show any spurious bias in absence of stimulation. Among other things, a scale factor was approximated to compensate for the network size on the ac¬tivity. Networks were then stimulated with the spatiotemporal patterns. The analysis of the connections remaining at the end of the simulations, as well as the analysis of the time series resulting from the interconnected units activity, suggest that feed-forward circuits emerge from the initially randomly connected networks by pruning. RESUME: L'élagage massif des synapses après une croissance excessive est une phase normale de la ma¬turation du cerveau des mammifères. L'élagage commence peu avant la naissance et est complété avant l'âge de la maturité sexuelle. Les facteurs déclenchants capables d'induire l'élagage des synapses pourraient être liés à des processus dynamiques qui dépendent de la temporalité rela¬tive des potentiels d'actions. La plasticité synaptique à modulation temporelle relative (STDP) correspond à un changement de la force synaptique basé sur l'ordre des décharges pré- et post- synaptiques. La relation entre l'efficacité synaptique et l'élagage des synapses suggère que les synapses les plus faibles pourraient être modifiées et retirées au moyen d'une règle "d'appren¬tissage" faisant intervenir une compétition. Cette règle de plasticité pourrait produire le ren¬forcement des connexions parmi les neurones qui appartiennent à une assemblée de cellules caractérisée par des motifs de décharge récurrents. A l'inverse, les connexions qui ne sont pas activées de façon récurrente pourraient voir leur efficacité diminuée et être finalement éliminées. Le but principal de notre travail est de déterminer s'il serait possible, et dans quelles conditions, que de telles assemblées de cellules émergent d'un réseau d'unités integrate-and¬-fire connectées aléatoirement et distribuées à la surface d'une grille bidimensionnelle recevant à la fois du bruit et des entrées organisées dans les dimensions temporelle et spatiale. L'originalité de notre étude tient dans la taille relativement grande du réseau, 10'000 unités, dans la durée des simulations, 1 million d'unités de temps (une unité de temps correspondant à une milliseconde), et dans l'utilisation d'une règle STDP originale compatible avec une implémentation matérielle. Une première série d'expériences a été effectuée pour tester que la connectivité produite aléatoirement et que l'élagage dirigé par STDP ne produisaient pas de biais en absence de stimu¬lation extérieure. Entre autres choses, un facteur d'échelle a pu être approximé pour compenser l'effet de la variation de la taille du réseau sur son activité. Les réseaux ont ensuite été stimulés avec des motifs spatiotemporels. L'analyse des connexions se maintenant à la fin des simulations, ainsi que l'analyse des séries temporelles résultantes de l'activité des neurones, suggèrent que des circuits feed-forward émergent par l'élagage des réseaux initialement connectés au hasard.

Dysregulated activation of the CXCR4/CXCL12 Axisand its role in the malignant phenotype of neural crest-derived neuroblastoma tumours

Résumé: Le neuroblastome (NB) est un néoplasme dévastateur de la petite enfance, pour lequel il n'existe pas encore de traitement efficace. Les chimiokines et leurs récepteurs ont été impliqués dans la croissance des tumeurs et la formation de métastases, et en particulier, il a été rapporté que l'axe CXCR4/CXCL12 dirigeait le guidage, ainsi que l'invasion des cellules cancéreuses vers des organes spécifiques. Notre étude avait pour objectif d'analyser le rôle de CxCR4 exogène dans le comportement malin du NB, en étudiant la croissance des cellules tumorales, leur capacité de survie, de migration et d'invasion in vitro et en validant ces résultats grâce à un modèle orthotopique murin de la progression tumorale du NB in vivo. La surexpression de CXCR4 dans les cellules faiblement métastatiques IGR-NB8 n'exprimant pas CXCR4, a augmenté la mobilité des cellules vers CXCL12 in vitro. De plus, les cellules surexprimant CXCR4 ont été moins affectées par la privation de sérum que les cellules contrôles. Le volume des tumeurs chez les animaux greffés de manière orthotopique avec les cellules NB8-CXCR4-C3 était significativement plus élevé que celui des tumeurs issues des cellules contrôles NB8-E6 au moment du sacrifice des animaux. Cependant, aucune induction des métastases n'a été observée. La lignée cellulaire IGR-N91, aux propriétés invasives et métastatiques in vivo, exprime constitutivement des quantités modérées de CXCR4. La surexpression du récepteur dans cette lignée a accéléré la croissance tumorale in vivo, mais n'a pas augmenté pas l'occurrence des métastases. Les cellules IGR-N91, dans lesquelles l'expression de CXCR4 a été éteinte, suite à l'introduction de shRNA stable contre CXCR4, a présenté une croissance cellulaire plus lente, in vitro et in vivo. Afin d'identifier les gènes et les voies de signalisation impliqués dans les effets dépendants de CXCR4-CXCL12 dans le NB, des analyses du profil d'expression des gènes ont été effectuées sur les lignées cellulaires transfectées ou non (contrôle). Trois clones contrôles ont été comparés à 3 clones surexprimant CXCR4 pour chacune des lignées (IGR-NB8 et IGR-N91). Les analyses biostatiques ont identifié 10 gènes induits, dont CXCR4, et 31 gènes réprimés, communs entre tous les clones surexprimant CXCR4. Ces observations démontrent que la surexpression de CXCR4 dans le NB stimule la croissance, la survie et la migration chémotactique des cellules tumorales, mais est insuffisante pour induire ou augmenter leurs capacités invasives et métastatiques. Les voies de signalisation activées suite à la surexpression de CXCR4 et identifiées à travers le profil global de l'expression des gènes pourraient être des cibles intéressantes pour le développement de drogues capables d'inhiber la croissance tumorale. Abstact: Neuroblastoma (NB) is a devastating childhood neoplasm for which there is not yet an efficient treatment. Chemokines and their receptors have been involved in tumour growth and metastasis, and in particular the CXCR4/CXCL12 axis has been reported to mediate organ-specific cancer cells homing and invasion. The purpose of the study was to investigate the role of ectopic CXCR4 in the malignant behaviour of NB by studying tumour cell growth, survival, migration, and invasion in vitro and by validating these results using a murine orthotopic model of NB tumour progression in vivo. CXCR4 overexpression in the low metastatic, CXCR4-negative IGR-NB8 cells resulted in CXCL12-mediated chemotaxis in vitro. Furthermore, CXCR4 overexpressing cells were less affected by serum deprivation than mock-transduced cells. In vivo studies revealed that, at sacrifice, volumes of tumours developing in mice with orthotopically implanted NB8-CXCR4-C3 cells, were significantly increased compared to NB8-E6 control tumours. However, no induction of metastases was observed. The in vivo invasive and metastatic cell line IGR-N91 cell line constitutively expresses moderate levels of CXCR4. Overexpression of CXCR4 enhanced in vivo tumour growth but did not increase the occurrence of metastases. IGR-N91 cells where CXCR4 has been knocked-down by stable shRNA grew slower in vitro and in vivo. To identify genes and pathways involved in the CXCR4/CXCL12-mediated effects in NB expression, profiles analyses (Affymetrix) were performed on transduced and control cell lines. Three mock-transduced clones were compared to three CXCR4 overexpressing clones of either cell line IGR-NB8 and IGR-N91. Biostatistical analysis identified 10 commonly upregulated genes (including CXCR4) and 31 downregulated genes common to all CXCR4 overexpressing clones. These observations demonstrate that overexpression of CXCR4 in NB stimulates tumour cell growth, survival, and chemotactic migration but is not sufficient to induce or enhance invasive and metastatic capacities. Activated pathways upon CXCR4 overexpression, identified through global gene expression profiling may be interesting targets for drugs inhibiting tumour growth.

Semaphorin7A regulates neuroglial plasticity in the adult hypothalamic median eminence.

Reproductive competence in mammals depends on the projection of gonadotropin-releasing hormone (GnRH) neurons to the hypothalamic median eminence (ME) and the timely release of GnRH into the hypothalamic-pituitary-gonadal axis. In adult rodents, GnRH neurons and the specialized glial cells named tanycytes periodically undergo cytoskeletal plasticity. However, the mechanisms that regulate this plasticity are still largely unknown. We demonstrate that Semaphorin7A, expressed by tanycytes, plays a dual role, inducing the retraction of GnRH terminals and promoting their ensheathment by tanycytic end feet via the receptors PlexinC1 and Itgb1, respectively. Moreover, Semaphorin7A expression is regulated during the oestrous cycle by the fluctuating levels of gonadal steroids. Genetic invalidation of Semaphorin7A receptors in mice induces neuronal and glial rearrangements in the ME and abolishes normal oestrous cyclicity and fertility. These results show a role for Semaphorin7A signalling in mediating periodic neuroglial remodelling in the adult ME during the ovarian cycle.

Neural detection of complex sound sequences in the absence of consciousness.

The neural response to a violation of sequences of identical sounds is a typical example of the brain's sensitivity to auditory regularities. Previous literature interprets this effect as a pre-attentive and unconscious processing of sensory stimuli. By contrast, a violation to auditory global regularities, i.e. based on repeating groups of sounds, is typically detectable when subjects can consciously perceive them. Here, we challenge the notion that global detection implies consciousness by testing the neural response to global violations in a group of 24 patients with post-anoxic coma (three females, age range 45-87 years), treated with mild therapeutic hypothermia and sedation. By applying a decoding analysis to electroencephalographic responses to standard versus deviant sound sequences, we found above-chance decoding performance in 10 of 24 patients (Wilcoxon signed-rank test, P < 0.001), despite five of them being mildly hypothermic, sedated and unarousable. Furthermore, consistently with previous findings based on the mismatch negativity the progression of this decoding performance was informative of patients' chances of awakening (78% predictive of awakening). Our results show for the first time that detection of global regularities at neural level exists despite a deeply unconscious state.

Targeting Oxidative Stress and Aberrant Critical Period Plasticity in the Developmental Trajectory to Schizophrenia.

Schizophrenia is a neurodevelopmental disorder reflecting a convergence of genetic risk and early life stress. The slow progression to first psychotic episode represents both a window of vulnerability as well as opportunity for therapeutic intervention. Here, we consider recent neurobiological insight into the cellular and molecular components of developmental critical periods and their vulnerability to redox dysregulation. In particular, the consistent loss of parvalbumin-positive interneuron (PVI) function and their surrounding perineuronal nets (PNNs) as well as myelination in patient brains is consistent with a delayed or extended period of circuit instability. This linkage to critical period triggers (PVI) and brakes (PNN, myelin) implicates mistimed trajectories of brain development in mental illness. Strategically introduced antioxidant treatment or later reinforcement of molecular brakes may then offer a novel prophylactic psychiatry.

Sex differences in brain plasticity: a new hypothesis for sex ratio bias in autism.

Several observations support the hypothesis that differences in synaptic and regional cerebral plasticity between the sexes account for the high ratio of males to females in autism. First, males are more susceptible than females to perturbations in genes involved in synaptic plasticity. Second, sex-related differences in non-autistic brain structure and function are observed in highly variable regions, namely, the heteromodal associative cortices, and overlap with structural particularities and enhanced activity of perceptual associative regions in autistic individuals. Finally, functional cortical reallocations following brain lesions in non-autistic adults (for example, traumatic brain injury, multiple sclerosis) are sex-dependent. Interactions between genetic sex and hormones may therefore result in higher synaptic and consecutively regional plasticity in perceptual brain areas in males than in females. The onset of autism may largely involve mutations altering synaptic plasticity that create a plastic reaction affecting the most variable and sexually dimorphic brain regions. The sex ratio bias in autism may arise because males have a lower threshold than females for the development of this plastic reaction following a genetic or environmental event.

Neural Circuits: Male Mating Motifs.

Characterizing microcircuit motifs in intact nervous systems is essential to relate neural computations to behavior. In this issue of Neuron, Clowney et al. (2015) identify recurring, parallel feedforward excitatory and inhibitory pathways in male Drosophila's courtship circuitry, which might explain decisive mate choice.

From bird to sparrow: Learning-induced modulations in fine-grained semantic discrimination.

Recognition of environmental sounds is believed to proceed through discrimination steps from broad to more narrow categories. Very little is known about the neural processes that underlie fine-grained discrimination within narrow categories or about their plasticity in relation to newly acquired expertise. We investigated how the cortical representation of birdsongs is modulated by brief training to recognize individual species. During a 60-minute session, participants learned to recognize a set of birdsongs; they improved significantly their performance for trained (T) but not control species (C), which were counterbalanced across participants. Auditory evoked potentials (AEPs) were recorded during pre- and post-training sessions. Pre vs. post changes in AEPs were significantly different between T and C i) at 206-232ms post stimulus onset within a cluster on the anterior part of the left superior temporal gyrus; ii) at 246-291ms in the left middle frontal gyrus; and iii) 512-545ms in the left middle temporal gyrus as well as bilaterally in the cingulate cortex. All effects were driven by weaker activity for T than C species. Thus, expertise in discriminating T species modulated early stages of semantic processing, during and immediately after the time window that sustains the discrimination between human vs. animal vocalizations. Moreover, the training-induced plasticity is reflected by the sharpening of a left lateralized semantic network, including the anterior part of the temporal convexity and the frontal cortex. Training to identify birdsongs influenced, however, also the processing of C species, but at a much later stage. Correct discrimination of untrained sounds seems to require an additional step which results from lower-level features analysis such as apperception. We therefore suggest that the access to objects within an auditory semantic category is different and depends on subject's level of expertise. More specifically, correct intra-categorical auditory discrimination for untrained items follows the temporal hierarchy and transpires in a late stage of semantic processing. On the other hand, correct categorization of individually trained stimuli occurs earlier, during a period contemporaneous with human vs. animal vocalization discrimination, and involves a parallel semantic pathway requiring expertise.

Prolonged Period of Cortical Plasticity upon Redox Dysregulation in Fast-Spiking Interneurons.

BACKGROUND: Oxidative stress and the specific impairment of perisomatic gamma-aminobutyric acid circuits are hallmarks of the schizophrenic brain and its animal models. Proper maturation of these fast-spiking inhibitory interneurons normally defines critical periods of experience-dependent cortical plasticity. METHODS: Here, we linked these processes by genetically inducing a redox dysregulation restricted to such parvalbumin-positive cells and examined the impact on critical period plasticity using the visual system as a model (3-6 mice/group). RESULTS: Oxidative stress was accompanied by a significant loss of perineuronal nets, which normally enwrap mature fast-spiking cells to limit adult plasticity. Accordingly, the neocortex remained plastic even beyond the peak of its natural critical period. These effects were not seen when redox dysregulation was targeted in excitatory principal cells. CONCLUSIONS: A cell-specific regulation of redox state thus balances plasticity and stability of cortical networks. Mistimed developmental trajectories of brain plasticity may underlie, in part, the pathophysiology of mental illness. Such prolonged developmental plasticity may, in turn, offer a therapeutic opportunity for cognitive interventions targeting brain plasticity in schizophrenia.

Programming Hippocampal Neural Stem/Progenitor Cells into Oligodendrocytes Enhances Remyelination in the Adult Brain after Injury.

Demyelinating diseases are characterized by a loss of oligodendrocytes leading to axonal degeneration and impaired brain function. Current strategies used for the treatment of demyelinating disease such as multiple sclerosis largely rely on modulation of the immune system. Only limited treatment options are available for treating the later stages of the disease, and these treatments require regenerative therapies to ameliorate the consequences of oligodendrocyte loss and axonal impairment. Directed differentiation of adult hippocampal neural stem/progenitor cells (NSPCs) into oligodendrocytes may represent an endogenous source of glial cells for cell-replacement strategies aiming to treat demyelinating disease. Here, we show that Ascl1-mediated conversion of hippocampal NSPCs into mature oligodendrocytes enhances remyelination in a diphtheria-toxin (DT)-inducible, genetic model for demyelination. These findings highlight the potential of targeting hippocampal NSPCs for the treatment of demyelinated lesions in the adult brain.