Literatura científica selecionada sobre o tema "Neurone granulaire"

1. Isolated extracellular neuronal responses to cutaneous stimulation were simultaneously recorded from corresponding peripheral representations in the ventrobasal nucleus and primary somatosensory cortex of intact, halothane-anesthetized rats. Thalamic and cortical neurons representing hairy skin on the forelimb were activated by hair movements produced by a series of 50 or 100 discrete air jets. A corresponding set of neurons representing the glabrous pads of the hind paw were activated by a similar number of punctate mechanical displacements. 2. Cortical electrode penetrations were histologically reconstructed, and 118 neurons in the glabrous skin representation exhibited cutaneous responses that were categorized into supragranular, granular, or infragranular groups according to their laminar position. Minimum latencies of cortical neurons responding to glabrous skin displacement were analyzed, and significant differences were found in the distribution of minimum latencies for the different cortical layers. Mean values for minimum latencies in the infragranular and granular layers were 15.8 and 16.3 ms, respectively, whereas supragranular neurons were characterized by minimum latencies having a mean of 20 ms. The differences between these groups suggests that stimulus-induced afferent activity reaches infragranular and granular layers before contacting supragranular neurons. Average latencies were also calculated on responses occurring during the 1st 20 trials, but the cortical distributions of these values overlapped considerably, and differences between the laminar groups were not statistically significant. 3. In several recording sites, two cortical neurons were recorded simultaneously, and the response latencies of these matched pairs were often substantially different despite the similarity in laminar position. This result indicates that laminar location is not the only determinant of response latency and that serially organized circuits are distributed within, as well as between, cortical layers. 4. From a sample of 302 neurons exhibiting cutaneous responses within histologically identified regions of thalamus or cortex, a set of 143 pairs of neurons recorded simultaneously from both regions was available for cross-correlation analysis. Significant thalamocortical interactions were found in 38 neurons pairs. Analysis of these significant interactions revealed that thalamocortical connection strength, as measured by neuronal efficacy, was two to four times larger for neuron pairs having the cortical cell in granular layer IV than for neuron pairs having an extragranular layer cortical neuron. There was no difference in thalamocortical connection strength between neuron pairs containing supra- or infragranular cortical neurons. 5. Summed peristimulus time histograms revealed stimulus-locked inhibition of spontaneous activity in 4% (8/195) or cortical and 18% (20/107) of thalamic neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

The density of cells and neurons in the neocortex of many mammals varies across cortical areas and regions. This variability is, perhaps, most pronounced in primates. Nonuniformity in the composition of cortex suggests regions of the cortex have different specializations. Specifically, regions with densely packed neurons contain smaller neurons that are activated by relatively few inputs, thereby preserving information, whereas regions that are less densely packed have larger neurons that have more integrative functions. Here we present the numbers of cells and neurons for 742 discrete locations across the neocortex in a chimpanzee. Using isotropic fractionation and flow fractionation methods for cell and neuron counts, we estimate that neocortex of one hemisphere contains 9.5 billion cells and 3.7 billion neurons. Primary visual cortex occupies 35 cm2 of surface, 10% of the total, and contains 737 million densely packed neurons, 20% of the total neurons contained within the hemisphere. Other areas of high neuron packing include secondary visual areas, somatosensory cortex, and prefrontal granular cortex. Areas of low levels of neuron packing density include motor and premotor cortex. These values reflect those obtained from more limited samples of cortex in humans and other primates.

Abstract The proliferation of Deep Neural Networks in various domains has seen an increased need for interpretability of these models. Preliminary work done along this line, and papers that surveyed such, are focused on high-level representation analysis. However, a recent branch of work has concentrated on interpretability at a more granular level of analyzing neurons within these models. In this paper, we survey the work done on neuron analysis including: i) methods to discover and understand neurons in a network; ii) evaluation methods; iii) major findings including cross architectural comparisons that neuron analysis has unraveled; iv) applications of neuron probing such as: controlling the model, domain adaptation, and so forth; and v) a discussion on open issues and future research directions.

We used cross-correlation analysis to characterize the coordination of stimulus-induced neuronal activity in the primary somatosensory barrel cortex of isoflurane-anesthetized rats. On each trial, multiple whiskers were simultaneously deflected at frequencies that corresponded to 2, 5, 8, or 11 Hz. Among 476 neuron pairs that we examined, 342 (71.8%) displayed significant peaks of synchronized activity that exceeded the 99.9% confidence limits. The incidence and strength of these functional associations varied across different cortical layers. Only 52.9% of neuron pairs in layer IV displayed synchronized responses, whereas 84.1% of the infragranular neuron pairs were synchronized during whisker stimulation. Neuronal synchronization was strongest in the infragranular layers, weakest in layer IV, and varied according to the columnar configuration of the neuron pairs. Thus correlation coefficients were largest for neuron pairs in the same whisker barrel row but were smallest for neurons in different rows and arcs. Spontaneous activity in the infragranular layers was also synchronized to a greater degree than in the other layers. Although infragranular neuron pairs displayed similar amounts of synchronization in response to each stimulus frequency, granular and supragranular neurons were synchronized mainly during stimulation at 2 or 5 Hz. These results are consistent with previous studies indicating that infragranular neurons have intrinsic properties that facilitate synchronized activity, and they suggest that neuronal synchronization plays an important role in transmitting sensory information to other cortical or subcortical brain regions.

The brain's energy supply determines its information processing power, and generates functional imaging signals, which are often assumed to reflect principal neuron spiking. Using measured cellular properties, we analysed how energy expenditure relates to neural computation in the cerebellar cortex. Most energy is used on information processing by non-principal neurons: Purkinje cells use only 18% of the signalling energy. Excitatory neurons use 73% and inhibitory neurons 27% of the energy. Despite markedly different computational architectures, the granular and molecular layers consume approximately the same energy. The blood vessel area supplying glucose and O2 is spatially matched to energy consumption. The energy cost of storing motor information in the cerebellum was also estimated.

Glucocorticoids are known to influence hippocampal function, but their rapid non-genomic effects on specific neurons in the hippocampal trisynaptic circuit remain underexplored. This study investigated the immediate effects of glucocorticoids on CA1 and CA3 pyramidal neurons, and dentate gyrus (DG) granule neurons in rats using the patch-clamp technique. We found that a 5 min extracellular application of corticosterone significantly reduced action potential firing frequency in CA1 pyramidal neurons, while no effects were observed in CA3 or DG neurons. The corticosterone-induced inhibition in CA1 was blocked by the glucocorticoid receptor antagonist CORT125281, but remained unaffected by the mineralocorticoid receptor antagonist spironolactone. Notably, membrane-impermeable bovine serum albumin-conjugated dexamethasone mimicked corticosterone’s effects on CA1 neurons, which exhibited prominent hyperpolarization-activated cyclic nucleotide-gated (HCN) channel currents. Pyramidal neurons in CA3 and granular neurons in the DG showed little HCN channel currents. Corticosterone enhanced HCN channel activity in CA1 neurons via glucocorticoid receptors, and the HCN channel inhibitor ZD7288 abolished corticosterone’s suppressive effects on action potentials. These findings suggest that glucocorticoids selectively inhibit CA1 pyramidal neuron activity through HCN channels, providing new insight into the mechanisms of glucocorticoid action in hippocampal circuits.

Dogs with mucopolysaccharidosis (MPS) IIIA were bred within an experimental colony. As part of characterizing them as a model for testing therapeutic strategies for the analogous disease of children, a pathologic study was undertaken. By histology, there were variably stained storage cytosomes within neurons, including many that stained for gangliosides. On ultrastructure examination, these cytosomes contained either moderately dense granular material, tentatively interpreted as precipitated glycosaminoglycan; a variety of multilaminar bodies, interpreted as being associated with secondary accumulation of gangliosides; or a mixture of both types. In the liver, storage vesicles also contained excess glycogen as a secondary storage product. In various tissues, there were large foamy macrophages. In the brain, many of these were in juxtaposition with neurons, and, on ultrastructure examination, they contained storage cytosomes similar to those in neurons. However, the neuron in association with such a macrophage frequently showed little such material.

The cerebellum input stage has been known to perform combinatorial operations on input signals. In this paper, two types of mathematical models were used to reproduce the role of feed-forward inhibition and computation in the granular layer microcircuitry to investigate spike train processing. A simple spiking model and a biophysically-detailed model of the network were used to study signal recoding in the granular layer and to test observations like center-surround organization and time-window hypothesis in addition to effects of induced plasticity. Simulations suggest that simple neuron models may be used to abstract timing phenomenon in large networks, however detailed models were needed to reconstruct population coding via evoked local field potentials (LFP) and for simulating changes in synaptic plasticity. Our results also indicated that spatio-temporal code of the granular network is mainly controlled by the feed-forward inhibition from the Golgi cell synapses. Spike amplitude and total number of spikes were modulated by LTP and LTD. Reconstructing granular layer evoked-LFP suggests that granular layer propagates the nonlinearities of individual neurons. Simulations indicate that granular layer network operates a robust population code for a wide range of intervals, controlled by the Golgi cell inhibition and is regulated by the post-synaptic excitability.

Many neurons in the mollusc Aplysia are identifiable and provide a useful model system for investigating the cellular mechanisms used by the neuroendocrine system to mediate simple behaviors. In this study we determined the subcellular localization of eight Aplysia neuropeptides using immunogold labeling techniques, and analyzed the size distribution of dense core and granular vesicles in peptidergic neurons. Recent observations demonstrate that many neurons use multiple chemical messengers. Thus, an understanding of the functional significance of cotransmitters requires an analysis of their relative subcellular distributions. The peptides are expressed in a subset of neurons, or the exocrine atrial gland, and are primarily localized to dense core vesicles. Multiple regions of precursors which are cleaved into several components are co-localized. Each neuron has a distinct size distribution of peptide-containing dense core vesicles ranging in size from 65 to 600 nm. The atrial gland contains very large (up to 2 micron) peptide-containing granules. Single neurons have multiple populations of granules whose quantal sizes agree with predictions based on physical constraints. Some cells contain very large peptide-containing granules which are found in the cell soma and not in processes. Thus, the genetic determination of neuronal cell type includes not only transmitter choices but also multiple modes of packaging the intercellular messengers.

Dans le gyrus denté (GD) de la formation hippocampique, la génération des neurones granulaires (NGs) commence vers la fin de l'embryogenèse, atteint un pic autour de la naissance, puis se poursuit à un faible niveau à l'âge adulte. Cette neurogénèse continue fait du GD une structure cérébrale unique, composée de NGs d'origines temporelles distinctes qui forment des sous-populations potentiellement dotées de caractéristiques anatomiques et fonctionnelles spécifiques dans l'hippocampe. Étonnamment, cette hypothèse a reçu peu d'attention. Dans ce contexte, ce travail de thèse a visé à élucider les caractéristiques morphologiques, électrophysiologiques et comportementales des sous-populations de NGs en fonction de leur origine temporelle. S’appuyant sur des découvertes antérieures de notre équipe qui avaient mis en évidence des différences dendritiques entre ces populations, nous avons centré nos investigations sur leurs axones, appelés fibres moussues. En utilisant des stratégies de marquage épars — l'électroporation pour cibler les NGs nés durant la période embryonnaire(E14.5) et néonatale (P0), ainsi que des injections rétrovirales pour les NGs nés à l’adolescence(P21) et à l’âge adulte (P84) — nous avons mis en évidence que les NGs générés à des périodes plus tardives développent des boutons plus larges avec davantage de filopodes et présentent un segment initial axonal plus court. De plus, en utilisant les lignées de souris Osteocalcin-Cre etAscl1CreERT2 pour marquer de larges cohortes de NGs générés durant la période embryonnaire et à l’âge adulte, respectivement, nous avons observé que les neurones nés précocement projettent davantage vers le CA2 comparativement aux neurones générés plus tardivement au cours de la vie. Suite à ces découvertes, nous avons étudié les caractéristiques fonctionnelles des NGs d’origines temporelles différentes, au niveau électrophysiologique et comportemental.Les études électrophysiologiques ont révélé que les NGs nés en période néonatale partagent des propriétés intrinsèques similaires à celles des NGs nés en période adulte, mais possèdent une transmission basale plus élevée, reflétant potentiellement un nombre plus important de sites actifs. Enfin, nous avons examiné le rôle des NGs nés en période embryonnaire dans le comportement de type social et montré qu’une inhibition aiguë de ces neurones retardait l’expression de la préférence sociale. Cependant, ces données fonctionnelles restent préliminaires et nécessitent des investigations supplémentaires.En conclusion, ce travail de thèse met en évidence l'impact significatif de l'origine temporelle des NGs sur leurs caractéristiques anatomiques et potentiellement fonctionnelles, soulignant l’importance de prendre en compte l’origine temporelle des NGs dans toute étude s’intéressant à l’aspect structurel ou fonctionnel du DG
In the dentate gyrus (DG) of the hippocampus, the generation of dentate granule neurons(DGNs) starts during late embryogenesis, peaks around birth and continues at low levels during adulthood. This continuous neurogenesis makes the DG a unique structure, composed of DGNs from distinct temporal origins, which form subpopulations potentially bearing unique anatomical characteristics and functional roles in hippocampal physiology. Surprisingly, this hypothesis has received limited attention. In this context, our research aimed to elucidate the morphological, electrophysiological, and behavioral characteristics of DGNs subpopulations based on their temporal origin. Building on prior findings from our team that high lighted dendritic differences between these populations, we focused on examining the features of their axons, called mossy fibers (MFs). Using sparse labeling strategies — electroporation to targetembryonically-born (E14.5) and neonatally-born (P0) DGNs, and retroviral injections foradolescent-born (P21) and adult-born (P84) DGNs — we uncovered that DGNs generated laterin life develop larger MF boutons with more filopodia, and exhibit a shorter axon initialsegment. Additionally, using the Osteocalcin-Cre and Ascl1CreERT2 mouse lines to selectivelylabel large cohorts of embryonically-born and adult-born DGNs, respectively, we found thatearlier-born neurons project further onto the CA2 compared to later-born neurons. Following these morphological findings, we further investigated the functional characteristics of temporally distinct DGNs at both the electrophysiological and behavioral levels. The electrophysiological studies revealed similar intrinsic properties between neonatally- and adult born DGNs, and higher basal transmission in neonatally-born DGNs, potentially reflecting alarger number of active sites. Finally, we examined the role of embryonic-born DGNs in socialbehavior, and showed that acute inhibition of these neurons delayed the expression of social preference. However, these functional data remain preliminary and need further investigation.Altogether, this PhD work highlights the significant impact of the birthdate of DGNs on their anatomical and potentially functional characteristics, and emphasizes the importance of considering their precise temporal origin in any structural or functional analysis of the DG

Dans la plupart des régions cérébrales, les neurones sont générés pendant l’embryogénèse. A l’inverse, dans le gyrus denté (DG) de l'hippocampe, la majorité des neurones granulaires (NGs) est générée en période postnatale et cette production neuronale se poursuit tout au long de l'âge adulte. Cette découverte selon laquelle de nouveaux neurones sont générés dans le cerveau des mammifères adultes a ouvert de nouvelles perspectives pour réparer le cerveau et a conduit de nombreuses recherches, au cours des 20 dernières années, à caractériser comment les nouveaux neurones se différencient et s'intègrent aux circuits neuronaux adultes. Cependant, d'autres études sont nécessaires pour mieux comprendre les mécanismes et les cascades de signalisation impliqués dans ce processus. Dans ce contexte, nous nous sommes concentrés sur Rnd2, une RhoGTPase particulièrement enrichie dans le DG adulte et décrite comme une actrice clé dans la régulation de la neurogenèse corticale embryonnaire. Nous avons montré, in vivo, que la suppression de Rnd2 spécifiquement dans les néo-neurones hippocampiques diminue la survie de ces cellules, et dans les cellules survivantes, conduit à une hypertrophie du soma, augmente l'arborisation dendritique et induit un mauvais positionnement. De façon intéressante cette suppression augmente également le comportement anxiogène des souris, identifiant ainsi Rnd2 comme un régulateur critique de la neurogénèse adulte hippocampique. De plus, nos données montrent que Rnd2 ne joue pas les mêmes fonctions dans les NGs nés à P0, mettant en évidence une régulation différentielle de la neurogenèse développementale et adulte dans la DG. Dans le même ordre d'idées, nous démontrons également que les NGs nés en période périnatale, en particulier les neurones embryonnaires, sont morphologiquement distincts par rapport aux NGs nés plus tard. L'ensemble de ces travaux de thèse apporte donc de nouvelles connaissances sur le développement des différentes populations de NGs dans la DG, soulignant davantage la particularité de cette structure cérébrale
In most areas of the brain, neurons are born during embryogenesis. In contrast, the majority of granule neurons in the dentate gyrus (DG) of the hippocampus are born postnatally and their generation continues throughout adulthood. This finding that new neurons are generated in the adult mammalian brain has opened novel avenues for brain repair and has initiated, in the last 20 years, tremendous efforts to characterize how new neurons differentiate and integrate into adult neural circuitries. However, further studies are needed to better understand the mechanisms and signaling cascades involved in this process. In this context, we focused on Rnd2, a RhoGTPase particularly enriched in the adult neurogenic DG and described as a key player in the regulation of embryonic cortical neurogenesis. We found, in vivo, that the deletion of Rnd2 specifically in adult-born hippocampal neurons decreases the survival of these cells, and in the surviving ones, leads to soma hypertrophy, increases dendritic arborization and induces mispositioning. Importantly, this deletion also increases anxiety-like behavior in mice, thus identifying Rnd2 as a critical regulator of adult newborn neuron development and function. In addition, our data show that Rnd2 does not play the same functions in granule neurons born at P0, highlighting a differential regulation of developmental and adult neurogenesis in the DG. In the same vein, we also demonstrate that perinatally-born granule neurons, especially the embryonic ones, are morphologically distinct compared with later-born neurons. Altogether, this PhD work provides new insights into the development of the different populations of granule neurons in the DG, further emphasizing the peculiarity of this brain structure

Dans le cervelet en développement, les neurones granulaires (ou grains) prolifèrent au sein de la partie superficielle de la couche des grains externe (ou EGL pour « External Granular Layer ») puis se différencient et migrent tangentiellement dans la partie profonde de l’EGL, avant de migrer radiairement vers la profondeur du cervelet. Ces étapes se déroulent dans des compartiments distincts du cortex cérébelleux, ce qui facilite l’étude des transitions entre ces processus. Les sémaphorines et leurs récepteurs, les plexines, sont des protéines exprimées dans le système nerveux, dans lequel elles contrôlent principalement le guidage axonal mais aussi la migration neuronale. Leur rôle dans le cervelet en développement était quasiment inconnu. Nous avons étudié la fonction de la sémaphorine transmembranaire Sema6A, et des plexines Plexin-A2 et Plexin-B2 au cours du développement des grains, en utilisant des approches in vitro et in vivo, principalement l’analyse du phénotype des souris déficientes en ces protéines. Nous avons montré que Plexin-B2 est exprimée par les progéniteurs des grains et qu’elle régule, dans l’EGL, la transition entre la prolifération et la migration. Par ailleurs, nous avons montré que Sema6A est exprimée par les grains migrant tangentiellement, et contrôle, avec son partenaire Plexin-A2, le passage entre migration tangentielle et migration radiaire. Dans ce système, Sema6A joue principalement le rôle d’un ligand pour Plexin-A2. Néanmoins, certains de nos résultats suggèrent que Sema6A puisse également agir en tant que récepteur. Ceci constituerait le deuxième exemple d’un mode de signalisation bidirectionnel qui pourrait être conservé parmi les sémaphorines transmembranaires. Toutes ces molécules sont largement exprimées dans le cerveau au cours du développement et chez l’adulte, suggérant qu’elles participent de manière plus générale à la régulation des processus de prolifération et de migration dans le système nerveux central.

Les acteurs moléculaires des modes de mort cellulaire alternatives à l'apoptose sont très mal connus en particulier pour les neurones. La mort des neurones granulaires de cervelet (NGC) induite par déplétion potassique présente toutes les caractéristiques de l'apoptose. L'induction de la voie de signalisation JNK constitue une étape primordiale dans l'activation des caspases. Cependant, la cascade de mort des NGC ne se limite pas à cette voie mais nécessite également une voie indépendante des caspases. Contrairement à d'autres modèles neuronaux, l'autophagie ne participe pas au déroulement de la mort des NGC. Nous avons également identifié la protéine Alix, qui joue un rôle crucial dans la formation des corps multivésiculaires, comme un acteur essentiel de la mort des NGC. Pour assurer sa fonction pro-apoptotique, Alix recrute les protéines Alg-2 et CIN85 suggérant qu'Alix pourrait connecter le trafic vésiculaire à la mort neuronale
Molecular actors of programmed cell death forms alternative to apoptosis are poorly understood, in particular for neurons. The death of cerebellar granule neurons (CGN) induced by potassium deprivation exhibits all the features of apoptosis The induction of the JNK signaling pathway is a crucial step for caspase activation. However, the death cascade also requires a caspase-independent pathway. In contrast to what is found in others neuronal models, autophagy does not play a role in CGN death. We have also identified Alix, a protein playing a pivotal role in multivesicular body formation, as a key mediator of CGN death. To fulfil its pro-apoptotic function, Alix recruits Alg-2 and CIN85 proteins suggesting that Alix may connect vesicular trafic and cell death

Le gyrus denté (GD), voie d’entrée dans la formation hippocampique, joue un rôle crucial dans l’apprentissage, la mémoire et la navigation spatiale. Seule une faible fraction des cellules granulaires matures (CGMs) est active lors d’un comportement, alors que la majorité reste silencieuse. Les propriétés de ce sous-ensemble de neurones actifs restent peu connues. Pour déterminer les propriétés des cellules recrutées dans différents environnements, nous avons examiné ex vivo les caractéristiques des CGMs activées ou non, provenant de souris maintenues dans leur cage ou entraînées dans un environnement en réalité virtuelle (RV). En utilisant des souris transgéniques fosGFP, nous avons observé que les CGs recrutées chez les souris maintenues dans leur cage, sont des CGs matures (CGMs) présentant une faible excitabilité intrinsèque par rapport aux cellules non recrutées. De plus, les CGMs activées, issues de souris entrainées en RV, présentent un état intermédiaire d’excitabilité entre les CGMs activées des souris maintenues dans leurs cages et les CGMs non activées. Chez les souris maintenues dans leur cage, l’hypoexcitabilité des CGMs est en partie due à la présence d’un important courant GABAergique de fuite qui réduit la résistance d’entrée. Cependant, ce courant de fuite est moindre pour les CGMs activées chez les souris entrainées en RV. De plus, nos données révèlent que les CGMs activées présentent un segment initial de l’axone court et un arbre dendritique étendu, indépendamment du contexte d’activation. En conclusion, nous proposons que les CGMs du gyrus denté aient des propriétés intrinsèques différentes selon le contexte comportemental de leur activation
The dentate gyrus (DG), an input region of the hippocampal formation, plays a crucial role in learning, memory and spatial navigation. Only a small fraction of mature dentate granule cells (mDGCs) is active during behavior, while the large majority remains silent. The properties of this active subset of neurons remain poorly investigated. To determine the properties of cells recruited in different environments, we examined ex vivo the properties of activated DGCs compared to the non-activated cells from mice maintained in their home cage and trained in a virtual reality (VR) environment. Using fosGFP transgenic mice, we observed that recruited DGCs, from mice maintained in their home cage, are mature neurons displaying a striking low intrinsic excitability compared to non-recruited cells. Remarkably, activated mDGCs, from mice trained in a virtual environment displayed an “intermediate” state of excitability between DGCs activated in home cage and non-activated DGCs. In home cage mice, this hypoexcitability is partly due to a GABAA-receptor-mediated shunting inhibition that reduces the input resistance. By contrast, this shunting effect was not observed in activated DGCs of mice trained with virtual reality. Furthermore, our data reveal that activated DGCs display a shorter AIS length and an extended dendritic arbor, which is independent from the environment of their activation. In conclusion, we propose that mature dentate granule cells show different intrinsic properties depending on the behavioral context of their activation

'Les neurones granulaires de cervelet (NGC) survivrent en présence de forte concentration de potassium (K+ 25mM) mais meurent lorsque ils sont placés en milieu appauvri en potassium (5mM). Alix et Alg-2 contrôlent la mort in vitro de ces neurones induite par retrait de potassium. Les recherches que j'ai conduites au cours de ma thèse se sont attachées à définir les mécanismes moléculaires sous-tendant la fonction pro-apoptotique du couple Alix/ Alg-2. J'ai montré qu'Alix et Alg-2 s'associent à la pro-caspase-8, et vérifié la pertinence fonctionnelle de ces interactions dans le modèle de mort des NGC. Outre une implication d'Alix et d'Alg-2 dans la mort cellulaire induite par retrait de support trophique, j'ai mis en évidence la participation d'Alix à la cascade apoptotique déclenchée à la suite d'un stress au réticulum endoplasmique induit par une perturbation d'homéostasie calcique, ainsi qu'une association calcium¬dépendante du couple Alix/Alg-2 et la caspase-9. L'ensemble de nos résultats suggère que l'association calcium dépendante d'Alix avec Alg-2 pourrait favoriser le recrutement des caspase-8 et-9 au sein de plates¬ formes macromoléculaires, ce qui mènerait à leur activation. En outre je me suis également intéressée à Pyk2, un potentiel régulateur négatif du coulpe Alix/Alg-2. Nous avons montré que Pyk2 est impliqué dans la voie de survie des NGC en conditions dépolarisantes et que cette kinase s'active en milieu appauvri en K+ afin d'assurer une réponse de protection contre le stress
Ln an effort to uncover the molecular mechanisms underlying the function of Alix and AIg-2 in cell death, we have found that Alix and AIg-2 can Ca2+-dependently associate with caspase-8 in BHK-21 cells. We investigated the possible existence of an Alix! AIg-2-caspase-8 relationship during cerebellar granule neuron death induced in vitro byeither potassium depletion or Alix overexpression. We showed that Alix is found in a caspase-8-containing complex following K+ depletion-induced CGN apoptosis. Moreover, we demonstrated that caspase-8 functions as initiator caspase in the apoptotic pathway induced by Alix overexpression. Ln a recent work, we gained evidence that the dosure of these Ca2+ channels, which follows the shift to K5 medium,could trigger compensatory Ca2+ mobilization from intracellular stores (Strappazzon, 2007). This prompted us to tum our attention to the putative functional relevance of Alix!Alg-2-caspase-8 interaction to ER stress-induced death. Using both dividing BHK-21 cells and post-mitotic CGN exposed to the ER stressor thapsigargin, we gathered several evidence supporting the idea that Alix, like its binding partner AIg-2, is involved in ER stress-induced death, linking specifficaly two initiator caspases: caspase-8 and -9. Overall our findings suggest that Alix, through its association with AIg-2, is a key mediator of the apoptotic Ca2+ signaling machinery. We also demonstrates the role of Pyk2 in mediating the trophic effect of membrane depolarization in CGN and its possible involvement in survival via the regulation of the binding between Alix and AIg-2 through phosphorylation of Alix

Durant el desenvolupament de les malalties neurodegeneratives les neurones moren. Una de les conseqüències més comuns del desenvolupament de malalties neurodegeneratives és l'activació en la majoria d'elles del programa de mort cel·lular, conegut com apoptosi. El coneixement exhaustiu d'aquest programa apoptòtic és clau per poder abordar estratègies terapèutiques que puguin aturar l'avanç d'aquestes malalties.
L'apoptosi és un procés fisiològic important durant el desenvolupament del SNC mantenint la homeòstasi cel·lular. El cerebel és una de les regions del cervell en la que aquest fenomen és especialment dramàtic. Durant el desenvolupament de les neurones granulars de cerebel (CGCs) pràcticament la meitat es perden durant el procés apoptòtic. Aquest fenomen pot mimetitzar-se in vitro, a partir d'un cultiu pur d'aquestes neurones. El cultiu primari de les CGCs és un model àmpliament utilitzat per a l'estudi de l'apoptosi, induint-la per deprivació de potassi. En aquest procés es pot produir un increment en les concentracions intracel·lulars de ceramida, implicada en aquest procés de mort.
La ceramida és una molècula senyalitzadora implicada en diferents processos cel·lulars com la proliferació, senescència, diferenciació i aturada del cicle cel·lular. Durant els últims anys s'ha proposat que la ceramida podria tenir un paper més important com a regulador de la mort apoptòtica. Un dels nostres objectius va ser, mitjançant la utilització d'aquest model, caracteritzar el procés de mort apoptòtica per ceramida.
Durant els últims anys s'han acumulat evidències suggerint que la exposició a estrògens disminueix el risc i retarda el principi de malalties neurodegeneratives com l'Alzheimer i el Parkinson, així com potencien la recuperació front a danys neurològics traumàtics com la isquèmia cerebral. Aquestes hormones poden realitzar aquestes funcions implicant diferents processos com la supervivència cel·lular, respostes regeneratives, creixement axonal, potenciació de la senyal sinàptica i neurogènesi.
Els resultats de les nostres investigacions indiquen que: (1) la ceramida indueix apoptosi en CGCs activant tant la caspasa-9 com la caspasa-2; dues vies a priori paral·leles i que en aquesta mort apoptòtica, (2) la inhibició d'Akt i l'activació de les MAPK estan implicades. (3) L'estradiol (E2) no protegeix front l'apoptosi en les CGCs i l'absència d'activació d'Akt pot ser clau en aquesta falta de neuroprotecció. (4) L'absència de neuroprotecció podria deure's a que el receptor d'estrògens ER-? no interacciona amb el receptor d'IGF-I. (5) ER-? està localitzat en la membrana plasmàtica de les CGCs i media l'activació de ERK1/2 per E2. L'activació de la via clàssica de les MAPKs per E2 implica un mecanisme diferent d'acció per a E2 en el model de les CGCs. (6) L'E2 exerceix un efecte neuroprotector en les CGCs degut a les seves propietats com a molècula antioxidant. (7) L'activació de la via Src/Ras/ERK/CREB estaria relacionada amb fenòmens de plasticitat sinàptica i el manteniment de connexions entre neurones de les CGCs tot i que no seria suficient per protegir les CGCs de la mort apoptòtica.
Malgrat que l'E2 no protegeix les CGCs de la mort apoptòtica, podria tenir gran rellevància el fet de conèixer com l'E2 posa en marxa mecanismes que desencadenin fenòmens de manteniment dendrític i disminució potencial de la vulnerabilitat de les neurones front a estímuls adversos, permetent poder incidir en un futur sobre models de malalties neurodegeneratives com l'Alzheimer o processos isquèmics, on el manteniment de les connexions dendrítiques existents i la generació de noves sinapsis, a més de mantenir la seva estructura, poden ser processos clau.
A lo largo del desarrollo de las enfermedades neurodegenerativas las neuronas mueren. Una de las consecuencias más comunes del desarrollo de enfermedades neurodegenerativas es la activación en la mayoría de ellas del programa de muerte celular, conocido como apoptosis. El conocimiento exhaustivo de este programa apoptótico es clave para poder abordar estrategias terapéuticas que puedan frenar el avance de estas enfermedades.
La apoptosis es un proceso fisiológico importante durante el desarrollo del SNC manteniendo la homeóstasis celular. El cerebelo es una de las regiones del cerebro en la cual este fenómeno es especialmente dramático. Durante el desarrollo de las neuronas granulares de cerebelo (CGCs) prácticamente la mitad se pierden durante el proceso apoptótico. Este fenómeno puede mimetizarse in vitro, a partir de un cultivo puro de estas neuronas. El cultivo primario de las CGCs es un modelo ampliamente utilizado para el estudio de la apoptosis, induciéndola por deprivación de potasio. En este proceso se puede producir un incremento en las concentraciones intracelulares de ceramida, implicada en este proceso de muerte.
La ceramida es una molécula señalizadora implicada en diferentes procesos celulares como la proliferación, senescencia, diferenciación y paro del ciclo celular. Durante los últimos años se ha propuesto que la ceramida podría tener un papel más importante como regulador de la muerte apoptótica. Uno de nuestros objetivos fue, mediante la utilización de este modelo, caracterizar el proceso de muerte apoptótica por ceramida.
Durante los últimos años se han acumulado evidencias sugiriendo que la exposición a estrógenos disminuye el riesgo y retrasa el principio y desarrollo de enfermedades neurodegenerativas como el Alzheimer y el Parkinson, así como potencian la recuperación frente a daños neurológicos traumáticos como la isquemia cerebral. Estas hormonas pueden desempeñar estas funciones implicando diferentes procesos como la supervivencia celular, respuestas regenerativas, crecimiento axonal, potenciación de la señal sináptica y neurogénesis.
Los resultados de nuestras investigaciones indican que: (1) la ceramida induce apoptosis en CGCs activando tanto la caspasa-9 como la caspasa-2; dos vías de muerte a priori paralelas y que en esta muerte apotótica, (2) la inhibición de Akt y la activación de las MAPKs están implicadas. (3) El estradiol (E2) no protege frente a la apoptosis en las CGCs y la ausencia de activación de Akt puede ser clave en esta falta de neuroprotección. (4) La ausencia de neuroprotección podría deberse a que el receptor de estrógenos ER-? no interacciona con el receptor de IGF-I. (5) ER-? está localizado en la membrana plasmática de las CGCs y media la activación de ERK1/2 por E2. La activación de la vía clásica de las MAPKs por E2 implica un mecanismo diferente de acción para E2 en el modelo de las CGCs. (6) El E2 ejerce un efecto neuroprotector en las CGCs debido a sus propiedades como molécula antioxidante. (7) La activación de la vía Src/Ras/ERK/CREB estaría relacionada con fenómenos de plasticidad sináptica y el matenimiento de conexiones entre neuronas de las CGCs aunque no sería suficiente para proteger las CGCs de la muerte apoptótica.
A pesar de que el E2 no protege a las CGCs de la muerte apoptótica, podría tener gran relevancia el hecho de conocer cómo el E2 pone en marcha mecanismos que desencadenan fenómenos de mantenimiento dendrítico y disminución potencial de la vulnerabilidad de las neuronas frente a estímulos adversos, permitiendo poder incidir en un futuro sobre modelos de enfermedades neurodegenerativas como el Alzheimer o procesos isquémicos, donde el mantenimiento de las conexiones dendríticas existentes y la generación de nuevas sinapsis, además de mantener su estructura, pueden ser procesos clave.
Along neurodegenerative disease development, neurons die. One of the most common consequences of the development of neurodegenerative diseases is the activation, in the majority of them, of the cellular death program, known as apoptosis. The exhaustive knowledge of apoptotic programme is a key to approach new therapeutical strategies to slow down the advance of these diseases.
Apoptosis is an important physiological process during development of CNS maintaining cellular homeostasis. Cerebellum is one of the cerebral regions in which this phenomenon is especially dramatic. During development of cerebellar granule neurons (CGNs) practically a half are removed during apoptotic process. This phenomenon is able to mimic in vitro from pure culture of these neurons. Primary cultures of CGNs are an extensively used model to study apoptosis, inducing it by potassium deprivation. In this process is able to produce an increase of intracellular concentrations of ceramide, implied in the process of cell death.
Ceramide is a signalling molecule implied in different cellular processes like proliferation, senescence, differentiation and control of cellular cycle. During the last years authors suggest ceramide with an important role like a regulator of apoptotic death. One of our objectives was, by means of using this model; characterize apoptotic death process by ceramide.
During the last years diverse accumulating evidences have suggested that estrogens exposition reduce risk and delay the onset and development of neurodegenerative diseases like Alzheimer and Parkinson, the same way as promote recovery from neurological shocks like cerebral ischemia. These hormones are able to carry out these functions implying different processes as cellular survival, regenerative responses, axonal growth, synaptic signal potentiation and neurogenesis.
Results of ours investigation shows that: (1) ceramide induce apoptosis in CGNs activating as caspase-9 as caspase-2; two death pathways beforehand parallels and that in this apoptotic death, (2) inhibition of Akt and activation of MAPKs are implicated. (3) Estradiol (E2) does not protect from apoptosis in CGNs and the absence of Akt activation can be key in this absence of neuroprotection. (4) The absence of neuroprotection could be due to estrogen receptor ER-? does not interact with IGF-IR. (5) ER-? is located in plasmatic membrane of the CGNs and mediates the ERK1/2 activation by E2. Activation of classic pathway MAPKs by E2 implies a different action mechanism to E2 in CGNs model. (6) E2 exerts a neuroprotective effect in CGNs due to proprieties as an antioxidant molecule. (7) Activation of Src/Ras/ERK/CREB pathway would be related with phenomena of synaptic plasticity and the maintenance of connexions between neurons of CGNs although it would not be enough to protect CGNs of apoptotic death.
In spite of E2 does not protect CGNs from apoptotic death, it could have great relevance the fact of known how E2 switch on mechanisms that triggers phenomena of dendrite maintenance and potential decrease of vulnerability of neurons in front of adverse stimuli, making possible to influence in the future on neurodegenerative disease models as Alzheimer or ischemic processes, where the maintenance of dendrite connexions existing and generating news, moreover of maintenance of structure can be key processes.

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O c?rtex cerebral de mam?feros ? histologicamente organizado em diferentes camadas de neur?nios excitat?rios que possuem diversos padr?es de conex?o com alvos corticais e subcorticais. Durante o desenvolvimento, essas camadas corticais se estabelecem sequencialmente atrav?s de uma intrincada combina??o de especifica??o neuronal e migra??o em um padr?o radial conhecida como ?de dentro para fora?: neur?nios infragranulares s?o gerados primeiro do que os neur?nios granulares e supragranulares. Nas ?ltimas d?cadas, diversos genes codificando fatores de transcri??o envolvidos na especifica??o de neur?nios destinados a diferentes camadas corticais foram identificados. Todavia, a influ?ncia dos neur?nios infragranulares sobre a especifica??o das coortes neuronais subsequentes permanece pouco entendida. Para investigar os poss?veis efeitos da abla??o de neur?nios infragranulares sobre a especifica??o de neur?nios supragranulares, n?s induzimos a morte seletiva de neur?nios corticais das camadas V e VI antes da gera??o dos neur?nios destinados ?s camadas II-IV. Nossos dados revelam que um dia ap?s a abla??o, progenitores continuaram a gerar neur?nios destinados a camada VI que expressam o fator de transcri??o TBR1, enquanto praticamente nenhum neur?nio expressando TBR1 foi gerado na mesma etapa do desenvolvimento em controles com a mesma idade. Curiosamente, alguns neur?nios TBR1-positivos gerados ap?s a abla??o de neur?nios infragranulares se estabeleceram em camadas corticais superficiais, como esperado para neur?nios supragranulares gerados neste est?gio, sugerindo que a migra??o de neur?nios corticais pode ser controlada independentemente da sua especifica??o molecular. Al?m disso, n?s observamos um aumento em neur?nios de camada V que expressam CTIP2 e neur?nios calosos que expressam SATB2 ? custa da diminui??o neur?nios de camada IV em animais P0. Quando estes animais se tornam adultos jovens (P30) o aumento de neur?nios SATB2 e CTIP2 n?o existe mais, todavia encontramos esses neur?nios distribu?dos de forma diferente na ?rea somatossensorial dos animais que sofreram abla??o. Experimentos in vitro revelaram que a organiza??o citoarquitet?nica laminar do c?rtex ? necess?ria para gerar novamente os neur?nios TBR1+ que foram eliminados anteriormente. Al?m disso, experimentos in vitro indicam que em condi??o de baixa densidade celular os neur?nios tem seu fen?tipo alterado, expressando v?rios fatores de transcri??o ao mesmo tempo. Em conjunto, nossos dados indicam a exist?ncia de um mecanismo regulat?rio entre neur?nios infragranulares e progenitores envolvidos na gera??o de neur?nios supragranulares e/ou entre neur?nios infragranulares e neur?nios p?s-mit?ticos gerados em seguida. Este mecanismo poderia ajudar a controlar o n?mero de neur?nios em diferentes camadas e contribuir para o estabelecimento de diferentes ?reas corticais.
The cerebral cortex of mammals is histologically organized into in different layers of excitatory neurons that have distinct patterns of connections with cortical or subcortical targets. During development, these cortical layers are sequentially established through an intricate combination of neuronal specification and migration in a radial pattern known as "inside-out": deep-layer neurons are generated prior to upper-layer neurons. In the last few decades, several genes encoding transcription factors involved in the specification of neurons destined to different cortical layers have been identified. However, the influence of early-generated neurons in to the specification of subsequent neuronal cohorts remains unclear. To investigate the possible effects early born neurons ablation on the specification of late born neurons, we induced the selective death of cortical neurons from layers V and VI neurons before the generation of neurons destined to layers II, III and IV. Our data shows that oneday after ablation, progenitors resumed generation of layer VI neurons expressing the transcription factor TBR1, whereas virtually no TBR1-expressing neuron was generated at the same developmental stage in age-matched controls. Interestingly, many TBR1-positive neurons generated after deep-layer ablation settled within superficial cortical layers, as expected for upper-layer neurons generated at that stage, suggesting that migration post-mitotic neurons is independent of fate-specification. Furthermore, we observed an increase in layer V neurons expressing CTIP2 and cortico-cortical neurons expressing SATB2 at the expense of layer IV neurons in P0 animals. When these animals became young adults (P30) the increase os SATB2 and CTIP2 neurons is no longer observed, however these neurons are distributed in a different way in somatosensory areas from ablated animals. In vitro experiments show that the laminar cytoarchitectural organization of the cortex is necessary to regenerate the previously deleted TBR1 + neurons. In addition, in vitro experiments indicate that in a condition of low cell density the neurons phnotype is altered, they express several transcription factors at the same time. Together, our data indicate the existence of feedback mechanism either from early-generated neurons to progenitors involved in the generation of upper-layer neurons or from deep-layer neurons to postmitotic neurons generated subsequently. This mechanism could help to control the number of neurons in different layers and contribute to the establishment of different cortical areas.

Abstract Understanding the structural growth of paediatric brains is a key step in the identification of various neuro-developmental disorders. However, our knowledge is limited by many factors, including the lack of automated image analysis tools, especially in Low and Middle Income Countries from the lack of high field MR images available. Low-field systems are being increasingly explored in these countries, and, therefore, there is a need to develop automated image analysis tools for these images. In this work, as a preliminary step, we consider two tasks: 1) automated quality assurance and 2) hippocampal segmentation, where we compare multiple approaches. For the automated quality assurance task a DenseNet combined with appearance-based transformations for synthesising artefacts produced the best performance, with a weighted accuracy of 82.3%, thus ranking in the 1st place in the LISA2024 Challenge. For the segmentation task, registration of an average atlas performed the best, with a final Dice score of 0.61. Our results show that although the images can provide understanding of large scale pathologies and gross scale anatomical development, there still remain barriers for their use for more granular analyses.

This chapter provides a comprehensive exploration of the role of thyroid hormones in the development of key brain structures: the cerebral cortex, hippocampus, striatum, and cerebellum, as well as the sense organs retina and cochlea. Hypothyroidism is generally associated with impairments in axodendritic development, synaptogenesis, neuron migration and differentiation, and myelination. In the developing cerebral cortex, hypothyroidism delays the appearance of Cajal-Retzius cells, critical for the proper migration of neurons, causing migration defects. The maturation of the transient subplate layer, crucial for establishing thalamocortical connections, is also delayed. The hippocampal formation experiences a reduction in the number of granular cells and mossy fibers. In the cerebellum, hypothyroidism arrests the maturation of the Purkinje cells and delays the migration of the granular cells to the internal granular layer. In the striatum, hypothyroidism delays the accumulation of the medium-spiny GABAergic neurons, the principal cells of the striatum. Parvalbumin interneurons in the cerebral and cerebellar cortices are also affected. Thyroid hormone induces extensive remodeling during cochlear and retinal maturation. Contrary to expectations, receptor-deficient mice often do not exhibit these alterations, while the expression of mutant receptors with impaired T3 binding results in hypothyroid features. In rodents, the effects of thyroid hormones are most prominent during the postnatal period. Conversely, in humans, the second trimester of pregnancy is a crucial period for neural development. The coordinated development of the thyroid hormone signaling system, encompassing brain T3 and the ontogenesis of receptors, deiodinases, and regulated genes, closely aligns with late maturational processes. This intricate interplay underscores the significance of thyroid hormones in shaping the structural and functional aspects of the developing brain.

In adult mammals, neurogenesis persists throughout life in two active sites: the ventricular-subventricular zone along the lateral ventricles and the subgranular zone of the hippocampus. In rodents, postnatal neural stem cells with astrocytic properties, originating from embryonic ventricular radial glia, generate a continuous, lifelong supply of neurons for the olfactory bulb and glia for the corpus callosum. Thyroid hormones play a regulatory role in this process. In humans, ventricular neurogenesis is minimal, but hippocampal neurogenesis extensively remodels the dentate gyrus, influencing memory and mood. Hippocampal neurogenesis begins with stem cells in the dentate gyrus subgranular layer, generating a sequential lineage of intermediate precursors and neuroblasts. These neuroblasts migrate to the granular layer, differentiate into granular cells, and integrate into the existing dentate gyrus neuronal pool. Thyroid hormone specifically regulates the late stages of this process, promoting the terminal differentiation of neuroblasts and facilitating their functional integration. Hypothyroidism disrupts hippocampal neurogenesis, impacting learning, memory, and mood. The intricate regulation of adult neurogenesis by thyroid hormone highlights their crucial role in maintaining cognitive and emotional functions.

Distúrbios de qualidade de energia elétrica ocorrem em várias partes de um sistema de potência e podem causar prejuízos financeiros a todos que estão a ele conectado. Portanto, é de fundamental importância a classificação automática destes distúrbios, com alto nível de acurácia e baixo custo computacional. São consideradas as redes neuro-fuzzy granulares evolutivas as quais são capazes de adaptar continuamente sua estrutura e atualizar seus parâmetros de acordo com um fluxo de dados. Devido ao seu processo de aprendizagem recursivo, as redes neuro-fuzzy evolutivas podem adaptar-se às não-estacionariedades que ocorrem em um sistema, evoluindo continuamente ao longo da vida. A rede neuro-fuzzy proposta é a eGNN (evolving Granular Neural Network). Na etapa de pré-processamento dos dados para extração de atributos é considerado o valor eficaz das tensões de fase e o filtro de Hodrick-Prescott. Este separa o sinal de entrada em componente de tendência e componente cíclica –suprimindo o ruído presente no sinal de tendência. A classificação de quatro distúrbios e da operação normal do sistema (problema de cinco classes) foi alcançada com acurácia média de 98%.

Climate change caused by anthropogenic environmental pollution has become one of the most pressing issues of our modern world. For instance, heat waves have been shown to seriously impair students’ health and productivity (Lala & Hagishima, 2023). The general problem of climate change has influenced recent research to focus on redesigning and restructuring the living environment to improve human health and productivity. Yet, according to Palme and Salvati (2021), there have been relatively few studies on the relationships between microclimates and human health and emotions. This is particularly detrimental as the in-depth knowledge obtained can be used to enhance human health and productivity, as well as influence their attitude towards the environment (Doell et al., 2023). This paper reports a study conducted by students as an independent research project under the mentorship of a senior research scientist at the National Institute of Education, Singapore. It represents a multidisciplinary, citizen science and neuroergonomic approach to investigate the relationships between human neuro-physiological health and mental well-being. To investigate both physical health as well as stress, low-cost, bespoken wearables were built, such as a mini weather station and physiological wristband. Electrodermal activity (EDA) was also introduced as a non-invasive method to detect stress and emotional arousal (Rahma et al., 2022) and as a marker of sympathetic network activity (Zangróniz et al., 2017). EDA features such as mean of tonic component and TVSymp (spectral powers in specific frequency bands according to Posada-Quintero et al. (2016a; 2016b) and their normalised versions were focused on as they were found to be highly sensitive to orthostatic, cognitive, and physical stress (Posada-Quintero et al., 2020). PPG was also introduced as a second source of data for analysis of stress and emotions, since it is influenced by the cardiac, vascular and autonomic nervous systems, which are all affected by stress. Machine learning models were trained to investigate relationships between emotional arousal, stress and the surrounding environment. To elaborate, climate change might precipitate changes to microclimates to the extent that for those inhabiting these biomes the changes might be detrimental to physical and mental well-being. Therefore, investigating EDA data may unveil hidden relationships as to how microclimate is related to our perception of well-being at a granular level. In this way, the present study builds on prior work (eg, Lim et al., 2022) that documented changes in microclimate on affective states. It is hoped that analyses of EDA and PPG data will further strengthen the emerging model describing the intersections between local microclimate, physiological stress and emotion. In the present study, we apply this paradigm to the use of EDA in the context of students’ scholastic activity. We seek to understand factors influencing the affective states of learners. Our preliminary findings suggest implications for the design of living and studying conditions with respect to the interaction of microclimate and human health and comfort.