There is a basic rule to mammalian neocortical expansion: as it expands, so does it fold. The degree to which it folds, however, cannot strictly be attributed to its expansion. Across species, cortical volume does not keep pace with cortical surface area, but rather folds appear more rapidly than expected. As a result, larger brains quickly become disproportionately more convoluted than smaller brains. Both the absence (lissencephaly) and presence (gyrencephaly) of cortical folds is observed in all mammalian orders and, while there is likely some phylogenetic signature to the evolutionary appearance of gyri and sulci, there are undoubtedly universal trends to the acquisition of folds in an expanding neocortex. Whether these trends are governed by conical expansion of neocortical germinal zones, the distribution of cortical connectivity, or a combination of growth- and connectivity-driven forces remains an open question. But the importance of cortical folding for evolution of the uniquely mammalian neocortex, as well as for the incidence of neuropathologies in humans, is undisputed. In this hypothesis and theory article, we will summarize the development of cortical folds in the neocortex, consider the relative influence of growth- vs. connectivity-driven forces for the acquisition of cortical folds between and within species, assess the genetic, cell-biological, and mechanistic implications for neocortical expansion, and discuss the significance of these implications for human evolution, development, and disease. We will argue that evolutionary increases in the density of neuron production, achieved via maintenance of a basal proliferative niche in the neocortical germinal zones, drive the conical migration of neurons toward the cortical surface and ultimately lead to the establishment of cortical folds in large-brained mammal species.

Cognitive processes in the human brain are mediated by complex interactions among distributed brain regions. The interaction between the hippocampus and neocortical regions is crucial for physiologic and pathologic long-term episodic memory processing in the brain. However, the network mechanisms of this hippocampal-cortical communication remain unclear. To address this issue, we first designed organic materials and conformable electronics to create integrated neural interface devices that increase the spatiotemporal resolution of electrophysiologic monitoring. These devices enabled acquisition of local field potentials and action potentials of individual cortical neurons from the surface of the human brain, enhancing the ability to investigate neural network mechanisms without breaching the tissue interface. Next, we employed these devices in tandem with hippocampal probes to analyze hippocampal-cortical interactions in the context of memory tasks in freely moving rodents. We determined that in the physiologic state, the spatial properties of cortical spindle oscillations predict the likelihood of coupling with hippocampal ripples and are modulated by memory demand. In the pathologic state, we showed that interictal epileptiform discharges (IEDs), ubiquitous markers of epileptic networks, disrupt hippocampal-cortical coupling required for memory consolidation. These IEDs induce spindle oscillations in the synaptically connected cortex, producing prolonged, hypersynchronous neuronal spiking and expanding the brain territory capable of generating IEDs. Spatiotemporally targeted closed-loop electrical stimulation triggered on hippocampal IED occurrence eliminated the abnormal cortical activity patterns, preventing spread of the epileptic network and ameliorating long-term spatial memory deficits in rodents. Our findings provide new insights into mechanisms of physiologic and pathologic memory processing and offer novel approaches to therapies aimed at addressing distributed network dysfunction in neuropsychiatric disorders.

In lokalen neokortikalen Netzwerken stellen GABAerge Interneurone die Quelle der Inhibition dar, wobei sie inhibitorische Verbindungen mit benachbarten exzitatorischen und anderen inhibitorischen Neuronen bilden. Man geht davon aus, dass synaptische Transmission in vivo als Folge spontaner Aktionspotentiale während aktiven depolarisierten Erregungszuständen des Netzwerks auftritt. Ziel dieser Studie war es monosynaptische inhibitorische Verbindungen in vivo zu detektieren um den Zusammenhang zwischen der Konnektivität kortikaler Interneurone und deren Spontanaktivität untersuchen zu können. Dafür wurden von zwei bis drei benachbarten GABAergen Interneuronen gleichzeitig gezielte elektrophysiologische Ganz-Zell-Ableitungen unter visueller Kontrolle des Zwei-Photonen-Mikroskops gemacht. Die Ableitungen wurden an Zellen in Schicht 2/3 des primären somatosensorischen Kortex der Vorderpfote von Mäusen durchgeführt, welche mit Urethan narkotisiert waren. Hierbei wurden zwei Mauslinien eingesetzt, um elektrophysiologische Ableitungen von genetisch identifizierten Interneuronen zu erhalten. GAD67-GFP Mäuse wurden genutzt, um Interneurone allgemein und unabhängig von ihrem Subtyp untersuchen zu können. Die Züchtung der dreifach transgenen Linie GIN-VIPcre-Ai9 erlaubte gezielte Ableitungen von SST und VIP Zellen. In beiden Linien konnten monosynaptische inhibitorische Verbindungen zwischen Interneuronen detektiert werden, wobei die Konnektivitätsrate zwischen ''nicht-schnell'' feuernden Interneuronen in GAD67-GFP Mäusen höher war als für SST und VIP Zellen. Die inhibitorische synaptische Transmission wurde jeweils stark vom aktuellen Erregungszustand des Kortex moduliert wobei ein Anstieg der IPSP-Amplitude während depolarisierter Zustände des Netzwerks festgestellt wurde. Es konnten subtyp-spezifische Korrelationen in der Aktivität neokortikaler Interneurone beobachtet werden, welche sich im unterschwelligen Membranpotential und auch der spontanen Feuerrate der Zellen zeigte. / GABAergic interneurons provide the source of inhibition in local neocortical networks, where they form inhibitory connections with nearby excitatory and other inhibitory neurons. In cortical circuits in vivo synaptic transmission is thought to emerge during depolarized active network states, when spontaneous spiking can occur. The aim of this study was to identify monosynaptic inhibitory connections in vivo in order to relate interneuron connectivity to their spontaneous activity. Therefore simultaneous two-photon targeted whole-cell recordings were made from two to three neighboring layer 2/3 GABAergic interneurons in the forepaw primary somatosensory cortex of urethane anesthetized mice. Two different mouse strains were used to record from genetically identified interneurons: in GAD67-GFP animals interneurons could be examined regardless to their subtype. Breeding of the triple transgenic mouse line GIN-VIPcre-Ai9 allowed to specifically target SST and VIP cells. Monosynaptic inhibitory connections could be identified in both mouse lines, with higher connectivity rates of non-fast spiking interneurons recorded in GAD67-GFP animals than for SST and VIP cells. Overall, the ongoing state of the cortex powerfully modulated inhibitory synaptic transmission, with IPSPs increasing in amplitude in depolarized network states. Subtype-specific correlations in the activity of neocortical interneurons could be observed and were reflected in the subthreshold and also spontaneous firing activity of cells.

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Le cortex cérébral constitue l’une des structures les plus évoluées et complexes de notre cerveau. Sa surface est divisée en de nombreuses aires fonctionnelles. La mise en place des aires corticales dépend à la fois de facteurs intrinsèques comme la sécrétion de morphogènes ou l’expression en gradient de différents facteurs de transcription, mais elle dépend aussi de facteurs extrinsèques au cortex, en particulier l'innervation par le thalamus. <p>Les ephrines et leurs récepteurs Eph constituent une famille multigénique de facteurs de signalisation impliqués dans divers événements clé du développement cortical où ils sont exprimés selon des profils spatio-temporels complexes. Aux stades tardifs du développement, EphA7 et l’ephrine-A5 sont exprimés en gradients complémentaires au sein de chaque territoire des aires présomptives, constituant ainsi les marqueurs les plus précoces de ces aires corticales. <p>Par la combinaison d’approches in-vitro utilisant la technique d’électroporation focale de tranches corticales embryonnaires, puis in-vivo en utilisant la technique de transgénèse d’addition, nous avons identifié une séquence régulatrice de EphA7 appelée pA7, capable de mimer l’expression endogène de EphA7 au sein du télencéphale dorsal en développement. La lignée de souris pA7-GFP ainsi générée exprime la GFP spécifiquement au sein du télencéphale dorsal durant les stades précoces. Aux stades périnataux cette expression se régionalise au sein de la plaque corticale de chacune des aires présomptives selon des gradients récapitulant ceux observés pour EphA7. Nous avons ensuite purifié des neurones exprimant différents niveaux d’EphA7 par la technique de FACS «Fluorescence-Activated Cell Sorting » et l’analyse de leur transcriptome nous a permis de trouver un grand nombre de gènes différentiellement exprimés. Tous ceux testés par la technique d’hybridation in situ sont exprimés selon un gradient latéral fort et médial faible dans le cortex pariétal, similaire à celui d’EphA7. L’examination de leur profil au sein de cortex de souris dépourvus d’afférences thalamiques, nous a permis de conclure que l’expression de ces gènes incluant EphA7 s’établit indépendamment de celles-ci. Ainsi, notre étude a permis d'identifier un répertoire de gènes neuronaux, pouvant agir en amont ou en combinaison avec EphA7 pour contrôler les facteurs intrinsèques essentiels à l’établissement des aires corticales./<p>The cerebral cortex is subdivided into distinct cortical areas characterized by specific patterns of gene expression and neuronal connectivity. The patterning of cortical areas is thought to be controlled by a combination of intrinsic factors that are expressed in the cortex, and external signals such as inputs from the thalamus. EphA7 is a member of the ephrin/Eph family of guidance factors that is involved in key aspects of the development of the cortex, and is expressed in several gradients within developing cortical areas. <p>By combining in vitro transcriptional assays and mouse transgenics, we identified a regulatory element of the EphA7 promoter, named pA7, that can recapitulate salient features of the pattern of expression of EphA7 in the developing forebrain, including gradients in the cortex. Using a mouse reporter line where GFP expression recapitulates EphA7 expression, we developed a GFP-based cell sorting procedure to isolate cortical neuron populations displaying different levels of EphA7 expression. Transcriptome analysis of these populations enabled to identify a specific array of differentially expressed genes. All genes validated further in vivo were confirmed to be expressed along distinct gradients in the developing cortical plate, similarly to EphA7. The expression of these genes was unchanged in mutant mice defective for thalamocortical projections, indicating that their graded pattern is largely intrinsic to the cortex. Our study identifies a novel repertoire of cortical neuron genes that may act upstream of, or together with EphA7, to control the intrinsic patterning of cortical areas. <p> <p> / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

The neocortex is considered the seat of higher cognitive function in humans. It develops from a sheet of neural progenitor cells, most of which eventually give rise to neurons. This process of cell fate determination is controlled by precise temporal and spatial gene expression patterns that in turn are affected by epigenetic mechanisms including Polycomb group (PcG) regulation. PcG proteins assemble in multiprotein complexes and catalyze repressive posttranslational histone modifications. Their association with neurodevelopmental disease and various types of cancer of the central nervous system, as well as observations in mouse models, has implicated these epigenetic modifiers in controlling various stages of cortex development. The precise mechanisms conveying PcG-associated transcriptional repression remain incompletely understood and are an active field of research. PcG activity appears to be highly context-specific, raising the question of species-specific differences in the regulation of neural stem and progenitor regulation. In this review, we will discuss our growing understanding of how PcG regulation affects human cortex development, based on studies in murine model systems, but focusing mostly on findings obtained from examining impaired PcG activity in the context of human neurodevelopmental disorders and cancer. Furthermore, we will highlight relevant experimental approaches for functional investigations of PcG regulation in human cortex development.

Проблематику алгоритмизации мышления и исследования в области создания систем искусственного интеллекта объединяет вопрос «Может ли машина мыслить?» Несмотря на то, что две данные области по-разному отвечают на вопрос о возможности мышления машины, результаты достигнутые в одной области могут повлиять на другую. Объектом исследования являются проблематика алгоритмизации мышления и интеллект в концепции Дж. Хокинса. Предметом исследования являются ограничения на алгоритмизацию в связи с моделью «память-предсказание». Цель исследования - рассмотреть проблематику алгоритмизации мышления в связи с концепцией Дж. Хокинса. Методы, применяемые в исследовании: концептуальный и логический анализ. Новизна данной диссертационной работы заключается в сопоставлении проблематики алгоритмизации мышления с современным исследование в области создания ИИ, концепцией Дж. Хокинса. В результате исследования установлено, что в основе интеллекта лежит модель «память-предсказание». Используя данную модель, становится возможным решить практически все проблемы, связанные с ограничениями на алгоритмизацию мышления. Выяснено, что концепт обозримости доказательства можно применить для оптимизации работы интеллектуальных систем. / The problem of algorithmizing thinking and research in the field of creating artificial intelligence systems unites the question "Can the machine think?" Although these two areas of knowledge respond differently to the question of the machine's thinking capabilities, the results achieved in one area can affect the other. The object of research work are problems of algorithmization of thinking and intellect in the theory of J. Hawkins. The subject of the research work are constraints on algorithmization in connection with the memory-prediction model. The purpose of the research work is to consider the problems of algorithmizing thinking in connection with the theory of J. Hawkins. Methods used in the research work: conceptual and logical analysis. The novelty of this research work is to compare the problems of algorithmizing thinking with modern research in the field of creating AI, the concept of J. Hawkins. As a result of the research it was established that the intellect is based on the memory-prediction model. Using this model, it becomes possible to solve almost all the problems associated with limitations on the algorithmization of thinking. It is clarified that the concept of surveyability of proof can be applied to optimize the operation of intelligent systems.

La période postnatale et l’expérience sensorielle sont critiques pour le développement du système visuel. Les interneurones inhibiteurs exprimant l’acide γ-aminobutyrique (GABA) jouent un rôle important dans le contrôle de l’activité neuronale, le raffinement et le traitement de l’information sensorielle qui parvient au cortex cérébral. Durant le développement, lorsque le cortex cérébral est très susceptible aux influences extrinsèques, le GABA agit dans la formation des périodes critiques de sensibilité ainsi que dans la plasticité dépendante de l’expérience. Ainsi, ce système inhibiteur servirait à ajuster le fonctionnement des aires sensorielles primaires selon les conditions spécifiques d’activité en provenance du milieu, des afférences corticales (thalamiques et autres) et de l’expérience sensorielle. Certaines études montrent que des différences dans la densité et la distribution de ces neurones inhibiteurs corticaux reflètent les caractéristiques fonctionnelles distinctes entre les différentes aires corticales. La Parvalbumine (PV), la Calretinine (CR) et la Calbindine (CB) sont des protéines chélatrices du calcium (calcium binding proteins ou CaBPs) localisées dans différentes sous-populations d’interneurones GABAergiques corticaux. Ces protéines tamponnent le calcium intracellulaire de sorte qu’elles peuvent moduler différemment plusieurs fonctions neuronales, notamment l’aspect temporel des potentiels d’action, la transmission synaptique et la potentialisation à long terme. Plusieurs études récentes montrent que les interneurones immunoréactifs (ir) aux CaBPs sont également très sensibles à l’expérience et à l’activité sensorielle durant le développement et chez l’adulte. Ainsi, ces neurones pourraient avoir un rôle crucial à jouer dans le phénomène de compensation ou de plasticité intermodale entre les cortex sensoriels primaires. Chez le hamster (Mesocricetus auratus), l’énucléation à la naissance fait en sorte que le cortex visuel primaire peut être recruté par les autres modalités sensorielles, telles que le toucher et l’audition. Suite à cette privation oculaire, il y a établissement de projections ectopiques permanentes entre les collicules inférieurs (CI) et le corps genouillé latéral (CGL). Ceci a pour effet d’acheminer l’information auditive vers le cortex visuel primaire (V1) durant le développement postnatal. À l’aide de ce modèle, l’objectif général de ce projet de thèse est d’étudier l’influence et le rôle de l’activité sensorielle sur la distribution et l’organisation des interneurones corticaux immunoréactifs aux CaBPs dans les aires sensorielles visuelle et auditive primaires du hamster adulte. Les changements dans l’expression des CaBPs ont été déterminés d’une manière quantitative en évaluant les profils de distribution laminaire de ces neurones révélés par immunohistochimie. Dans une première expérience, nous avons étudié la distribution laminaire des CaBPs dans les aires visuelle (V1) et auditive (A1) primaires chez le hamster normal adulte. Les neurones immunoréactifs à la PV et la CB, mais non à la CR, sont distribués différemment dans ces deux cortex primaires dédiés à une modalité sensorielle différente. Dans une deuxième étude, une comparaison a été effectuée entre des animaux contrôles et des hamsters énucléés à la naissance. Cette étude montre que le cortex visuel primaire de ces animaux adopte une chimioarchitecture en PV similaire à celle du cortex auditif. Nos recherches montrent donc qu’une suppression de l’activité visuelle à la naissance peut influencer l’expression des CaBPs dans l’aire V1 du hamster adulte. Ceci suggère également que le type d’activité des afférences en provenance d’autres modalités sensorielles peut moduler, en partie, une circuiterie corticale en CaBPs qui lui est propre dans le cortex hôte ou recruté. Ainsi, nos travaux appuient l’hypothèse selon laquelle il serait possible que certaines de ces sous-populations d’interneurones GABAergiques jouent un rôle crucial dans le phénomène de la plasticité intermodale. / The postnatal period and sensory experience are critical for the development of the visual system. The inhibitory interneurons expressing the γ-aminobutyric acid (GABA) play an important role in the control of neural activity, refinement and treatment of sensory information which reaches the cerebral cortex. During development, when the cerebral cortex is very likely to be influenced by extrinsic factors, GABA acts in the formation of critical period of receptivity as well as in experience dependent plasticity. Thus, this inhibitory system adjusts the functioning of the primary sensory areas according to the specific conditions of activity from the environment, cortical afferents (e.g. of thalamic origin), and sensory experience. Several studies show that differences in the distribution and density of these inhibitory interneurons tend to reflect functional discrepancies between the different neocortical areas. Parvalbumin (PV), Calretinin (CR) and Calbindin (CB) are calcium-binding proteins (CaBPs) found in different sub-populations of GABAergic cortical interneurons. These proteins buffer intracellular calcium levels, which can in turn modulate several neural functions, notably the temporal aspect of action potentials, synaptic transmission and long-term potentiation. Several recent studies are showing that CaBPs immunoreactive (ir) interneurons are also very sensitive to experience and sensory activity during development and adulthood. Therefore, these neurons may have a critical role in intermodal plasticity or compensatory processes between primary sensory cortices. In the hamster (Mesocricetus auratus), after enucleation at birth, the primary visual cortex can be recruited by other sensory modalities such as touch and audition. After this type of visual deprivation, there is establishment of permanent ectopic projections between the inferior colliculus (IC) and the lateral geniculate nucleus (LGN). This phenomenon leads to the rerouting of auditory information to the primary visual cortex (V1) during postnatal development. By using this animal model, the general objective of this thesis is to study the influence and the role of sensory activity on the distribution and organization of cortical interneurons that display immunoreactivity for CaBPs in the primary visual and auditory sensory areas in adult hamsters. Changes in the expression of CaBPs were quantitatively determined by assessing the laminar distribution profiles of cell bodies revealed by immunohistochemistry. In the first experiment, we studied laminar distribution of CaBPs in the primary visual (V1) and auditory (A1) cortices of normal hamsters. PVir and CBir, but not CRir neurons, are distributed in a dissimilar fashion between the two primary cortices devoted to each sensory modality. In the second study, a comparison was performed between control animals and hamsters which were enucleated at birth. The results of this study show that the primary visual cortex of these animals adopts a PVir chemoarchitecture similar to that of the auditory cortex. Our research shows that the abolition of visual activity at birth can influence the expression of CaBPs in V1 of the adult hamster. The present results also suggest that the type of activity in afferents from other sensory modalities can at least in part modulate the cortical circuitry of CaBPs in the host or recruited cortex. Thus, our work supports the hypothesis that sub-populations of GABAergic interneurons may play a critical role in the intermodal cortical plasticity.

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