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[Structural basis of the intracortical synchronization of epileptic potentials in the sensomotor region of the rat neocortex].

In control rats, penicillin-induced epileptiform discharges were completely synchronous in the neocortex sites at a distance of up to 4 mm from each other. Number of the cells decreased by 45.5% during 90 days in isolated cortical slabs and the synchronisation disappeared. The data obtained show that the loss of large pyramidal neurones of the layer V entailed a loss of the spatial synchronisation. The main axonal collaterals of large pyramidal neurones of the layer V could be followed horizontally for a distance of up to 2 mm in the somatosensory cortex. The neuronal network formed by the large pyramidal neurones of the layer V seems to provide a spatial synchronisation in the neocortex.

Animals↗

Increased neuronal and glial expression of protein kinase C isoforms in neocortex of transgenic Tg2576 mice with amyloid pathology.

We investigated the influence of five- to sevenfold neuronal overexpression of the Swedish mutation of human APP695 (APPsw) in the transgenic mouse strain Tg2576 on neocortical protein kinase C (PKC) expression and subcellular distribution. Using specific antibodies to PKC alpha, PKC beta, PKC gamma, PKC epsilon and PKC zeta isoforms for Western blot analysis, we observed increased immunoreactivity for PKC alpha and PKC gamma isoforms in crude tissue homogenates from the neocortex of 16-month-old APPsw mice as compared with nontransgenic littermates, which was not present in 6 month-old Tg2576 mice. We also observed elevated levels of PKC alpha, PKC beta, PKC gamma and PKC zeta in membrane fractions and reduced concentrations of PKC alpha and PKC gamma in cytosolic fractions of aged Tg2576 mice, indicating that these PKC isoforms are in their activated state. In young, 6-month-old Tg2576 mice, however, the increase in membrane-bound PKC isoforms and concomitant decrease in cytosolic PKC isoforms was much less pronounced, demonstrating the age-dependent nature of alterations in PKC isoforms. Immunocytochemistry of brain sections supported these findings and revealed increased neuronal labelling for PKC alpha, PKC gamma and PKC lambda isoforms in neocortex of 16-month-old APPsw mice compared with nontransgenic littermates, with the increase being strongest for PKC gamma and PKC lambda isoforms. Additionally, PKC gamma and to a lesser extent PKC lambda isoforms were induced in reactive astrocytes in proximity to amyloid plaques. Our data indicate that neuronal overexpression of APPsw causes a dynamic change in neuronal expression and activation of multiple PKC isoforms known to be regulators of proteolytic amyloid precursor protein (APP) processing (PKC alpha) and of neuronal survival (PKC lambda and PKC zeta). The induction of the PKC gamma and PKC lambda isoforms in reactive astrocytes surrounding amyloid plaques might be required for astrocyte activation and astrocytic cytokine expression in response to amyloid plaque formation.

Alzheimer Disease↗

[Reactive invagination of the neuroepithelium in anlages of the human neocortex, tectum of the midbrain, and the retina at various stages of development].

Intensity of invagination of neuroepithelium of neocortex of human embryonal anlages of neocortex, tectum of the midbrain and retina was studied as a response to mechanic damage of ventricular zone induced in the course of preparation of the anlages to explanation. It was shown that no invagination formed in 24 hrs of the explantation. In neocortical anlage intensity of invagination was meximal in 6.5 wks embryo. In tectum invagination intensity of th explants lowered gradually from wk 5 to wk 7.

Cell Movement↗

[Effects of donepezil on the delayed rectifier-like potassium current in pyramidal neurons of rat hippocampus and neocortex].

AIM: To investigat the effects of donepezil on delayed rectifier-like potassium currents (IK) in rat hippocampus and neocortex. METHODS: Whole cell configuration of the patch-clamp techniques were used to characterize IK in acutely isolated rat hippocampal and neocortical pyramidal neurons. RESULTS: The slowly inactivating outward currents (IK) were recorded in all cells under investigation. Donepezil in micromolar concentrations were shown to supress the IK of all cells in a dose-dependent and voltage-dependent manner. The steady-state activation curves of IK were characterized by half-activation potentials of -15.5 mV in hippocampal and -4.1 mV in neocortical pyramidal neurons and were changed to -26.2 mV and -18.6 mV, respectively, after perfusion with donepezil (10 mumol.L-1). CONCLUSION: At concentrations as low as 1 mumol.L-1, donepezil was found to block the IK in a voltage-dependent manner in hippocampus and neocortex. This effect may be synergistic with the anticholinesterase activity of donepezil to increase its therapeutic effectiveness.

Animals↗

Layer specification of transplanted interneurons in developing mouse neocortex.

The six-layered neocortex is composed of excitatory projection neurons and inhibitory interneurons. Recent studies have established separate embryological origins for these two cellular populations. However, it remains uncertain how interneurons arising from the subcortical ganglionic eminences are able to participate in the orderly stratification of the cortical layers. A related question concerns whether or not early and late interneuron progenitors have equivalent developmental potentials. To address these issues, we performed transplantation experiments to test the fates of early-versus late-born interneuron populations using cells labeled with a genetic marker. Our results indicate that transplanted interneurons from the medial ganglionic eminence give rise to specific layers of the neocortex in an inside-out order. To test the potency of interneurons born at different ages, heterochronic transplantations were also performed. Both early- and late-born progenitors were able to switch their fates in the new environment, and, similar to projection neurons, fate-switching was dependent on progenitor receptivity to environmental cues during their last round of cell division. Our data also demonstrate, for the first time, that interneuron-layering cues are present within the medial ganglionic eminence, suggesting that, before the commencement of long-distance tangential migration, interneurons are already specified with respect to their future layer addresses. So, although the generation of diverse neuronal phenotypes in separate locations is an effective strategy to pursue separate developmental programs, our results indicate that excitatory and inhibitory neurons share similar mechanisms for integrating sequentially born neurons from two places into a single layered structure.

Animals↗

CXCR4 regulates interneuron migration in the developing neocortex.

The chemotactic factors directing interneuron migration during cerebrocortical development are essentially unknown. Here we identify the CXC chemokine receptor 4 (CXCR4) in interneuron precursors migrating from the basal forebrain to the neocortex and demonstrate that stromal cell-derived factor-1 (SDF-1) is a potent chemoattractant for isolated striatal precursors. In addition, we show that CXCR4 is present in early generated Cajal-Retzius cells of the cortical marginal zone. In mice with a null mutation in CXCR4 or SDF-1, interneurons were severely underrepresented in the superficial layers and ectopically placed in the deep layers of the neocortex. In contrast, the submeningeal positioning of Cajal-Retzius cells was unaffected. Thus, our findings suggest that SDF-1, which is highly expressed in the embryonic leptomeninx, selectively regulates migration and layer-specific integration of CXCR4-expressing interneurons during neocortical development.

Animals↗

[A comparative analysis of restoration of electroencephalographic and protein-synthesizing activities in neocortex and hippocampus in hibernating (ground squirrels) and nonhibernating (rats) animals during exit from hypothermia].

A similarity in the sequence of restoration of the EEG spectrum between ground squirrels arousing from torpor and rats passing out of artificial hypothermia (17-18 degrees C) was shown. First of all, the low-frequency part of the EEG spectrum was restored. As animals warmed up, their breathing became hurried, cold shivering appeared, and the theta- and alpha-rhythms increased. During the exit from hypothermia, the activity of the protein-synthesizing system in both rats and ground squirrels was almost entirely restored when the animal body temperature achieved 21-22 degrees C. In ground squirrel, the rate of protein synthesis in the neocortex was lower than in hippocampus CA1 and CA3 areas, whereas in rats, on the contrary, it was higher in the neocortex in comparison with the CA3 area.

Animals↗

[Astroglia formation in the neocortex of mice after temporary prenatal serotonin depletion].

Time-course of astrocyte appearance in the neocortex of F1 (CBA/C57B1) mice after prenatal serotonin depletion was studied. To suppress serotonin synthesis, para-chlorophenylalanine was administered to females once at the early postimplantation stage of gestation. To visualize differentiating astrocytes, the immunohistochemical method for demonstration of astrocyte intermediate filament protein--glial fibrillary acidic protein (GFAP) was used, which allowed not only to label the cells, but also to evaluate the starting point, extent and time-course of their differentiation. The results obtained have shown that in all the neocortical areas studied (area cingularis, area occipitalis, area parietalis, area insularis, area praepiriformis, area piriformis, area entorhinalis and area subiculum), normally, GFAP-positive cells appeared in the layer I at postnatal week 1. In the course of development, the process of astrocyte differentiation was shown to become progressively more intensive. At the same time, the process of barrier structures formation took place. During the first days of postnatal development astrocytes and their processes were shown to appear close to the blood vessels and lateral ventricle walls. In the neocortex of animals that developed during the serotonin depletion, GFAP-positive cells were formed in decreased numbers, in particular, in the white matter, at all the stages of postnatal development studied.

Animals↗

Intermittent hypobaric hypoxia during development--morphological and functional changes in the neocortex.

Infant rats, together with their mother, were exposed to the simulated altitude of 7,000 m for 8 hours per day since birth to the age of 17 days. Animals were studied the 25th day, 8 days after the last exposure to hypoxia. The experimental and control animals were sacrificed the 25th day by the transaortic perfusion with 4% buffered neutral formaldehyde under ether anaesthesia. Brains were processed for classical neurohistological analysis (Nissl staining), Fluoro-Jade B and Hoechst. Cortical area in the AP plane 3 mm posterior to bregma was subjected to quantification and "laminar analysis" of the neurones count. The findings were as follows: a) The cytoarchitectonics of the brain in animals exposed to hypoxia was not severely damaged. b) The thickness of neocortex is in the experimental animals lower than that in the controls. c) The "laminar analysis" of neocortex showed a relative increase of neuronal density in layers I., II., V. and VI. of the cortex. d) The electrical stimulation of sensorimotor cortex 8 days after the end of hypoxia brought about prolongation of evoked cortical after discharges. These results demonstrate that the intermittent hypobaric hypoxia has a profound effect on morphological maturation of the central nervous system in infant rats. Hypoxia influenced the excitation-- inhibition mechanisms of cortical neurones.

Animals↗

[Nucleolar apparatus of proliferating and differentiating cells of human embryonic neocortex during formation of the cortical plate].

Human neocortex was studied using light and electron microscopy in embryos 6-10 wks of development. Vast majority of proliferating cells was established to be concentrated in ventricular zone. Nuclear, nucleolar and cytoplasmic organelle structure indicate various level of synthetic processes activity in cells of different layers of the developing human neocortex. The dynamics in nucleolar number in the cells of ventricular zone and cortical plate was demonstrated.

Cell Differentiation↗

[Intermittent hypobaric hypoxia during development--morphologic changes in the neocortex and hippocampus].

Infant rats, together with their mother, were exposed to the simulated altitude of 7,000 m for 8 hours per day since birth to the age of 18 days. Animals were studied the 25th day, 7 days after the last exposure to hypoxia. The experimental and control animals were killed the 25th day by the transaortic perfusion with 4% buffered neutral formaldehyde under ether anaesthesia. Brains were processed for classical neurohistological analysis (Nissl staining). 1. Cortical area in the AP plane 3 mm posterior to bregma were subjected to quantification and "laminar analysis" of the neuron count. 2. Hilus of the dentate gyrus between the AP plane 2.5 mm and 4 mm posterior to bregma were subjected to quantification of the neurons. The findings were as follows: a) The cytoarchitectonics of the brain in animals exposed to hypoxia was not severely damaged. b) The thickness of neocortex is in the experimental animals lower than that in the controls. c) The "laminar analysis" of neocortex showed a relative increase of neuronal density in layers I., II., V. and VI. of the cortex. d) The quantification of the neuron count showed a decrease in hilus of the dentate gyrus. These results demonstrate that the intermittent hypobaric hypoxia has a profound effect on morphological maturation of central nervous system in infant rats.

Altitude↗

Prenatal development of reelin-immunoreactive neurons in the human neocortex.

Reelin, the protein defective in reeler mutant mice, is a secreted glycoprotein involved in the architectonic development of the central nervous system, more particularly in the development of neocortical lamination. In mice, reelin mRNA and protein expression are most robust in horizontal neurons of the embryonic marginal zone (MZ). By using monoclonal anti-reelin antibodies (de Bergeyck et al. [1998] J. Neurosci. Methods), the morphology and evolution of reelin-expressing neurons were studied in the MZ of the prenatal human neocortex. At 11 gestational weeks (GW), the MZ contained a single layer of reelin-positive mono- or bipolar horizontal Cajal-Retzius (CR) cells. From 14 GW onward, the subpial granular layer (SGL) invaded the MZ, forming a transient layer of undifferentiated, initially reelin-negative granule cells. In parallel to the emergence of the SGL and the morphological differentiation of the CR cells, a second population of reelin-positive cells appeared within the SGL. These cells, termed CR-like cells, were intermediate in size and shape between the CR cells and SGL granule cells. Between 16 GW and 24 GW, the packing density of the reelin-producing cells remained remarkably stable, despite the continuous growth of the cortical surface. During this period, CR cells settled progressively deeper within the MZ, although they remained in contact with the pial surface through radially ascending processes. Most CR cells disappeared at around 27 GW, in parallel with the dissolution of the SGL. During the last weeks of gestation, reelin was expressed by a few medium-sized, often horizontal neurons. These observations show that different neuronal populations in the human MZ express reelin and suggest that a possible function of the SGL is to supply reelin-producing cells through a gradual transformation of reelin-negative precursor cells into reelin-immunoreactive CR-like cells, thus coping with the protracted neurogenesis and dramatic surface expansion of the human neocortex.

Calbindin 2↗

Distribution of descending projections from primary auditory neocortex to inferior colliculus mimics the topography of intracollicular projections.

To ascertain whether the auditory neocortex also innervates the central nucleus of the inferior colliculus (CNIC) and not only its dorsal (DCIC) and external (ECIC) cortices, the anterograde tracers Phaseolus vulgaris-leucoagglutinin (PHA-L) and biotinylated dextran (BD) were injected into the primary auditory neocortex of albino rats (Te1), and labeled corticocollicular fibers were studied via light and electron microscopy. Axons from discrete regions of Te1 form two rostrocaudally oriented laminar plexuses of terminal fibers in the ipsilateral inferior colliculus (IC) and one in the contralateral IC. The first ipsilateral plexus, located in the medial half of the IC, has a dorsomedial to ventrolateral orientation, parallel to the isofrequency planes of the IC; is continuous through the CNIC and DCIC; and extends into the rostral ECIC. The second plexus is located in the deep layers of the lateral ECIC. These two plexuses meet caudally and ventrally, at the border between the CNIC and the lateral ECIC. The plexus in the contralateral IC is less dense and shorter than the two ipsilateral plexuses and is symmetric to the medial plexus. The thickness of the three plexuses is correlated with the size of the injection site, and their mediolateral and dorsoventral positions change as the injection site in Te1 is displaced rostrocaudally, with more caudal injections resulting in more dorsolateral medial plexuses and more dorsomedial lateral plexuses. Furthermore, the ventromedial border of the IC receives nontopographic, convergent projections from wide regions of rostral portions of Te1. The distribution of these corticocollicular plexuses mimics the topography of previously described intracollicular fibers. Electron microscopy shows that, in all three subdivisions of the ipsilateral IC, corticocollicular fibers form small boutons with features generally associated with excitatory transmission; i.e., they contain round synaptic vesicles and form asymmetric synapses with thin dendritic shafts and spines. These results demonstrate that the auditory corticocollicular projections innervate more extensive regions of the IC than were previously observed. Although peripheral regions receive the densest projection, the entire IC appears to be the target of corticofugal input.

Animals↗

Considerations arising from a complementary learning systems perspective on hippocampus and neocortex.

We discuss a framework for the organization of learning systems in the mammalian brain, in which the hippocampus and related areas form a memory system complementary to learning mechanisms in neocortex and other areas. The hippocampal system stores new episodes and "replays" them to the neocortical system, interleaved with ongoing experience, allowing generalization as cortical memories form. The data to account for include: 1) neurophysiological findings concerning representations in hippocampal areas, 2) behavioral evidence demonstrating a spatial role for hippocampus, 3) and effects of surgical and pharmacological manipulations on neuronal firing in hippocampal regions in behaving animals. We hypothesize that the hippocampal memory system consists of three major modules: 1) an invertible encoder subsystem supported by the pathways between neocortex and entorhinal cortex, which provides a stable, compressed, invertible encoding in entorhinal cortex (EC) of cortical activity patterns, 2) a memory separation, storage, and retrieval subsystem, supported by pathways between EC, dentate gyrus and area CA3, including the CA3 recurrent collaterals, which facilitates encoding and storage in CA3 of individual EC patterns, and retrieval of those CA3 encodings, in a manner that minimizes interference, and 3) a memory decoding subsystem, supported by the Shaffer collaterals from area CA1 to area CA3 and the bi-directional pathways between EC and CA3, which provides the means by which a retrieved CA3 coding of an EC pattern can reinstate that pattern on EC. This model has shown that 1) there is a trade-off between the need for information-preserving, structure-extracting encoding of cortical traces and the need for effective storage and recall of arbitrary traces, 2) long-term depression of synaptic strength in the pathways subject to long-term potentiation is crucial in preserving information, 3) area CA1 must be able to exploit correlations in EC patterns in the direct perforant path synapses.

Amnesia↗

Spatial memory deficits in patients with lesions affecting the medial temporal neocortex.

Lesion studies in monkeys suggest that neocortical subregions of the medial temporal lobe (MTL) carry memory functions independent of the hippocampal formation. The present study investigates possible differential contributions of MTL subregions to spatial memory in humans. Eye movements toward remembered spatial cues (memory-guided saccades) with unpredictably varied memorization delays of up to 30 seconds were recorded in patients with postsurgical lesions of the right MTL, either restricted to the hippocampal formation (n = 3) or including the adjacent neocortex (n = 5) and in 10 controls. Although saccadic targeting errors of patients with selective hippocampal lesions did not differ from controls, saccadic targeting errors of patients with additional neocortical involvement showed a significant and contralaterally pronounced increase at memorization delays above 20 seconds. We conclude that the human medial temporal neocortex carries spatial memory functions independent of the hippocampal formation and distinct from spatial short-term memory.

Adult↗

Analysis of neocortex in three males with the fragile X syndrome.

Fragile X [fraX] syndrome is a common hereditary disorder associated with a fragile site marker at Xq27.3 which clinically presents as a form of mental retardation (MR). Postmortem investigation of 3 fraX positive males with mild to moderate MR did not document any gross neuropathological changes. Golgi analysis of neocortical dendritic spine morphology extended our previous observations of immature, long, tortuous spines in one adult case of fraX (Rudelli, et al., Acta Neuropathologica 67:289-295, 1985) to 2 new cases. Evidence for similar dendritic spine abnormalities was found, although Golgi analysis was less than optimal because of incomplete dendritic stain impregnation. Neocortical intra-layer cell density was also investigated in all 3 cases. Cresyl violet stained neurons were counted in 10 randomly selected fields in neocortical layers II-VI of cingulate and temporal association areas (Brodmann's areas 23 and 38). Neuron counts in fraX and control neocortex showed no significant differences. Thus, abnormal dendritic spine morphology with preservation of neuronal density appears to characterize the neocortex in individuals with this common form of mental retardation.

Adolescent↗

Characterization of the monoaminergic innervation of immature rat neocortex: a histofluorescence analysis.

In the neocortex of 6-day-old rat, abundant axon terminals which exhibit specific catecholamine fluorescence are found in all regions and throughout all cortical layers. The overall density of axons in 6-day-old cortex is similar to the density in the adult cortex. In immature cortex, there are two distinct fluorescent plexuses, both presumably noradrenergic, one in the molecular layer and another in the lower half of the cortex. The superficial plexus is composed primarily of horizontal fibers, and the deep plexus of a dense feltwork of obliquely oriented fibers suggestive of a terminal field. The cortical plate itself is traversed by a few vertical processes. Following lesions of the midbrain tegmentum no fluorescent axons are seen in cortex, providing evidence that the fluorescent axons in cortex arise from brain stem neurons. The deep and superficial plexuses can be differentially visualized depending on the histochemical techniques employed and on pharmacological treatment, such as loading with a monoamine congener. Both deep and superficial axons are shown to contain endogenous catecholamines but those fibers in the deep plexus are filled to far less than their maximum capacity. The pharmaco-histochemical differences between axons in the two plexuses suggest that there may exist two distinct catecholaminergic projections to lateral neocortex. The demonstration of an extensive cortical monoamine innervation early in ontogeny supports the possibility that monoamine neurons play an important role in information processing and/or developmental interactions in the immature brain.

Age Factors↗

Prenatal and postnatal development of GABA-accumulating cells in the occipital neocortex of rat.

The development of the 3H-GABA-accumulating cells in the neocortex has been followed by light microscopical autoradiography, and after resectioning of the original autoradiograms, by electron microscopy. The validity of the methods used are discussed. The study has been limited to the primary visual cortex and its precursors of rat, from embryonic day (E) 15 to adult. GABA-accumulating cells were found from E 16 onwards in the occipital cortex, which is one to two days after cells arrive in the pallial anlage and one day before the first synapses have been found. Until E 18, the prevalent positions of labeled cells were in lamina I and below the cortical plate. Later, labeled cells also occurred as strands within the cortical plate. During the perinatal period, more and more GABA-accumulating neurons and glial cells began to differentiate and show a characteristic distribution at the periphery of unlabeled cell clusters. From postnatal day 11, no apparent change in density or position of labeled neurons took place. At prenatal stages, two main types of labeled cells were found: 1) Comparatively large cells with rounded nuclei and rough endoplasmic reticulum consisting of narrow, electron-lucent cisterns. These cells were tentatively identified as preneurons. 2) Smaller, polymorphous cells with irregular nuclei and rough endoplasmic reticulum with wide cisterns filled with a dense matrix. These cells are probably precursors of glial cells. Both labeled neurons and glial cells were identified at postnatal stages. In young and adult rats, only neurons to be characterized as nonpyramidal neurons were labeled. Synapses were not found on the perikarya of labeled cells until E 21. Also, in postnatal preparations, labeled neurons showed few axo-somatic synapses. These data were correlated with other events of the structural and functional development of the neocortex. The delay between the appearance of GABA accumulating cells and synaptogenesis indicates that apart from being an inhibitory neurotransmitter, GABA might play a specific morphogenetic role in synaptogenesis. This could even be its primary function during early developmental stages.

Animals↗