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PubMed2000

Developmental history of the subplate and developing white matter in the murine neocortex. Neuronal organization and relationship with the main afferent systems at embryonic and perinatal stages.

The neuronal diversity of the subplate and developing white matter in the mouse was studied using a variety of neuronal markers. The subplate was first visible in lateral cortical areas at E13, coinciding with the emergence of the cortical plate. During prenatal development, this layer was formed by morphologically heterogeneous neurons, subsets of which were immunoreactive for GABA- and calcium-binding proteins. From E18 onwards, a few subplate cells also contained neuropeptides. Colocalization experiments demonstrated that the percentages of neurons immunoreactive for each antigen were similar to those described in adult neocortex. By E15, subplate cells had received synaptic contacts. Moreover, a second early-neuronal population was conspicuous from E13 in the lower intermediate zone: the intermediate-subventricular population. Unlike subplate cells, these neurons were morphologically uniform, smaller and horizontally oriented. Nevertheless, a few of these cells also appeared within the ventricular zone, with a perpendicular/ oblique orientation. Most of these cells were GABA-positive and showed calbindin immunoreactivity. At the electron microscopic level, no synaptic contacts were found in these neurons. Tracing studies using DiI showed that subplate neurons were the first to send axons outside the neocortex towards the ganglionic eminence at E13. At E14, subplate axons and ingrowing thalamic fibers met in the striate primordium. Subplate cells retained their projection to the thalamus during prenatal development. Thalamocortical axons reached the subplate at E15, and 1 day later began to invade the upper cortical layers. Early callosal axons, in contrast, did not run through the subplate to reach the contralateral hemisphere, nor did subplate cells send out callosal fibers. Callosal axons ran just above the subventricular zone, intermingled with the intermediate-subventricular neuronal population. We conclude that the subplate neuronal population has a chemical heterogeneity reminiscent of that of the adult cortex and is crucial to the establishment of thalamocortical relationships, whereas the intermediate-subventricular neurons constituted a particular GABAergic population, which includes resident cells and tangentially migrating postmitotic neurons spatially related to the development of callosal connections.

Afferent Pathways↗
PubMed2001

The early differentiation of the neocortex: a hypothesis on neocortical evolution.

During development, a cerebral cortex appears in the wall of the telencephalic vesicle in reptiles and mammals. It arises from a cell-dense cortical plate, which develops within a primordial preplate. The neurons of the preplate are essential for cortical development; they regulate the neuronal migration of the cortical plate neurons and form the first axonal connections. In the reptilian cortex and in the hippocampus of the mammalian cerebral cortex, most ingrowing afferent axons run above the cortical plate, in the zone where the receptive tufts of apical dendrites of the cortical pyramidal neurons branch extensively. In the mammalian neocortex, however, axons enter mainly from below the cortical plate where they do not encounter the apical tufts of these pyramidal neurons. In this paper, we discuss the idea that this difference in cortical development has relieved a functional constraint in the expansion of the cortex during evolution. We hypothesize that the entrance of axons below the cell-dense cortical plate, together with the inside-out migration of cortical neurons, ensures that the neocortex remains an "open" system, able to differentiate into new (sub)layers and more cortical areas.

Animals↗
PubMed2005

Cortical sources of CRF, NKB, and CCK and their effects on pyramidal cells in the neocortex.

In order to investigate how neuropeptide transmission can modulate the neocortical network, we mapped the expression of neurokinin (NK) B, cholecystokinin (CCK), and corticotropin-releasing factor (CRF) and their receptors to neuronal types using patch-clamp and single-cell reverse transcription-polymerase chain reaction in acute slices of rat neocortex. Classification of neurons by unsupervised clustering based on the analysis of multiple electrophysiological and molecular properties disclosed 3 GABAergic interneuron clusters and 1 pyramidal cell cluster. The 3 neuropeptides were expressed in a cluster of interneurons characteristically expressing vasoactive intestinal peptide. CRF was additionally found in a cluster containing almost exclusively somatostatin-expressing interneurons, whereas CCK was present in all clusters. The respective receptors of these peptides, NK-3, CCK-B, and CRF-1, were essentially expressed in pyramidal cells. At -60 mV, pyramidal cells were weakly depolarized by each of these peptides. When pyramidal neurons were maintained to about 5 mV below spike threshold, depolarization induced by each peptide resulted in a long-lasting action potential discharge. Neuropeptide effects were prevented by selective antagonists of NK-3, CCK-B, and CRF-1 receptors. These results suggest that pyramidal neurons are the primary target of NKB, CCK, and CRF in the neocortex. They further indicate that specific interneuron types coordinate the release of these peptides and can induce a long-lasting increase of the excitability of the neocortical network.

Action Potentials↗
PubMed2006

The distribution of chandelier cell axon terminals that express the GABA plasma membrane transporter GAT-1 in the human neocortex.

Chandelier cells represent a unique type of cortical GABAergic interneuron whose axon terminals (Ch-terminals) form synapses exclusively with the axon initial segments of pyramidal cells. In this study, we have used immunocytochemistry for the high-affinity plasma membrane transporter-1 (GAT-1) to analyze the distribution and density of Ch-terminals in various cytoarchitectonic and functional areas of the human neocortex. The lowest density of GAT-1-immuoreactive (-ir) Ch-terminals was detected in the primary and secondary visual (areas 17 and 18) and in the somatosensory areas (areas 3b and 1). In contrast, an intermediate density was observed in the motor area 4 and the associative frontolateral areas 45 and 46, whereas the associative frontolateral areas 9 and 10, frontal orbitary areas 11, 12, 13, 14, and 47, associative temporal areas 20, 21, 22, and 38, and cingulate areas 24 and 32 displayed the highest density of GAT-1-ir Ch-terminals. Despite these differences, the laminar distribution of GAT-1-ir Ch-terminals was similar in most cortical areas. Hence, the highest density of this transporter was observed in layer II, followed by layers III, V, VI, and IV. In most cortical areas, the density of GAT-1-ir Ch-terminals was positively correlated with the neuronal density, although a negative correlation was detected in layer III across all cortical areas. These results indicate that there are substantial differences in the distribution and density of GAT-1-ir Ch-terminals between areas and layers of the human neocortex. These differences might be related to the different functional attributes of the cortical regions examined.

Adult↗
PubMed1997

Expression of peripherin, NADPH-diaphorase and NOS in the adult rat neocortex.

Peripherin is mainly expressed in peripheral neurones and in CNS neurones which extend axons into peripheral nerves. However, this intermediate filament protein has also been detected in a few other neurones entirely located within the CNS. The present study focuses on the adult rat neocortex. Peripherin immunoreactive (P+) neuronal somata and their neuritic extensions were observed in cortical layers II, III, V and VI, while a few P+ nerve fibres could be seen in layer I. All the P+ neurones could be selectively stained using reduced nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry, a typical feature of aspiny neurones. Some of the P+ neurones could also be immunostained with an antibody raised against nitric oxide synthase (NOS). These results provide evidence that peripherin is present in a discrete population of aspiny interneurones of the adult rat neocortex. The functional significance of the co-expression of peripherin and NOS needs further investigation.

Animals↗
PubMed2001

Microglia/macrophages proliferate in striatum and neocortex but not in hippocampus after brief global ischemia that produces ischemic tolerance in gerbil brain.

The current study determined whether short durations of ischemia that produce ischemia-induced tolerance stimulate glial proliferation in brain. Adult male gerbils were injected with BrdU (50 mg/kg) and dividing cells were detected using immunocytochemistry after sham operations, 2.5 or 5 minutes of global ischemia, or ischemia-induced tolerance. The 2.5-minute ischemia and the ischemia-induced tolerance did not kill hippocampal CA1 pyramidal neurons, whereas the 5-minute ischemia did kill the neurons. At 4 days after 2.5-minute global ischemia, when cell proliferation was maximal, BrdU-labeled cells increased in striatum and in neocortex, but not in hippocampus. The majority of the BrdU-labeled cells were double-labeled with isolectin B4, showing that these dividing cells were primarily microglia or macrophages, or both. Similarly, BrdU-labeled microglia/macrophages were found in striatum and neocortex but not in hippocampus of most animals 4 days after ischemia-induced tolerance (2.5 minutes of global ischemia followed 3 days later by 5 minutes of global ischemia). No detectable neuronal cell death existed in striatal and cortical regions where the microglia/macrophage proliferation occurred. Though 3 of 7 animals subjected to 2.5 minutes of ischemia showed decreased myelin-associated glycoprotein (MAG) immunostaining and increased numbers of adenomatous polyposis coli-stained oligodendrocytes in lateral striatum, this did not explain the microglia/macrophage proliferation. Data show that ischemia-induced tolerance in the gerbil is associated with proliferation of microglia/macrophages in striatum and cortex but not in hippocampus. Because there is no apparent neuronal death, it is postulated that the microglia/macrophage proliferation occurs in response to an unknown nonlethal injury to neurons or glia and may be beneficial.

Adenomatous Polyposis Coli Protein↗
PubMed2001

COUP-TFI: an intrinsic factor for early regionalization of the neocortex.

Regionalization of the cerebral cortex is thought to involve two phases: an early regionalization phase and a later refinement phase. It has been shown that early regionalization of the neocortex does not require thalamic inputs and is regulated by intrinsic factors. Recently, two such intrinsic factors, Pax6 and Emx2, have been identified. In this study, we identified COUP-TFI as a regulatory factor for early neocortical regionalization. The spatial and temporal expression pattern of COUP-TFI suggested a role in specification of the neocortex and in maintaining cortical identity. Altered region-specific expression of marker genes in the cortex as well as miswired area-specific connections between the cortex and the thalamus in COUP-TFI null mice indicate COUP-TFI plays a critical role in regulating early regionalization. Our results substantiate that COUP-TFI, an intrinsic factor, may work in concert with Pax6 and Emx2 to specify neocortical identity.

Animals↗
PubMed2004

Pharmacological profile of nociceptin/orphanin FQ receptors regulating 5-hydroxytryptamine release in the mouse neocortex.

A synaptosomal preparation was employed to pharmacologically characterize the role of presynaptic nociceptin/orphanin FQ (N/OFQ) receptors (NOP receptors) in the regulation of 5-hydroxytryptamine release in the Swiss mouse neocortex. In the present study, the NOP receptor ligands N/OFQ, Ac-RYYRWK-NH(2) and [Phe(1)psi(CH(2)-NH)Gly(2)]N/OFQ(1-13)-NH(2) inhibited the K(+)-induced [(3)H]-5-HT overflow with similar maximal effects ( approximately -35%) but different potencies (pEC(50) of 8.56, 8.35 and 7.23, respectively). The novel agonist [Arg(14),Lys(15)]N/OFQ also inhibited [(3)H]-5-HT overflow, but the concentration-response curve was biphasic and the efficacy higher ( approximately -45%). Receptor selectivity of NOP receptor agonists was demonstrated by showing that synaptosomes from NOP receptor knockout mice were unresponsive to N/OFQ, [Arg(14),Lys(15)]N/OFQ and [Phe(1)psi(CH(2)-NH)Gly(2)]N/OFQ(1-13)-NH(2) but maintained full responsiveness to endomorphin-1. Moreover, the inhibitory effect of N/OFQ was prevented by peptide ([Nphe(1)]N/OFQ(1-13)-NH(2) and UFP-101) and nonpeptide (J-113397 and JTC-801) NOP receptor selective antagonists. Desensitization occurred under perfusion with high (3 and 10 microm) N/OFQ concentrations. This phenomenon was prevented by the protein kinase C inhibitor, bisindolylmaleimide. Moreover, N/OFQ-induced desensitization did not affect mu opioid receptor responsiveness. Finally, it was observed in a similar preparation of rat cerebrocortical synaptosomes, although it was induced by higher N/OFQ concentrations than that used in the mouse. Together, these findings indicate that presynaptic NOP receptors inhibit 5-hydroxytryptamine release in the mouse neocortex. Based on present and previous studies, we conclude that NOP receptors in the mouse are subtly different from the homologous receptor population in the rat, strengthening the view that there exist species differences in the pharmacology of central NOP receptors.

Animals↗
PubMed2005

A pentylenetetrazole-induced generalized seizure in early life enhances the efficacy of muscarinic receptor coupling to G-protein in hippocampus and neocortex of adult rat.

We have previously shown that exposure to the anti-cholinesterase eserine provokes interictal-like discharges in the CA3 area of hippocampal slices from adult rats in which a generalized seizure has been induced by pentylenetetrazole (PTZ) when immature (at 20 days). Such increased responsiveness to acetylcholine (ACh) was not associated with any change in hippocampal acetylcholine or gamma-aminobutyric acid (GABA) content, GABAergic inhibition or density of ACh innervation, but was blocked by the muscarinic receptor antagonist atropine. We therefore turned to quantitative radioligand binding autoradiography, in situ hybridization and the [35S]GTPgammaS method to assess the properties of hippocampal and neocortical muscarinic receptors in adult rats having experienced a PTZ seizure at P20. The densities of M1 and M2 receptor binding sites, respectively labeled with [3H]pirenzepine and [3H]AFDX-384, as well as the amount of m1, m2 and m3 receptor mRNAs, did not differ from control in the hippocampus and neocortex of these rats. In contrast, in PTZ rats, both brain regions displayed a marked increase in [35S]GTPgammaS incorporation stimulated by ACh, bethanechol and particularly oxotremorine. This finding indicates that a generalized seizure in immature rat can entail a long-term and presumably permanent increase in the efficacy of G-protein coupling to muscarinic receptors in the hippocampus and neocortex of the adult. By analogy, such a mechanism could account for the susceptibility to epilepsy of human adults having suffered from prolonged convulsions in early life.

Animals↗
PubMed2006

Gene expression profiling of primate neocortex: molecular neuroanatomy of cortical areas.

One hundred years have passed since Brodmann's mapping of the mammalian neocortex. Solely on the basis of morphological observations, he envisaged the conservation and differentiation of cortical areal structures across various species. We now know that neurochemical, connectional and functional heterogeneity of the neocortex accompanies the morphological divergence observed in such cytoarchitectonic studies. Nevertheless, we are yet far from fully understanding the biological significance of this cortical heterogeneity. In this article, we review our past works on the gene expression profiling of the postnatal primate cortical areas, by quantitative real-time polymerase chain reaction (PCR), DNA array, differential display PCR and in situ hybridization analyses. These studies revealed both the overall homogeneity of gene expression across different cortical areas and the presence of a small number of genes that show markedly area-specific expression patterns. In situ hybridization showed that, among such genes, occ1 and retinol-binding protein (RBP) mRNAs are selectively expressed in the neuronal populations that seem to be involved in distinct neural processing such as sensory reception (for occ1) and associative function (for RBP). Such a molecular neuroanatomical approach has the promise to provide an important link between structure and function of the cerebral cortex.

Animals↗
PubMed2002

A single dose of methamphetamine rescues the blunted dopamine D(1)-receptor activity in the neocortex of D(2)- and D(3)-receptor knockout mice.

Knockout mice deficient for dopamine D(2) and D(3) receptors exhibit blunted c-fos responses to D(1)-agonist stimulation. A single dose of methamphetamine (METH), however, leads to a long-term reversal of these blunted c-fos responses in both mutants, and the same effect is obtained with a single administration of a full D(1)-agonist. Consistent with the predominant c-fos expression in the neocortex induced by METH itself, METH pretreatment leads to the largest D(1)-agonist-stimulated c-fos responses in the neocortex of these mutants. For example, a pronounced blunting of neocortical c-fos responses is detected in the prefrontal cortex, a region in which D(1) receptors play a critical role in working memory. METH pretreated mutants, however, exhibit robust c-fos responses in this region that are indistinguishable from wild type. Recent studies indicate that different mechanisms operate in brains of D(2) and D(3) mutants to lead to decreased D(1)-receptor activity. For example, drug-naive D(2), but not D(3), mutants show significantly decreased G protein activation in response to D(1)-agonist stimulation, and METH pretreatment also rescues this abnormal molecular phenotype. Moreover, although the protein phosphatases (PP) 1/2A and 2B play a critical role in modulating G protein activation in wild type, their effect is either diminished (PP1/2A) or abolished (2B) in D(2) mutants. Interestingly however, METH pretreatment does not rescue the activities of these phosphatases in the mutants, suggesting that the long-term effects of a single dose of METH are mediated via effector systems that act downstream of G protein activation.

Animals↗
PubMed2001

Neocortex patterning by the secreted signaling molecule FGF8.

A classic model proposes that the mammalian neocortex is divided into areas early in neurogenesis, but the molecular mechanisms that generate the area map have been elusive. Here we provide evidence that FGF8 regulates development of the map from a source in the anterior telencephalon. Using electroporation-mediated gene transfer in mouse embryos, we show that augmenting the endogenous anterior FGF8 signal shifts area boundaries posteriorly, reducing the signal shifts them anteriorly, and introducing a posterior source of FGF8 elicits partial area duplications, revealed by ectopic somatosensory barrel fields. These findings support a role for FGF signaling in specifying positional identity in the neocortex.

Animals↗
PubMed2002

Coordinated reactivation of distributed memory traces in primate neocortex.

Conversion of new memories into a lasting form may involve the gradual refinement and linking together of neural representations stored widely throughout neocortex. This consolidation process may require coordinated reactivation of distributed components of memory traces while the cortex is "offline," i.e., not engaged in processing external stimuli. Simultaneous neural ensemble recordings from four sites in the macaque neocortex revealed such coordinated reactivation. In motor, somatosensory, and parietal cortex (but not prefrontal cortex), the behaviorally induced correlation structure and temporal patterning of neural ensembles within and between regions were preserved, confirming a major tenet of the trace-reactivation theory of memory consolidation.

Action Potentials↗
PubMed1999

Neurogenesis in the neocortex of adult primates.

In primates, prefrontal, inferior temporal, and posterior parietal cortex are important for cognitive function. It is shown that in adult macaques, new neurons are added to these three neocortical association areas, but not to a primary sensory area (striate cortex). The new neurons appeared to originate in the subventricular zone and to migrate through the white matter to the neocortex, where they extended axons. These new neurons, which are continually added in adulthood, may play a role in the functions of association neocortex.

Aging↗
PubMed2000

Organizing principles for a diversity of GABAergic interneurons and synapses in the neocortex.

A puzzling feature of the neocortex is the rich array of inhibitory interneurons. Multiple neuron recordings revealed numerous electrophysiological-anatomical subclasses of neocortical gamma-aminobutyric acid-ergic (GABAergic) interneurons and three types of GABAergic synapses. The type of synapse used by each interneuron to influence its neighbors follows three functional organizing principles. These principles suggest that inhibitory synapses could shape the impact of different interneurons according to their specific spatiotemporal patterns of activity and that GABAergic interneuron and synapse diversity may enable combinatorial inhibitory effects in the neocortex.

Action Potentials↗
PubMed2001

Relations between hypometabolism in the posterior association neocortex and hippocampal atrophy in Alzheimer's disease: a PET/MRI correlative study.

OBJECTIVES: Hippocampal atrophy and hypometabolism in the posterior association neocortex are two well known features of Alzheimer's disease. A correlation between these two features was reported twice previously, suggesting intriguing relations. This question has been reassessed, this time controlling for severity of dementia as well as assessing each side of the brain separately and using a voxel based image analysis in addition to the previously employed regions of interest (ROIs). PATIENTS AND METHODS: Eleven patients were studied with probable Alzheimer's disease and mild to moderate dementia in whom both volume MRI and PET assessed cerebral glucose consumption (CMRGlc) were available. Hypothesis driven correlations between hippocampal width (an index of atrophy) and CMRGlc were performed for two posterior association regions, the superior temporal and the inferior parietal (angular gyrus) cortices, using ROIs set separately for each hemisphere. To confirm significant correlations from the ROIs approach, if any, and to assess their specificity for the posterior association neocortex, CMRGlc image voxel based analysis of correlations with hippocampal width was then carried out. RESULTS: There was a significant correlation, in the positive-neurobiologically expected-direction, between right hippocampal width and right angular gyrus metabolism (p< 0.01, Spearman), which remained significant with Kendall partial correlation controlling for dementia severity (estimated by mini mental state scores). Statistical non-parametric mapping (SnPM) confirmed this correlation (p< 0.025), and showed a single additional correlation in the right middle temporal gyrus (p< 0.005), which is also part of the posterior association cortex. CONCLUSION: The findings with both ROIs and voxel based mapping replicate earlier reports of a relation between hippocampal atrophy and ipsilateral association cortex hypometabolism in Alzheimer's disease, and for the first time document that this relation is both region specific and independent of the dementing process itself. Why the correlation was significant only for the right hemisphere is unclear but may be related to the limited sample. Hippocampal-neocortical disconnection due to early and severe medial temporal lobe pathology may at least partly explain the posterior association cortex hypometabolism found in Alzheimer's disease.

Aged↗
PubMed2004

Neuronal circuits of the neocortex.

We explore the extent to which neocortical circuits generalize, i.e., to what extent can neocortical neurons and the circuits they form be considered as canonical? We find that, as has long been suspected by cortical neuroanatomists, the same basic laminar and tangential organization of the excitatory neurons of the neocortex is evident wherever it has been sought. Similarly, the inhibitory neurons show characteristic morphology and patterns of connections throughout the neocortex. We offer a simple model of cortical processing that is consistent with the major features of cortical circuits: The superficial layer neurons within local patches of cortex, and within areas, cooperate to explore all possible interpretations of different cortical input and cooperatively select an interpretation consistent with their various cortical and subcortical inputs.

Animals↗
PubMed2003

Spatiotemporal effects of microstimulation in rat neocortex: a parametric study using multielectrode recordings.

Using microstimulation to imprint meaningful activity patterns into intrinsically highly interconnected neuronal substrates is hampered by activation of fibers of passage leading to a spatiotemporal "blur" of activity. The focus of the present study was to characterize the shape of this blur in the neocortex to arrive at an estimate of the resolution with which signals can be transmitted by multielectrode stimulation. The horizontal spread of significant unit activity evoked by near-threshold focal electrical stimulation (charge transfer 0.8-4.8 nC) and multielectrode recording in the face representation of the primary somatosensory cortex of ketamine anesthetized rats was determined to be about 1,350 microm. The evoked activity inside this range consisted in a sequence of fast excitatory response followed by an inhibition lasting >100 ms. These 2 responses could not be separated by varying the intensity of stimulation while a slow excitatory rebound after the inhibitory response was restricted to higher stimulus intensities (>2.4 nC). Stimulation frequencies of 20 and 40 Hz evoked repetitive excitatory response standing out against a continuous background of inhibition. At 5- and 10-Hz stimulation, the inhibitory response showed a complex interaction pattern attributed to highly sublinear superposition of individual inhibitory responses. The present data help to elucidate the neuronal underpinnings of behavioral effects of microstimulation. Furthermore, they provide essential information to determine spatiotemporal constraints for purposeful multielectrode stimulation in the neocortex.

Action Potentials↗