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PubMedDate not supplied

Initiation of synchronized neuronal bursting in neocortex.

Epilepsy is characterized by highly synchronized paroxysmal bursts of activity within a large population of cortical neurones. Because such spontaneous, synchronized discharges can occur even in isolated blocks of neocortex, mechanisms for initiating and coordinating this activity must reside within the cortex itself. However, the specific cellular properties and local neural circuitry responsible for such behaviour are unknown. In a previous study of neocortex in vitro, we found that treatment with the convulsants penicillin and bicuculline led to synchronized bursts which were driven by unusually large and long-lasting excitatory synaptic conductances. I now report evidence that synchronized bursts are initiated by a small, spacially discrete subpopulation of cells located in the area comprising layer IV and upper layer V. Neural elements in these layers appear to project paroxysmal synaptic excitation radially, onto the neurones of other layers.

Animals↗
PubMed1993

Transforming growth factor-beta 1 prevents glutamate neurotoxicity in rat neocortical cultures and protects mouse neocortex from ischemic injury in vivo.

Transforming growth factor-beta 1 (TGF-beta 1) has been shown to be an injury-related peptide growth factor within the mammalian central nervous system. We tested whether TGF-beta 1 has the capacity to protect rat neocortical neurons against excitotoxic damage in vitro and mouse neocortex against ischemic injury in vivo. After 14 days in vitro, cultured neurons from rat cerebral cortex were exposed to 1 mM L-glutamate in serum-free culture medium. The cultures received TGF-beta 1 immediately after the addition of glutamate. Eighteen hours later, the cell viability of the cultures was determined using trypan blue exclusion. TGF-beta 1 (1-10 ng/ml) significantly reduced the excitotoxic neuronal damage in a concentration-dependent manner. In vivo, male NMRI mice were subjected to a permanent occlusion of the left middle cerebral artery by microbipolar electrocoagulation. After 48 h, the animals received a transcardiac injection of carbon black. The area of ischemia (devoid of carbon) was restricted to the neocortex and its size was determined planimetrically by means of an image-analyzing system. The treatment with TGF-beta 1 (1 microgram/kg i.c.v.) at 6, 4, or 2 h prior to vessel occlusion reduced the area of ischemia by 5.3, 10.0, and 9.6%, respectively. The effect of the treatment with TGF-beta 1 was statistically significant (p < 0.05 by two-way ANOVA). The present in vitro and in vivo data suggest that TGF-beta 1 has the capacity to diminish the deleterious consequences of an excitotoxic or ischemic insult.

Animals↗
PubMed1979

Evidence for a cholinergic projection to neocortex from neurons in basal forebrain.

Unilateral stereotaxic injection of 3.5 nmol of kainic acid into the ventral globus pallidus of rats reduced biochemical cholinergic neuronal markers by 45-50% and virtually eliminated histochemical staining for acetylcholinesterase in neocortex ipsilateral to the lesion. At the lesion site, the large, multipolar neurons that stain densely for acetylcholinesterase were absent when compared with the uninjected side. Kainate was as effective as electrocoagulation for reducing cholinergic markers although it did not affect aminergic projections ascending through the lesioned area. The conclusion that the cholinergic projection originated in neuronal perikarya at the lesion site was supported by the failure of kainate or electrolytic lesions in contiguous regions to produce similar effects. These studies provide strong evidence for a cholinergic projection to neocortex from neurons in the forebrain in the nucleus basalis.

Acetylcholinesterase↗
PubMed1985

Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease.

The numbers and distribution of the neurofibrillary tangles and neuritic plaques have been determined in several areas of the neocortex in brains affected by various degrees of severity of Alzheimer disease. The homotypical cortex of the "association" areas of the temporal, parietal, and frontal lobes are severely involved, whereas the motor, somatic sensory, and primary visual areas are virtually unaffected. The neurofibrillary tangles are mainly in the supra- and infragranular layers, particularly in layers III and V. In all areas except area 18 in the occipital lobe, there are approximately twice as many tangles in layer V as in layer III. The tangles are arranged in definite clusters, and those in the supra- and infragranular layers are in register. The neuritic plaques occur in all layers but predominantly affect layers II and III and do not show clustering. These data on the severity of the pathological involvement in different areas of the neocortex and the laminar distribution and the clustering of the tangles support the suggestion that the pathological changes in Alzheimer disease affect regions that are interconnected by well-defined groups of connections and that the disease process may extend along the connecting fibers. The invariable and severe involvement of the olfactory areas of the brain in this disease is in striking contrast to the minimal changes in the somatic sensory and primary visual areas and raises the possibility that the olfactory pathway may be initially involved.

Aged↗
PubMed1991

Barrel construction in rodent neocortex: role of thalamic afferents versus extracellular matrix molecules.

The rodent primary somatosensory cortex is characterized by aggregates of cellular and axonal elements that replicate the distribution of mystacial vibrissae on the face. The periphery-related cortical pattern ("barrels") is influenced by an amalgam of elements extrinsic (i.e., afferents) and intrinsic (i.e., neurons, glia, and their substrate) to the developing neocortex. To assign the role of some of these elements in cortical pattern formation, we have examined the temporal correlation between periphery-related patterns formed by thalamocortical axons and by extracellular matrix (ECM) molecules associated with neurons and glia in the cortex. Thalamocortical axons were labeled with the lipophilic tracer 1,1'-dioctydecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) in aldehyde-fixed neonatal rat brains, and the same brains were also prepared for immunohistochemical localization of ECM molecules cytotactin and cytotactin-binding proteoglycan. We present evidence that thalamocortical axons form a periphery-related pattern well before such an organization is detectable in the distribution of ECM molecules. Furthermore, a patterned distribution of ECM molecules results from the down-regulation of these molecules from barrel centers, where thalamic axons have established vibrissa-specific patches. We conclude that thalamic axons convey the blueprint of the sensory periphery onto the neocortex and that ECM molecules do not participate in the initial formation of this pattern.

Afferent Pathways↗
PubMed1992

Early regional specification for a molecular neuronal phenotype in the rat neocortex.

The timing of neocortical regional specification was examined using a monoclonal antibody, designated PC3.1, that binds a 29-kDa polypeptide and recognizes a neuronal subpopulation located in the lateral but not dorsomedial neocortex in the rat. When lateral cortical tissue fragments at embryonic days 12 and 16 were maintained in an organotypic culture system, a substantial number of neurons became PC3.1-immunopositive. In marked contrast, considerably fewer, if any, PC3.1-positive neurons were observed in cultures of dorsal cortical tissue. The selective appearance of PC3.1-immunopositive neurons was also observed in dissociated cultures derived from the lateral, but not dorsal, cortical primordium at embryonic day 13 and later. In light of previous reports showing that the interactions between developing neocortical neurons and cortical afferents begin at embryonic day 14 or later, our findings imply that some regional specification occurs well before these interactions and suggest the importance of elements intrinsic to the neocortex in establishing neocortical regional specificity. Furthermore, [3H]thymidine birth-dating experiments revealed that the majority of presumptive PC3.1-immunopositive neurons underwent their final mitosis around embryonic day 15, suggesting that the regional specification events for these neurons occur before their neurogenesis.

Animals↗
PubMed1992

gamma-Aminobutyric acid-containing basal forebrain neurons innervate inhibitory interneurons in the neocortex.

The basal forebrain-neocortex pathway--involved in higher cognitive processing, selective attention, and arousal--is considered one of the functionally most important ascending subcortical projections. The mechanism by which this relatively sparse subcortical pathway can control neuronal activity patterns in the entire cortical mantle is still unknown. The present study in the cat provides evidence that gamma-aminobutyric acid-containing basal forebrain neurons participate in the neocortical projection and establish multiple synaptic connections with gamma-aminobutyric acid-releasing interneurons containing somatostatin or parvalbumin. We propose that a mechanism by which the numerically small ascending pathways can exert a powerful global effect in the neocortex is by the selective innervation of gamma-aminobutyric acid-releasing interneurons, which, in turn, control the activity of large populations of pyramidal cells through their extensive axon arborizations. Finally, these results demonstrate a direct anatomical link between two cell populations implicated in Alzheimer disease pathology: basal forebrain neurons and cortical somatostatin cells.

Animals↗
PubMed1997

Area-specific regulation of gamma-aminobutyric acid type A receptor subtypes by thalamic afferents in developing rat neocortex.

Targeting and innervation of the cerebral cortex by thalamic afferents is a key event in the specification of cortical areas. The molecular targets of thalamic regulation, however, have remained elusive. We now demonstrate that thalamic afferents regulate the expression of gamma-aminobutyric acid type A (GABAA) receptors in developing rat neocortex, leading to the area-specific expression of receptor subtypes in the primary visual (V1) and somatosensory (S1) areas. Most strikingly, the alpha1- and alpha5-GABAA receptors exhibited a reciprocal expression pattern, which precisely reflected the distribution of thalamocortical afferents at postnatal day 7. Following unilateral lesions at the birth of the thalamic nuclei innervating V1 and S1 (lateral geniculate nucleus and ventrobasal complex, respectively), profound changes in subunit expression were detected 1 week later in the deprived cortical territories (layers III-IV of V1 and S1). The expression of the alpha1 subunit was strongly down-regulated in these layers to a level comparable to that in neighboring areas. Conversely, the alpha5 subunit was up-regulated and areal boundaries were no longer discernible in the lesioned hemisphere. Changes similar to the alpha5 subunit were also seen for the alpha2 and alpha3 subunits. These results indicate that the differential expression of GABAA receptor subtypes in developing neocortex is dependent on thalamic innervation, contributing to the emergence of functionally distinct areas.

Animals↗
PubMed1996

The emergence of hierarchical clustered representations in a Hebbian neural network model that simulates aspects of development in the neocortex.

In this paper we show how clustered representations emerge within a simple neural network which simulates some aspects of the development of the mammalian neocortex. Synapse death and stabilization, postulated to occur in the real neocortex are modelled. The representations that emerge under certain conditions show a spatially hierarchical coarse- and fine-grain cluster structure. In two sets of simulations where the relative lengths of excitory and inhibitory links are different we show that the emergence of clustered representations depends upon changes to this parameter.

Journal Article↗
PubMedDate not supplied

Nonphosphorylated neurofilament protein and calbindin immunoreactivity in layer III pyramidal neurons of human neocortex.

Subpopulations of pyramidal neurons in the neocortex have been shown to contain nonphosphorylated neurofilament protein (NPNFP) and calbindin D28K (Morrison et al., 1987; Campbell and Morrison, 1989; Hof et al., 1990; Kobayashi et al., 1990; Hof and Morrison, 1991; Mesulam and Geula, 1991). However, it is not known what relations, if any, exist between the pyramidal neurons containing each of these proteins. In this study, the expression of NPNFP and calbindin immunoreactivity was compared in six regions of human neocortex. Characteristic laminar patterns of immunoreactivity for each protein were seen in most regions examined, and both NPNFP- and calbindin-labeled pyramidal neurons were found in layer III. However, the pyramidal neurons labeled with NPNFP and calbindin differed in several respects. First, the sublaminar distribution of NPNFP-labeled pyramids within layer III differed across regions, ranging from an even distribution throughout the layer in a visual association region (area 18) to a predominance of labeled neurons in the deep half of that layer in a higher association region (area 20). The distribution of calbindin-immunoreactive pyramidal neurons also varied regionally, but in a different manner than that of the NPNFP-labeled neurons. Second, in every region examined, the average size of NPNFP-labeled layer III pyramids was greater than that of calbindin-immunoreactive pyramids. However, there was substantial regional heterogeneity in the extent to which the size distributions of neurons in each of the two populations overlapped. Third, in the regions in which NPNFP- and calbindin-immunoreactive neurons were most similar in size, the amount of colocalization (as identified by double-labeling studies) was also greatest. Similarly, in the regions in which there was minimal overlap in the size of the NPNFP- and the calbindin-immunoreactive neurons, there was minimal colocalization. These regional characteristics of NPNFP- and calbindin-immunoreactive layer III pyramidal neurons have implications for the involvement of these neuronal populations in Alzheimer's disease.

Adult↗
PubMedDate not supplied

Tetraethylammonium-induced synaptic plasticity in rat neocortex.

Recordings were obtained from neurons in layer II/III of slices of rat frontal cortex maintained in vitro. We investigated whether brief application of the potassium channel blocker tetraethylammonium (TEA), which induces a novel form of synaptic plasticity in the CA1 region of the hippocampus referred to as LTPK, evokes similar responses in neocortex. Consistent with previous findings, TEA produced a persistent enhancement of excitatory transmission, which was independent of NMDA receptor activation but required the activation of nifedipine-sensitive voltage-dependent Ca2+ channels (VDCC), presumably the L-type. We also observed a persistent enhancement of presumptive CI(-)-dependent GABAA receptor-mediated transmission. Enhancement of excitatory and inhibitory synaptic transmission did not require activation of synapses with electrical stimulation during TEA application. The enhancement of excitatory, but not inhibitory synaptic transmission, was blocked when the Ca2+ chelator 1,2-bis(2-aminophenoxy)-ethane N,N,N',N'-tetraacetic acid (BAPTA) was included in the recording electrode. Under voltage clamp conditions that minimized the activation of L-type channels robust enhancement of both excitatory and inhibitory transmission was still observed. No enhancement of excitatory synaptic transmission was observed in the presence of NiCl2, a putative T-type channel blocker. The possible involvement of kinase activation was studied by including the non-specific and competitive kinase inhibitor (+/-)-1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) in the patch pipette. H-7 retarded the time course and reduced the magnitude of the enhancement of excitatory transmission. These results suggest that TEA-induced enhancement of excitatory transmission in the neocortex requires entry of Ca2+ into the postsynaptic neuron via VDCCs and possibly the activation of a kinase.

Animals↗
PubMed1993

Neuronal and glial gene expression in neocortex of Down's syndrome and Alzheimer's disease.

The association cortex of Down's syndrome (DS) predictably and prematurely undergoes neurofibrillary degeneration of Alzheimer type. Hence studies of DS are potentially useful in defining the earliest pathogenetic events in Alzheimer's disease (AD). Previous reports have described altered expression of several mRNAs in AD cortex; but the pathogenetic stage at which expression of these mRNAs begins to deviate from the norm has not been defined. We have examined this issue in neocortex of DS. Expression of mRNAs, known to be altered in AD cortex, was studied by Northern analysis, comparing frontal cortex of DS (15-45 years) with age-matched controls and with AD. Chromosome 21- and non-21-encoded mRNAs were studied, including transcripts expressed preferentially in neurons (neurofilament light subunit and amyloid precursor transcripts) and in glia (glial fibrillary acidic protein [GFAP] and S100 beta). Chromosome 21-encoded mRNAs were increased in DS cortex as expected. Except in the DS case with extensive neurofibrillary degeneration, GFAP was expressed at levels significantly below the control, suggesting that trisomy 21 exerts a suppressive effect on GFAP gene expression. We found no instance in which AD-type changes of transcript expression preceded the appearance of neurofibrillary degeneration. The findings indicate that in trisomy 21, certain changes of mRNA prevalence previously described for AD neocortex are not a necessary antecedent to neurofibrillary degeneration.

Adolescent↗
PubMed1991

Chronic epileptic foci in neocortex: in vivo and in vitro effects of tetanus toxin.

Injection of 0.2 - 3.0 ng of tetanus toxin into rat parietal neocortex resulted in permanent (> 7 months) changes in the local circuit properties of this tissue. It caused excessive synchronization of neuronal activity. This was seen as spontaneous paroxysmal field potentials and/or evoked all-or-none population burst discharges. Such activity was recorded widely over the parietal and temporal areas of both the injected and the contralateral hemispheres from as little as 16 h after injection up to the maximum survival time of 7 months. Several observations suggest that the speed with which the hypersynchronous activity spread to the opposite hemisphere reflects transport of the toxin through corticocortical axons, and consequent blockade of synaptic inhibition. However, from what is known of the half life of the peptide in brain, it is unlikely that the persistent, widespread distribution of epileptiform discharge several months after injection was due to the continued presence of toxin. Thus, intracortical application of tetanus toxin provides a good experimental model of chronic focal epilepsies, and raises fundamental questions regarding the long term regulation of local circuit properties in the neocortex.

Journal Article↗
PubMed1987

Molecular forms of butyrylcholinesterase in the human neocortex during development and degeneration of the cortical cholinergic system.

The total levels of butyrylcholinesterase (BChE) activity and, more specifically, the distribution of BChE molecular forms were measured in the human neocortex during fetal development. Both the amount of total activity and the abundance of the different molecular forms (G1 and G4) remained relatively constant between gestational ages of 8-22 weeks and were similar to those observed in samples of cortex from aged brain. In addition, in both Alzheimer-type and parkinsonian dementia, the levels of total BChE activity as well as the relative abundance of the G1 and G4 molecular forms were similar to those observed in control tissue. Hence, both the levels of total activity and the distribution of molecular forms did not change significantly either during fetal development or in the neurodegenerative disorders of Alzheimer-type and parkinsonian dementias. Because these situations are accompanied by changes in the cortical cholinergic system (including an increase and decrease in levels of the G4 form of acetylcholinesterase, respectively), it is concluded that, at least in the human neocortex, BChE is unrelated to cholinergic neurotransmission associated with subcortical cholinergic projection fibres.

Aged↗
PubMed1993

Endogenous noradrenaline activates alpha 2-adrenoceptors on serotonergic nerve endings in human and rat neocortex.

Slices from human neocortex preincubated with [3H]serotonin ([3H]5-HT) were superfused and stimulated electrically to investigate whether the alpha 2-adrenoceptors on serotonergic terminals can be stimulated by endogenous noradrenaline (NA) released from neighboring noradrenergic fibers. The stimulation-evoked 3H overflow, representing action potential-induced, exocytotic release of 5-HT, was depressed by the NA uptake blocker (+)-oxaprotiline. Rauwolscine (a mixed alpha 2-adrenoceptor antagonist/5-HT autoreceptor agonist) or phentolamine [a combined alpha-adrenoceptor/5-HT autoreceptor antagonist; the latter drug in the presence of (+)-oxaprotiline] enhanced the release when the 5-HT autoreceptors had previously been blocked by metitepine. Under hypothermia the release of 5-HT was found to be decreased and that of NA to be increased; under these conditions idazoxan (an alpha 2-adrenoceptor antagonist) enhanced the release of 5-HT. In neocortex slices from rats (+)-oxaprotiline similarly depressed the release of 5-HT (measured with the same methods) as in human tissue. When rats were pretreated with 6-hydroxydopamine, the inhibitory effect of exogenous NA on 5-HT release was increased, and in slices from rats pretreated with desipramine, it was decreased. In conclusion, alpha 2-heteroreceptors can be activated by endogenous NA released from neighboring noradrenergic fibers. Because regulatory processes analogous to those in rats probably occur in humans as well, an up- or down-regulation of alpha 2-heteroreceptors in depressed patients with a (pathological) decrease or a (therapeutic) enhancement of the noradrenergic neurotransmission may also be assumed to occur.

Action Potentials↗
PubMed1988

Quinoxalinediones selectively block quisqualate and kainate receptors and synaptic events in rat neocortex and hippocampus and frog spinal cord in vitro.

1. Two quinozalinediones, FG9041 and FG9065, which had previously been shown to displace binding to the quisqualate receptor, were tested on rat neocortex and frog spinal cord in vitro against depolarizations induced by quisqualate, kainate and N-methyl-D-aspartate (NMDA). In both preparations effects of quisqualate were reduced the most and those of NMDA the least. 2. The near unitary slopes of the Schild plots were consistent with a competitive type of interaction. pA2 values for FG9041 were estimated to be 6.6, 6.1 and 5.1 in frog cord and 5.9, 5.3 and and about 4 in the rat neocortex for quisqualate, kainate and NMDA antagonism, respectively. FG9065 gave equivalent pA2 values of 6.2, 5.6 and 4.5. 3. At concentrations, which were without effect on depolarizations induced by NMDA, FG9041 and FG9065 reduced or blocked synaptically-evoked field potentials in hippocampal and neocortical slices superfused with normal magnesium-containing medium. Since these synaptic components are also insensitive to NMDA antagonists, these results are consistent with their mediation by postsynaptic receptors of the quisqualate (or kainate) type. 4. By contrast, quinoxalinediones had only limited effects on spontaneous epileptiform activity seen in both neocortical and hippocampal preparations when superfused with magnesium-free medium. These burst discharges were, however, abolished by NMDA antagonists. 5. In the frog spinal cord the early component of the dorsal root to ventral root reflexes was selectively reduced by FG9041 whereas NMDA antagonists reduced the longer latency components. 6. Our results suggest that the quinoxalinediones are likely to be useful pharmacological probes for elucidating the role of non-NMDA receptors in the vertebrate central nervous system.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMedDate not supplied

Excitatory amino acids modulate phosphoinositide signal transduction in human epileptic neocortex.

Stimulation of phosphoinositide (PI) hydrolysis by norepinephrine (NE), carbachol (Carb), and excitatory amino acids (EAAs) was measured in slices prepared from neocortex excised during epilepsy surgery. NE and Carb markedly enhanced PI turnover (EC50: NE, 12 microM; Carb, 661 microM) as reflected by [3H]inositol monophosphate (IP1) accumulation in tissue slices prelabeled with [3H]myoinositol. These effects were dose-dependent, saturable, and five to six times higher than basal IP1 accumulation. A weaker stimulation (twofold) was observed with quisqualate (QUIS; EC50, 1.1 microM) and glutamate (GLU; EC50, greater than 1 mM), while minimal or no stimulation was seen with kainate (KA) and N-methyl-D-aspartate (NMDA). Agonist-stimulated PI turnover was significantly reduced in samples from actively spiking epileptic neocortex versus nonspiking areas as defined by electrocorticography (NE, -23%, p less than 0.05; Carb, -44%, p less than 0.01). Preincubation of slices with various EEAs inhibited Carb-induced IP1 formation. The maximal extent of inhibition (1 mM) was both amino acid-dependent (IC50: NMDA, 5 microM; KA, 3.3 microM; QUIS, 47 microM; GLU, greater than 1 mM). These data suggest that epileptic activity modulates PI metabolism and alters receptor-effector coupling. As important mediators of epileptogenesis, EAAs may interfere++ with the efficiency of this second messenger system.

Carbachol↗
PubMed1986

Electrophysiological effects of monoamine-derived aldehydes on single neurons in neocortex and cerebellum in rats.

The electrophysiological effects of aldehydes derived from several monoamines were studied on single neurons in the cerebellum and neocortex of rats. The aldehydes derived from dopamine (3,4-dihydroxyphenylacetaldehyde) and serotonin (5-hydroxy-3-acetaldehyde) were prepared as stable disulfite complexes, from which free aldehydes were extracted. Serotonin and 5-hydroxy-3-acetaldehyde caused pronounced depression of firing rates both of cerebellar Purkinje neurons and neurons in prefrontal cortex. When locally applied from multibarrel micropipettes by pressure ejection, 5-hydroxy-3-acetaldehyde was twice as potent in the neocortex as in the cerebellum, and was equipotent with serotonin in both brain areas. The aldehyde of tryptamine also caused depressions of neuronal activity in cerebellum, but only at 5-fold higher doses than were effective for 5-hydroxy-3-acetaldehyde. 3,4-Dihydroxyphenylacetaldehyde was without effect in prefrontal cortex, but had mixed responses in the cerebellum. The results show that monoamine-derived aldehydes are physiologically active. It is possible that changes in the steady state level of these aldehydes caused by drugs such as ethanol and barbiturates might influence the electrophysiological properties of neurons in the central nervous system.

3,4-Dihydroxyphenylacetic Acid↗