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PubMed1996

Nitric oxide-stimulated increase in intracellular cGMP modulates gap junction coupling in rat neocortex.

In the present study we demonstrate that gap junction coupling between developing layer II/III pyramidal cells in rat sensorimotor cortex is strongly modified by the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) system. Dye coupling was revealed by intracellular injection of the gap junction-permeable tracer neurobiotin into single neurones. Following incubation of slices with sodium nitroprusside, a source of NO, the size of dye-coupled cell clusters was significantly reduced. In many cases, 2-3 cells remained strongly dye-coupled. These effects were blocked by intracellular injection of the guanylyl cyclase inhibitor cystamine and mimicked by both application of the membrane-permeant cGMP analogue 8-Br-cGMP and intracellular injection of cGMP. cGMP injection also induced a 60% increase in neuronal input resistance. These results indicate that NO modulates gap junction coupling in the developing neocortex via stimulation of guanylyl cyclase.

Animals↗
PubMed1996

Developmental neuropathology and impact of perinatal brain damage. I: Hemorrhagic lesions of neocortex.

To establish developmental correlates among perinatal neocortical damage, its impact on the infant developing brain, and its possible role in the pathogenesis of ensuing neurologic sequelae, the neuropathology of acute, subacute (healing), and chronic (repaired) stages of periventricular and layer I (subpial) hemorrhagic lesions have been studied. Thirty-three cases of infants who survived brain damage for hours, days, weeks, months, and/or years and have been studied with the rapid Golgi and other methods. In periventricular hemorrhagic injury: (a) the local destruction of radial glia stop all cellular migration above the lesion; (b) precursor cells already traveling in damaged radial glia also stop their migration, miss their target, and form acquired heterotopias; and, (c) the cytoarchitecture of the overlying and differentiating gray matter may be secondarily altered. In layer I (subpial) hemorrhagic injury: (a) the neocortex external glial limiting membrane is disrupted and must be repaired; (b) its reparation often causes superficial leptomeningeal heterotopias; (c) the cytoarchitecture and intrinsic circuitry of layer I and underlying gray matter are secondarily altered; and, (d) partially damaged (pruning) and/or displaced gray matter neurons undergo post-injury morphologic transformations, atrophy, hypertrophy, and reestablished new "abnormal" connections. These post-injury gray matter cytoarchitectural alterations could eventually play a role in cortical dysfunction and, hence, in the pathogenesis of neurologic sequelae.

Adolescent↗
PubMed1996

Intraischemic hypothermia attenuates neutrophil infiltration in the rat neocortex after focal ischemia-reperfusion injury.

OBJECTIVE: The mechanisms by which hypothermia influences postischemic outcome remain a matter of discussion. One mechanism thought to play an important role in neuronal damage after ischemia/reperfusion is the accumulation of polymorphonuclear leukocytes in compromised brain tissue. To better understand the potential impact of hypothermia on this injurious mechanism, the present study examined the effect of intraischemic hypothermia on polymorphonuclear leukocyte accumulation after transient focal ischemia. METHODS: The effect of intraischemic hypothermia (30 degrees C) on the accumulation of polymorphonuclear leukocytes was quantified by measuring myeloperoxidase (MPO) activity in the neocortex of Sprague-Dawley rats. Reversible focal ischemia was created by subjecting rats to temporary occlusion of the left middle cerebral artery and both carotid arteries for 3 hours; animals were killed 24 hours after reperfusion. RESULTS: Normothermic animals exhibited significantly greater MPO activity in the infarction core (P < 0.05) and the pericore areas (P < 0.05), compared with corresponding areas in sham-operated animals. Hypothermic animals exhibited significantly greater MPO activity in the core (P < 0.05) but not in the pericore region, compared with sham-operated animals. MPO activity in the pericore region of the hypothermic group was significantly less than that observed in the corresponding region of the normothermic group (P < 0.01). In addition, the total volume of cerebral infarction was reduced by 59% in the hypothermic group. CONCLUSION: These findings demonstrate that intraischemic hypothermia attenuates the inflammatory response to transient focal ischemia in the pericore region, i.e., the region spared from infarction under hypothermic conditions. The findings raise the possibility that a reduction in the inflammatory response after ischemia/reperfusion contributes to the neuroprotective effects of hypothermia.

Animals↗
PubMed1975

Network analysis of dendritic fields of pyramidal cells in neocortex and Purkinje cells in the cerebellum of the rat.

The connectivity within the dendritic array of Purkinje cells in the cerebellum and pyramidal cells of the neocortex of the rat, stained by the Golgi-Cox method, has been quantified by the method of network analysis. Connectivity was characterized either by applying the system of Strahler ordering, which assigns a relative order of magnitude to each branch of the arborescence or by the identification of unique topological branching patterns within the tree. The former method has been used to define the entire dendritic array of the Purkinje cell and the apical system of neocortical pyramids. It has been shown that the relation between the numbers of branches of successive Strahler order in Purkinje cells form an inverse geometric series in which the highest order is unity and the ratio between successive orders approximates to 3. On the other hand, the apical dendrites of neocortical pyramids exhibit two bifurcation ratios, i.e. a ratio of 3 between low orders and a ratio of 4 between higher orders. A computer simulation technique was used to generate networks of a size comparable with the Purkinje cell networks and grown according to two hypotheses namely, a 'terminal growth model' in which additional segments were added randomly to the terminal branches only and a 'segmental growth model' in which additional segments were added randomly to any branch within the array including terminal branches. Subsequent ordering of the simulated trees revealed that the relation between the numbers of successive orders for networks generated according to the 'segmental model' tended towards an inverse geometric series with a ratio of 4 and that generated according to the 'terminal model' tended towards a ratio of 3. This result showed that the dendritic tree of Purkinje cells grow in a manner indistinguishable from a system adding branches to random terminal segments and that neocortical apical dendrites add their collateral branches to random segments of the apical shaft but that the collateral branches themselves grow by random terminal branching. The possibility that such conclusions may be influenced by loss of branches incurred by either a failure of impregnation, by sectioning, or by environmental influences was investigated by means of a computer technique...

Animals↗
PubMedDate not supplied

Fibre disorganization in the neocortex of patients with senile dementia of the Alzheimer type.

The loss of neurons, which is thought to occur during senile dementia of the Alzheimer type, could alter the fibre organization of the neocortex. In the present study, the density and course of the fibres were measured in histological sections in 14 cases: all were women over 75 years of age who had been living in a long-stay hospital and had been prospectively assessed by the test score of Blessed et al. (1968). Their intellectual status ranged from nearly normal to severely demented. Samples from the supramarginal and prefrontal gyri were studied after Bodian's impregnation. The course of the fibres in 3-dimensional space was determined by two angles: (a) the angle which characterized their orientation in the plane of section and discriminated between horizontal (tangential), vertical (radial) and oblique fibres and (b) the angle of section with which the fibres were cut. The total density of fibres correlated neither with the test score nor with the density of neurofibrillary tangles or senile plaques. The percentage of obliquely orientated fibres and of fibres with a high sectioning angle increased in the course of the disease. This increase was mainly at the expense of the horizontal fibres in the supramarginal gyrus and could be explained by the presence of a great number of small, tortuous and abnormally orientated fibres (kinked fibres) in the most severely affected cases. The methodology employed in this study could be useful in the investigation of fibre architecture in other diseases involving the cerebral cortex.

Aged↗
PubMed1983

The production of T-cell-inducing factors in mice is controlled by the brain neocortex.

The synthesis of factors that monitor the expression of the Thy-1 cell surface component by marker-negative precursor cells requires an intact left cerebral cortex, whereas the activity of sodium diethyldithiocarbamate, an immunopotentiator that increases this synthesis, seems to require an intact right neocortex. These results suggest a role for the cerebral cortex in the coordinated interregulation of lymphocyte subclasses. The finding extends previous information suggesting relationships between the central nervous system and the T-cell arm of the immune system.

Animals↗
PubMed1989

Intracellular Calcium and Control of Burst Generation in Neurons of Guinea-Pig Neocortex in Vitro.

Response properties of neurons in brain slices of guinea pig parietal neocortex were examined following intracellular injection of the Ca2+ chelators, EGTA and BAPTA. Although chelator injection did not cause any consistent change in passive membrane properties, it did induce 81% of neurons encountered at all sub-pial depths to become 'bursters', in that just-threshold depolarizing current pulses triggered all-or-none bursts of 2 - 5 fast action potentials. Transition to 'burstiness' was associated with disappearance of an AHP and appearance of a DAP. Although chelator caused a slight increase in steady-state firing rate, marked accommodation persisted. Extracellular Co2+ or Mn2+ had an effect on steady-state firing rate similar to that of the intracellular chelators; however, exposure to these Ca2+ channel blockers also caused steady state depolarization, increased resting input resistance and time constant, and profound spike broadening. This treatment never induced transition to 'burstiness'. Chelator-injected neurons ceased to generate bursts when Ca2+ was replaced by Mn2+ in the Ringer's solution. During exposure to 10-6 M TTX and 20 mM TEA, 50 - 200 msec Ca2+ spikes followed brief depolarizing pulses. As chelator was injected into the cell, there was progressive prolongation of the Ca2+ plateaus, which was associated with slowing of the rate at which membrane resistance gradually recovered following the initial increase in conductance. These findings indicate that under normal conditions, activity-related increases in intracellular Ca2+ activate processes which prevent most neocortical neurons from being bursters. These processes probably include Ca2+-dependent K+ currents, and Ca2+-dependent Ca2+ channel inactivation.

Journal Article↗
PubMed1991

The Effect of Calcium Channel Antagonists on Spontaneous and Evoked Epileptiform Activity in the Rat Neocortex In Vitro.

Calcium influx through voltage-activated calcium channels may play a crucial role in the propagation and maintenance of seizure activity. We have examined the contribution of various types of calcium currents to epileptogenesis by studying the effects of various calcium channel blockers on epileptiform activity. N-methyl-d-aspartate receptor-mediated epileptiform activity was induced by removal of magnesium ions superfusing the cortex, or by low-frequency stimulation of the underlying white matter. CoCl2, CdCl2 and omega-conotoxin, acting at the N- and L-type calcium channels, significantly reduced epileptiform activity. L-channel antagonists nifedipine and verapamil, and the agonist BAY K 8644, increased spontaneous bursting in cortical wedges, but had no effect upon evoked activity. The T-channel blocker NiCl2 had variable effects on epileptiform activity, whereas phenytoin consistently reduced such activity. These results suggest that calcium influx underlying epileptiform activity in the rat neocortex may occur at least partially via the activation of the N-type calcium channel. However, contributions from other calcium channel types cannot be excluded.

Journal Article↗
PubMed1993

The contribution of intracortical connections to horizontal spread of activity in the neocortex as revealed by voltage sensitive dyes and a fast optical recording method.

Coronal slices from guinea-pig visual neocortex were stained with voltage-sensitive fluorescence dyes RH414 or RH795. Activity was evoked by electrical stimulation of either the white matter or layer I. Emitted light intensity changes representing summated changes of membrane potential were recorded by a 10 x 10 photodiode array with a temporal resolution of 0.4 ms and a spatial resolution of 94 microns. The distribution and spread of activity in the horizontal direction was analysed. Following stimulation of the white matter or layer I, two regions of activity were differentiated in the medio-lateral direction: a central region (approximately 1 mm wide) of high-amplitude activity close to the stimulation electrode and, distant from the stimulation electrode, peripheral regions of low-amplitude activity. Central and peripheral regions differed in their rates of decline, their relative extent with stimulation of different sites and within different layers. The total extent of non-synaptic evoked activity did not exceed that of the central region of high-amplitude activity. Along the extent of non-synaptic activity, onset latencies of potentials were almost constant. Thus, activity of high amplitude in the central region was likely mediated by simultaneous activation of distributed afferent fibres. In contrast, no non-synaptic activity was found in peripheral regions. Therefore it is suggested that this low-amplitude activity was mediated without direct afferent activation but via long-distance intracortical horizontal pathways. These pathways are known to terminate in layer III, and accordingly latencies of responses in the periphery were shortest in upper cortical layers, whereas in the central region, latencies increased from lower to upper cortical layers.

Animals↗
PubMed1995

Ischaemia-induced long-term hyperexcitability in rat neocortex.

The long-term structural and functional consequences of transient forebrain ischaemia were studied with morphological, immunohistochemical and in vitro electrophysiological techniques in the primary somatosensory cortex of Wistar rats. After survival times of 10-17 months postischaemia, neocortical slices obtained from ischaemic animals were characterized by a pronounced neuronal hyperexcitability in comparison with untreated age-matched controls. Extra- and intracellular recordings in supragranular layers revealed all-or-none long-latency recurrent responses to orthodromic synaptic stimulation of the afferent pathway. These responses were characterized by durations up to 1.7 s, by multiple components and by repetitive synaptic burst discharges. The reversible blockade of this late activity by DL-amino-phosphonovaleric acid (APV) suggested that this activity was mediated by N-methyl-D-aspartate (NMDA) receptors. The peak conductance of inhibitory postsynaptic potentials was significantly smaller in neurons recorded in neocortical slices obtained from ischaemic animals than those from the controls. However, the average number of parvalbumin (PV)-labelled neurons per mm3, indicative of a subpopulation of GABAergic interneurons, and the average number and length of dendritic processes arising from PV-containing cells was not significantly different between ischaemic and control cortex. The prominent dysfunction of the inhibitory system in ischaemic animals occurred without obvious structural alterations in PV-labelled cells, indicating that this subpopulation of GABAergic interneurons is not principally affected by ischaemia. Our data suggest a long-term down-regulation of inhibitory function and a concurrent NMDA receptor-mediated hyperexcitability in ischaemic neocortex. These alterations may result from structural and/or functional properties of inhibitory non-PV-positive neurons or permanent functional modifications on the subcellular molecular level, i.e. alterations in the phosphorylation status of GABA and/or NMDA receptors. The net result of these long-term changes is an imbalance between the excitatory and inhibitory systems in the ischaemic cortex with the subsequent expression and manifestation of intracortical hyperexcitability.

Animals↗
PubMed1997

Chondroitin/dermatan sulphate promotes the survival of neurons from rat embryonic neocortex.

Recently we have shown that biglycan, a small chondroitin sulphate proteoglycan of the extracellular matrix, supports the survival of cultured neurons from the developing neocortex of embryonic day 15 rats. Here we investigate the structure-function relationship of this neurotrophic proteoglycan and show that chondroitin/dermatan sulphate chains are the active moieties supporting survival. Heparin, a highly sulphated glucosaminoglycan, is less active than the galactosaminoglycans (chondroitin-4-sulphate, chondroitin-6-sulphate and dermatan sulphate), whereas hyaluronic acid, an unsulphated glucosaminoglycan, does not support neuron survival. Galactosaminoglycans must be in direct contact with neurons to cause survival. Experiments with elevated potassium concentrations and antagonists of voltage-gated calcium channels exclude the involvement of membrane depolarization. However, genistein and an erbstatin analogue, which are inhibitors of tyrosine kinases with low specificity, abolished neuron survival in the presence of chondroitin/dermatan sulphate, whereas a selective inhibitor of neurotrophin receptor kinases (K252a) had no suppressive effect. Thus, yet unidentified tyrosine kinases are involved in the chondroitin/dermatan sulphate-dependent survival of neocortical neurons. In the embryonic stages of rat neocortical development chondroitin sulphate is mainly located in layers I, V and VI and the subplate. Chondroitin sulphate expression is maintained after birth, extends up to cortical layer IV on postnatal day 7, and is down-regulated until postnatal day 21 concomitant with the period of naturally occurring cell death. The latter observation is consistent with a putative role of chondroitin sulphate in the control of neuron survival during cortical histogenesis.

Animals↗
PubMed1997

Relations between long-term synaptic modifications and paired-pulse interactions in the rat neocortex.

The phenomenon of paired-pulse facilitation (PPF) was exploited to investigate the role of presynaptic mechanisms in the induction and maintenance of long-term synaptic plasticity in the neocortex. Long-term potentiation (LTP) and depression (LTD) were induced without afferent activation by applying tetani of intracellular pulses. Our results show that synaptic modifications closely resembling LTP and LTD can be induced by postsynaptic activation alone. The polarity of these synaptic modifications depends on initial properties of the input, as indicated by a correlation between initial PPF ratio and post-tetanic amplitude changes: inputs exhibiting strong PPF, which might be associated with low release probability tend to be potentiated, while inputs with small PPF are more likely to show depression. Maintenance of both LTP and LTD involve presynaptic mechanisms, as indicated by changes in PPF ratios and in failure rate after LTP or LTD induction. Presynaptic mechanisms could include changes in release probability and/or in the number of active release sites. Because induction was postsynaptic, this supports the notion of a retrograde signal. The relative contribution of pre- and postsynaptic mechanisms in the maintenance of long-term synaptic modifications depends on the initial state of the synaptic input and on LTP magnitude. PPF changes were especially pronounced in inputs which had initially high PPF and underwent strong potentiation. Since LTP and LTD are associated with changes of PPF ratios these synaptic modifications do not only alter the gain but also the temporal properties of synaptic transmission. Because of the LTP associated reduction of PPF, potentiated inputs profit less from temporal summation, favouring transmission of synchronized, low frequency activity.

Animals↗
PubMed1983

Metabolic processes in Alzheimer's disease: adenine nucleotide content and production of 14CO2 from [U-14C]glucose in vitro in human neocortex.

Samples of neocortex removed at diagnostic craniotomy from patients with Alzheimer's disease and incubated in vitro showed an increased production of 14CO2 from [U-14C]glucose compared with neurosurgical controls. This was a feature of incubations in the presence of both 5 mM K+ (142% control) and 31 mM K+ (126%). Specific labelling of the amino acid pool was unaltered, suggesting that the apparent increase of CO2 production was not merely a reflection of changes in dilution of the radiolabel from glucose. The content of adenine nucleotides was significantly less than control values in the tissue from patients with Alzheimer's disease after in vitro incubations but the adenylate energy charge was unchanged, indicating that normal energy metabolism was not grossly impaired in these preparations.

Acetylcholine↗
PubMed1988

A quantitative pharmacological analysis of some excitatory amino acid receptors in the mouse neocortex in vitro.

1. The effects of 2-amino-5-phosphonovalerate and kynurenate, either alone or in combination, were tested on responses evoked by the excitatory amino acid agonists quinolinate, ibotenate, N-methyl-D-aspartate and N-methyl-DL-aspartate by use of an in vitro preparation of mouse neocortex and artificial cerebrospinal fluid nominally free of magnesium. 2. Schild plots for 2-amino-5-phosphonovalerate, using each of the excitatory amino acids, were linear and had a slope not significantly different from one. The apparent pA2 values for 2-amino-5-phosphonovalerate using each of the excitatory amino acids were 4.98 (quinolinate), 5.00 (N-methyl-DL-aspartate), 4.92 (N-methyl-D-aspartate) and 5.05 (ibotenate). The apparent pA2 obtained using ibotenate was distinct from that of N-methyl-D-aspartate but there were no significant differences between pA2 estimates for quinolinate, N-methyl-D-aspartate or N-methyl-DL-aspartate. 3. Schild plots for kynurenate, using each of the excitatory amino acids, were linear and had a slope of 1.36 +/- 0.03, significantly greater than one. The estimated apparent pA2 values for kynurenate were 3.65 (quinolinate), 3.71 (N-methyl-DL-aspartate), 3.65 (N-methyl-D-aspartate) and 3.89 (ibotenate). The apparent pA2 obtained using ibotenate was distinct from that of the other agonists. 4. Experiments using combinations of 2-amino-5-phosphonovalerate and kynurenate indicated that both antagonists apparently acted competitively at receptors activated by ibotenate or by quinolinate. 5. These results indicate that ibotenate acts at a site distinct form that of quinolinate, N-methyl-D-aspartate and N-methyl-DL-aspartate.

2-Amino-5-phosphonovalerate↗
PubMed1990

Anaesthetic suppression of transmitter actions in neocortex.

1. The effects of general anaesthetics were investigated on neuronal sensitivities to transmitter substances, which were determined by iontophoretic applications of acetylcholine, glutamate, N-methyl-D-aspartate (NMDA) and gamma-aminobutyrate (GABA) during intracellular recording in in vitro slice preparations of neocortex (guinea-pig). 2. In most of the 65 neurones studied, perfusion of isoflurane (0.5-2.5 minimum alveolar concentration (MAC)) or Althesin (25-200 microM) and, in some cases, halothane (0.5-2 MAC), markedly reduced the depolarizing responses and associated membrane conductance changes evoked by dendritic applications of acetylcholine, glutamate, NMDA and GABA. 3. The order of depression was acetylcholine greater than glutamate or NMDA much greater than GABA. This selectivity could also be assessed from the EC50 for the isoflurane-induced depression of the just-maximal responses to acetylcholine, which was 0.9 MAC compared with an EC50 = 1.9 MAC for the suppression of glutamate responses. The selectivity was less pronounced in the case of the actions of Althesin, where the EC50s were 75 microM for the depression of acetylcholine responses and 90 microM for the depression of glutamate responses. 4. The hyperpolarizing responses observed when GABA was applied near the perikaryon in 7 neurones, were slightly reduced (approximately 15%) in 4, and unchanged in 3 neurones during anaesthetic application. 5. The pronounced depression of the responsiveness to the putative arousal transmitters and an observed blockade of acetylcholine-induced potentiation of glutamate actions suggest that anaesthetics produce unconsciousness, at least in part, by interfering with subsynaptic mechanisms of neocortical activation.

Acetylcholine↗
PubMed1975

Epileptogenic effects of several penicillins and penicillin-related compounds in rat neocortex.

Several penicillins and penicillin-related compounds were tested for their ability to produce epileptiform activity in rat neocortex. (1) Alterations in the side chain of penicillin G decreased epileptogenic capability in all the compounds tested in this study: Phenoxymethylpenicillin produced a primary focus but no mirror focus, suggesting a dissociation of the mechanisms underlying these two processes. Ampicillin, 6-aminopenicillanic acid, and potassium 6-aminopenicillanic acid, and potassium 6-aminopenicillanic acid produced little or no epileptiform activity. All these compounds have free amino grounds and are amphoteric. (2) Breaking the beta lactam ring of penicillin G (potassium penicillin G penicilloate) eliminated epileptogenic capability. (3) Potassium salts of penicillin or its derivatives (potassium penicillin G, propicillin, potassium 6-aminopenicillanic acid, potassium penicillin G penicilloate) consistently suppressed cortical activity, regardless of the ability of the compound to produce spike discharges. Thus, mechanisms underlying these two properties can be dissociated. (4) Antibiotic activity of penicillins bears no relationship to epileptogenic capability.

Ampicillin↗
PubMed1980

Mechanisms of interaction of asymmetrical bilateral epileptogenic foci in neocortex.

The mechanisms of interaction of bilateral asymmetrical foci on cat neocortex were studied with varying concentrations of the epileptogenic agent and with callosal splitting and cortical-callosal isolation. When epilepsy was severe, a facilitatory interaction occurred. This was the result of two opposing mechanisms simultaneously operating, namely a transcallosal inhibitory mechanism and a predominant facilitatory subcortical mechanism. When epilepsy was less intense, subcortical structures were not involved and only the inhibitory transcallosal mechanism was at work, leading to an inhibitory interaction. The conclusion is put forward that two asymmetrical cortical foci do not necessarily interact in only one simple way. Their type of interaction (facilitatory or inhibitory) depends on the pathways involved in the interaction and this, in turn, depends on the severity of epilepsy.

Animals↗
PubMed1997

Synaptogenesis, heterochrony and epigenesis in the mammalian neocortex.

In the neocortex of the macaque monkey we have identified and described quantitatively five different phases of synaptogenesis and related them to its functional maturation. In all the cortical areas observed so far, the most rapid phase of synaptogenesis occurs within a time-window of only 40 days, centred on birth. The modifiability of phase 3 has been tested by bilaterally equilibrated stimulation or deprivation, using experimentally obtained preterm or blind monkeys. Our developmental and experimental observations, as well as phylogenetic comparisons, strongly suggest that the timing and rate of production of synapses during phase 3 are determined by mechanisms that are both intrinsic and common to the whole cortical mantle but can be modified epigenetically later on.

Animals↗