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Modulation of epileptiform activity by metabotropic glutamate receptors in immature rat neocortex.

1. Intracellular and extracellular recordings were obtained from neocortical brain slices of immature rats (postnatal days 9-16) maintained in vitro. Spontaneous and evoked epileptiform discharges (termed paroxysmal depolarizing shifts or PDSs) were recorded from upper cortical laminae (layers II-III) after exposure to the gamma-aminobuturic acid-A receptor antagonist, bicuculline methiodide. The effects of mGluR activation on PDS duration, spontaneous frequency, and threshold for evoking a PDS were determined. Putative mGluR agonists and antagonists also were tested. 2. Bath application of the mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD, 50-200 mM) elicited biphasic, time-dependent effects on evoked and spontaneous epileptiform discharges. At times early in drug wash-in, ACPD increased PDS duration and spontaneous PDS frequency. In > 60% of the slices, the spontaneous PDSs became regular. Subsequently, ACPD reduced PDS duration and increased the stimulus threshold for evoking a PDS, suggesting that the actions of ACPD were dose dependent. 3. Investigation of the concentration-dependence revealed that sustained low ACPD concentrations (5 microM) elicited only facilitatory actions, whereas higher concentrations were suppressive. These observations suggest the activation of different mGluR subtypes, which may be localized differentially at pre- and postsynaptic sites. 4. Bath application of the mGluR agonists, L-2-amino-4-phosphonobutyrate or (2S,3S,4S)-alpha-(carboxycyclopropyl) glycine, produced only suppressive effects on epileptiform activity in the immature neocortex. L-2-amino-3-phosphonopropionate was an ineffective antagonist of ACPD-mediated modulation of epileptiform activity. Application of the putative antagonist, alpha-methyl-4-carboxyphenylglycine (MCPG), failed to antagonize the biphasic actions of ACPD. MCPG had suppressive effects of epileptiform activity, suggesting activation of mGluRs by endogenous agonists. 5. Simultaneous recordings from deeper and upper cortical layers indicated that the initial negativity of both evoked and spontaneous PDSs began in deeper cortical layers under control conditions and in the presence of ACPD. Intracellular records from neurons in deeper layers displayed two distinct patterns of activity during mGluR activation. Most deep layer neurons received a barrage of excitatory postsynaptic potentials before a spontaneous PDS during ACPD application. A small population of neurons depolarized and entered a tonically firing mode, which was interrupted by spontaneous PDSs. Different neuronal populations, possible expressing different mGluR subtypes or coupling mechanisms, may play integral roles in the induction and generation of epileptiform activities. 6. Thapsigargin or dantrolene, agents thought to block release of Ca2+ from intracellular stores, were both applied for periods < or = min.(ABSTRACT TRUNCATED AT 400 WORDS)

6-Cyano-7-nitroquinoxaline-2,3-dione↗

Inhibitory control of excitable dendrites in neocortex.

1. Many dendrites of pyramidal cells in mature neocortex express active Na+ and Ca2+ conductances. Dendrites are also the target of numerous inhibitory synapses. We examined the interactions between the intrinsic excitability of dendrites and synaptic inhibition using whole cell recordings from the apical dendrites of layer 5 pyramidal cells. Experiments were performed on slices of somatosensory cortex from mature rats. Slices were bathed in the glutamate receptor antagonists 2-amino-5-phosphonopentanoic acid and 6,7-dinitroquinoxaline-2,3-dione, and maintained at 32-36 degrees C. 2. In agreement with previous findings, intradendritic current injection evoked two distinct types of dendritic firing. Type I dendrites generated monophasic fast spikes, whereas type II dendrites showed more complex firing patterns, consisting of fast and slow spike components. 3. Stimulation of cortical layers 2/3 evoked fast inhibitory postsynaptic potentials (IPSPs) in all dendrites tested. IPSP reversal potentials were bimodally distributed, with means of about -53 and -85 mV when recorded with high-Cl(-)-concentration-filled electrodes. Interestingly, IPSP reversal potentials were correlated with the type of dendritic spiking pattern. 4. IPSPs were able to delay, completely block, or partially block spiking in dendrites, depending on the relative timing between inhibition and dendritic spiking. Slow, Ca(2+)-dependent spike components could be blocked selectively by IPSPs. Furthermore, inhibition could either phase advance or phase delay repetitive patterns of dendritic spiking, depending on the timing of the IPSP.

Animals↗

Recovery cycle of the cerebral neocortex: preliminary observations in epileptic patients.

The recovery cycle of the amplitude of the potential evoked in the cerebral neocortex by paired electrical stimuli of the underlying white matter was studied in 5 epileptic patients with intracerebral electrodes chronically implanted stereotactically. A reproducible pattern was apparent for the late components of the potential (i.e., the peak-to-peak amplitude between the second and the third peak, with an average peak latency of 14 and 35 ms, respectively). There was an early period of facilitation (5-10 ms interstimulus interval) followed by a period of relative or absolute depression (20-100 ms) with recovery at an interstimulus interval of about 150 ms. The recovery function of the early components of the potential (i.e., the peak-to-peak amplitude between the first and the second peak, with an average peak latency of 6 and 14 ms, respectively) was variable; recovery was reached at about 150 ms. The responsiveness seemed less in the most epileptogenic cortical areas.

Afferent Pathways↗

Distribution of iron in the basal ganglia and neocortex in postmortem tissue in Parkinson's disease and Alzheimer's disease.

Post-mortem tissue was obtained from subjects with Parkinson's disease (PD), Alzheimer's disease (AD) and age-matched controls. Iron levels were measured from various sites of the basal ganglia and neocortex using atomic absorption spectrophotometry. The results indicate that iron levels are increased in the substantia nigra and the lateral segment of the globus pallidus of parkinsonian tissue. In contrast, the medial segment of the globus pallidus shows reduced iron levels in AD when compared to age-matched controls. No significant alterations of iron concentration were detected in AD in any region. These results are discussed in terms of the role of iron in the basal ganglia, mechanisms of abnormal deposition and possible neurotoxicity in PD.

Aged↗

Synaptogenesis in the neocortical anlage and early developing neocortex of rat embryos.

The recent finding of synapses in Monodelphis domestica (South American grey short-tailed opossum) before the establishment of the cortical plate raises the question of whether this finding is species-specific. Therefore, the establishment of the first synapses in the developing neocortex has been studied in the sensorimotor cortex of rat fetuses with a gestational age ranging from embryonic day 12 (E12) to birth. At E14, we found well-defined synapses with postsynaptic thickening and containing several vesicles in the presynaptic element in the primordial plexiform layer, before the appearance of the cortical plate. The postsynaptic elements were probably dendrites of Cajal-Retzius cells in the primordial plexiform layer and/or differentiating dendrites of presumptive cortical plate neurons. At E16, in addition to the presence of axodendritic and very few axosomatic synapses in the marginal and the subplate zones, synapses of both types were present within the cortical plate. Thus, this paper provides evidence for the presence of synapses in the developing rat brain both at an earlier stage and with a wider distribution than previously reported.

Animals↗

Prostaglandin secretion by the neocortex and fetal zones of the human fetal adrenal gland.

Previously, we reported that the human fetal adrenal (HFA) gland secretes various prostaglandins (PGs) in vitro and that PG secretion is inhibited by endogenously synthesized glucocorticosteroids. In this investigation, the neocortex (NC) and fetal zone (FZ) of the HFA gland were separated by microdissection and maintained as tissue fragments in organ culture. The rate of PG secretion into the culture medium was determined by measuring various PGs using specific RIAs in media collected at 24-h intervals. During the first 24 h in culture, the secretion rates of PGF2 alpha and PGE2 were 6- and 7-fold greater by NC [14 +/- 5 and 9.9 +/- 3 ng mg protein-1 24 h-1 (mean +/- SE)], respectively, than by FZ tissue (2.5 and 1.4 ng mg protein-1 24 h-1). The secretion rates of PGFM and PGD2 were 2-fold greater in NC tissue than in FZ tissue, but the secretion rates of thromboxane B2 were similar in both zones of HFA tissue. In another study, the patterns of secretion of PGF2 alpha and PGE2 were determined as a function of days in culture. The secretion rates of PGF2 alpha and PGE2 fell rapidly in NC from 19.0 +/- 11 and 38.3 +/- 9.7 ng mg protein-1 24 h-1, respectively, to 1.3 +/- 7.2 and 4.8 +/- 3.3 by day 4. In contrast, the secretion rates of PGF2 alpha and PGE2 rose 8- and 3-fold in FZ tissue (from 0.7 +/- 0.2 and 0.9 +/- 0.6 ng mg protein-1 24 h-1, respectively, to 5.9 +/- 0.5 and 3.1 +/- 1.2 by day 4). The addition of ACTH or dexamethasone inhibited PG secretion in both zones, but to a greater degree in FZ tissue than in NC tissue. In summary, the NC secretes larger quantities of PG than the FZ, and the patterns of secretion are different in the two zones. The secretion of PGs is inhibited more in FZ than in NC tissue by ACTH and glucocorticosteroids.

Adrenal Glands↗

Adenylate cyclase activity in neocortex and fetal zone membrane fractions of the human fetal adrenal gland.

Whether peptide hormones other than ACTH may be responsible for the difference in size or rate and pattern of steroidogenesis of the fetal zone (FZ) compared to those of the neocortex (NC) of the human fetal adrenal gland is controversial. In the present investigation, the activity of adenylate cyclase in membrane fractions of separated zones of the human fetal adrenal gland was determined. Basal adenylate cyclase activity was 2- to 3-fold greater in NC than in FZ membrane fractions. The addition of ACTH-(1-24) stimulated adenylate cyclase activity in both zones, but the activity was more sensitive to ACTH (10(-10) M) in NC fractions than in FZ fractions (10(-7) M). In addition to ACTH-(1-24), the effect of other ACTH-related peptides on the activity of adenylate cyclase in the separated zones of the adrenal gland was investigated. 16K fragments 2-36, gamma 3MSH, alpha MSH, beta-endorphin, leu-enkephalin, and met-enkephalin, as well as hCG, FSH, prostaglandin E2, prostaglandin F2 alpha, epinephrine, and norepinephrine did not stimulate adenylate cyclase activity in either zone. It is concluded that basal and ACTH-(1-24)-stimulated adenylate cyclase activities are greater in NC than in FZ membrane fractions. In addition, the results of the present investigation do not support the concept that other ACTH-related peptides or peptide or protein hormones increase steroidogenesis by stimulating adenylate cyclase activity in the human fetal adrenal gland.

Adenylyl Cyclases↗

A case of Alzheimer's disease and hippocampal sclerosis with normal cholinergic activity in basal forebrain, neocortex, and hippocampus.

A 76-year-old man without apparent dementia met pathologic criteria at autopsy for Alzheimer's disease, which included a maximum senile plaque density greater than 15 per square millimeter of neocortex. Despite hippocampal sclerosis, changes typical of Alzheimer's disease were not found in this region or in basal forebrain. Choline acetyltransferase activity in hippocampus, septum, and parietal cortex was normal.

Aged↗

Quantitative synaptic alterations in the human neocortex during normal aging.

We quantified the synaptic population density in the frontal cortex of 25 individuals without dementia 16 to 98 years old, using sections double-immunolabeled for beta/A4 amyloid and for synaptophysin, and found a significant inverse correlation between the presynaptic terminal (PT) counts and age (r = -0.7, p < 0.001). Individuals older than 60 years had an average 20% decrease in PT density compared with individuals younger than 60 years. There were no significant correlations between the age and the number of beta/A4 amyloid-positive plaques or between synaptic density and the number of amyloid plaques. Further analysis of the digitized serial optical images showed focal areas of synapse loss and distended synaptophysin-containing boutons in the mature plaques of the normal aged cases. However, we found no microscopic changes in the synaptic content inside and outside the diffuse plaques. We suggest that a loss of synaptic input in the neocortex is an age-dependent factor that contributes to the overall synaptic loss in Alzheimer's disease, but that this might be largely independent of the beta/A4-amyloid deposition.

Adolescent↗

A role for subplate neurons in the patterning of connections from thalamus to neocortex.

During cerebral cortical development, ingrowing axons from different thalamic nuclei select and invade their cortical targets. The selection of an appropriate target is first evident even before thalamic axons grow into the cortical plate: initially axons accumulate and wait below their cortical target area in a zone called the subplate. This zone also contains the first postmitotic neurons of the cerebral cortex, the subplate neurons. Here we have investigated whether subplate neurons are involved in the process of target selection by thalamic axons by ablating them from specific cortical regions at the onset of the waiting period and examining the subsequent thalamocortical axon projection patterns. Subplate neurons were ablated at the onset of the waiting period by intracortical injections of kainic acid. The effect of the ablation on the thalamocortical projection from visual thalamus was examined by DiI-labeling of the LGN days to weeks following the lesion. At two to four weeks post-lesion, times when LGN axons would have normally invaded the cortical plate, the axons remained below the cortical plate and grew past their appropriate cortical target in an anomalous pathway. Moreover, examination of LGN axons at one week post-lesion, a time when they would normally be waiting and branching within the visual subplate, indicated that the axons had already grown past their correct destination. These observations suggest that visual subplate neurons are involved in the process by which LGN axons select and subsequently grow into visual cortex. In contrast, subplate neurons do not appear to play a major role in the initial morphological development of the LGN itself. Subplate ablations did not alter dendritic growth or shapes of LGN projection neurons during the period under study, nor did it prevent the segregation of retinal ganglion cell axons into eye-specific layers. However, the overall size of the LGN was reduced, suggesting that there may be increased cell death of LGN neurons in the absence of subplate neurons. To examine whether subplate neurons beneath other neocortical areas play a similar role in the formation of thalamocortical connections, subplate neurons were deleted beneath auditory cortex at the onset of the waiting period for auditory thalamic axons. Subsequent DiI labeling revealed that in these animals the majority of MGN axons had grown past auditory cortex instead of innervating it. Taken together these observations underscore a general requirement for subplate neurons throughout neocortex in the process of cortical target selection and ingrowth by thalamic axons.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Laminar specific attachment and neurite outgrowth of thalamic neurons on cultured slices of developing cerebral neocortex.

In nervous system development, the growth cones of advancing axons are thought to navigate to their targets by recognizing cell-surface and extracellular matrix molecules that act as specific guidance cues. To identify and map cues that guide the growth of a particular axonal system, the thalamocortical afferents, an assay was devised to examine short-term interactions of dissociated embryonic thalamic cells with living, approximately 150 microns slices of developing mouse forebrain. Thalamic cells rapidly (< 3 hours) and efficiently attached to and extended neurites on pre- and postnatal slices, but a broad zone throughout the neocortex was generally non-permissive for both thalamic cell attachment and the ingrowth of neurites. This zone coincided with the cortical plate at early stages (embryonic day 15), but later became restricted, in rostral-to-caudal fashion, to cortical laminae 2/3. Thus, at each stage, thalamic cells in vitro avoided just that area that thalamic axons confront, but generally do not enter, in vivo. In addition, neurites that extended on some layers were found to be significantly oriented in directions that coincide with the pathways that thalamic axons follow in vivo. These results imply that local adhesive cues and signals that affect process outgrowth are distributed among developing cortical laminae in a manner that could underlie much of the temporal and spatial patterning of thalamocortical innervation.

Animals↗

Control of complex conation and emotion in the neocortex by the limbic entorhinal, subicular, and cingulate cortices and the hypothalamus, mammillary body, and thalamus.

The neocortex appears to contain columnar neuron populations that function as unitary information structures. The interactions between these structures, and the sensorimotor relationships they process, are regulated by subcortical regions. The reticular formation, hypothalamus, thalamus and basal ganglia have been proposed as a hierarchical control system that regulates the processing carried out by hierarchies of the cortical information structures in basic behavioral states. The regulation is carried out by means of operations on conative information components that circulate through the subcortical-neocortical system. It is proposed that in complex behavioral states, composite modalities of conative information are formed. These are processed in a complex-state system that involves parts of the limbic lobe and related nuclei: the entorhinal cortex, subiculum, mammillary body, thalamus, and posterior and anterior cingulate cortices. This system can accommodate new modalities of conation, including those relating to social behavior. Genetic specification of engrams in the system provides for evolution of conative and emotional states, matching increases in sophistication of cognitive processing.

Animals↗

Cytoskeletal messenger RNA stability in human neocortex: studies in normal aging and in Alzheimer's disease.

Total RNA was extracted from human brain temporal and parietotemporal neocortical grey matter with postmortem intervals (PMI) of up to 13.5 hours. The integrity and rank abundance of heterogeneous nuclear RNA (HnRNA) and messenger RNA (mRNA) were analyzed by Northern gel dot blot hybridization with specific cloned probes of neurobiological interest: the RNA messages for four cytoskeletal components including glial fibrillary acidic protein (GFAP), alpha-tubulin, beta-actin and the human neurofilament light chain (HNF-L) genomic sequence, the Alu repetitive element, the scrapie prion PrP DNA probe and the chromatin condensing agent linker histone H1(0) genomic probe. Our observations indicate that for the cytoskeletal RNA messages studied here: (1) short postmortem intervals (of up to 4.5 hours) had only small effects upon RNA quality in these neocortices, (2) GFAP and HNF-L transcripts were represented at relatively high levels in the cerebral neocortex and (3) each RNA species in normal human brain had both unique and characteristic intracellular levels of abundance and decay kinetics. In the pathological condition, Alzheimer's disease (AD), cells of the temporal and parietotemporal neocortices of afflicted brains showed selective reductions in cytoskeletal RNA pool size which are not attributable to RNA transcript stability.

Adult↗

Myopia, intelligence, and the expanding human neocortex: behavioral influences and evolutionary implications.

The first two parts of this monograph document that areas of the human neocortex heavily used to cope with a complex, language-driven society have been expanding rapidly and suggest strongly that this is linked with the huge upsurge that's occurred in myopia, and with the large gradual 20th-century increase in measured intelligence. Part III proposes mechanisms capable of supporting such rapid changes, without violating the basic precepts of Darwin's thinking. Part IV discusses the social and evolutionary ramifications of our apparent proclivity for rapid, progressive, adaptive neocortical change, and suggests areas for productive research.

Age of Onset↗

Alzheimer's disease-related alterations in synaptic density: neocortex and hippocampus.

Alzheimer's disease (AD) is a progressive disorder that is characterized by the accumulation of neuropathologic lesions and neurochemical alterations. Ultrastructural investigations in many association regions of the neocortex and the hippocampal dentate gyrus have demonstrated a disease-related decline in numerical synaptic density. This decline in brain connectivity occurs early in the disease process and strongly correlates with the cognitive decline observed in AD. The synapse loss does not appear to be an inevitable consequence of the aging process. This article reviews the ultrastructural studies assessing AD-related synaptic loss and the possible compensatory changes in the synaptic complex that occur as a result of the loss in brain connectivity.

Age Factors↗

[Structure of the cerebral cortex. Intrinsic organization and comparative analysis of the neocortex].

We review our present knowledge on the intrinsic organization of the neocortex based on studies carried out with the Golgi method in several mammalian species. An outline is presented on certain general aspects of the termination of specific afferent fibers in layer IV in insectivora, rodents, carnivora and primates. The principal components of the cerebral cortex have been classified in two broad types: pyramidal cells, which account for nearly 70% of the total population, and intrinsic neurons. We review different morphological characteristics of pyramidal cells and intrinsic neurons with a full description of cell varieties, dendritic morphology and several aspects of synaptic connectivity of intrinsic neurons in comparison between different species. Special attention has been paid to the description of spinous stellate cells which seems unique for a given animal species. We have reviewed intrinsic cortical circuits linking several neocortical layers, the distribution of dendritic plexuses, and the excitatory and inhibitory synaptic connections established between various neuronal categories. We finally review modern concepts of functional neocortical architecture based on the modular organization of the cerebral cortex, concluding that the cerebral cortex is rather uniform at en elementary level but the differences appear substantial when the comparison is made between different species.

Animals↗

[Spatial perception of stimuli during unilateral exclusion of the temporal portion of the neocortex by cold].

Behavioral reaction of twelve cats were studied in conditions of inactivation by cold of the temporal area (AI, AII, Ep and partly I-T) of one hemisphere. A typical vestibular ataxy was observed: deflection of the cats when walking, circular movements in the direction of the inactivated temporal area. Orienting reactions both to acoustic and photic stimuli persisted, but their spatial localization was completely lost. In every case the animals exhibited a clear orienting reaction towards the inactivated hemisphere, regardless of the localization of the source of signal. Reactions ot pain and olfactory stimulations likewise proceded in one direction. such a one-sided perception of sounds in the case of inactivation by cold of the temporal neocortex of one hemispheres is apparently due to the functional elimination of contralateral auditory structures. Disturbance of adequate spatial perception of photic, pain and olfactory stimuli under similar conditions results from a sharp drop in the tone predominantly of the ipsilateral hemisphere.

Animals↗

[The sterologic method of determining the surface area of the mammalian neocortex].

A method for calculation of the square surface area of the cerebral cortex is proposed which represents a combination of the method of averaged reconstruction after a continuous series of histological sections and the stereological method of determination of the length of any curve disposed on the surface. A comparative analysis of the proposed method with curvometrical and stereological (after Hennig's formula) method used earlier for this purpose is made taking as an example the calculation of the neocortex square surface area of some mammals. The results of calculation of the surface by the proposed method were found to coincide with curvometrical data within the range of 5% while the data obtained by stereological method of determination of the absolute square surface area differ from curvometrical data by more than 22%. The proposed method is very convenient and allows considerable acceleration in obtaining results.

Animals↗