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A major direct GABAergic pathway from zona incerta to neocortex.

Retrograde fluorescent tracers were used to demonstrate a previously unknown but sizable direct gamma-aminobutyric acid (GABA)-containing neuronal pathway from the zona incerta to the neocortex in rats. This incertocortical pathway was found to project bilaterally to the entire neocortex and exhibited a rough corticotopic organization. Many of the zona incerta neurons projecting to the parietal and occipital cortices could also be immunohistochemically stained with antibodies to glutamic acid decarboxylase and GABA. Few of these neurons were immunoreactive to tyrosine hydroxylase antibodies, which identify dopamine-containing neurons. Injections in the frontal and entorhinal cortices labeled many neurons near or within the dopaminergic A13 subdivision of the zona incerta. In addition, the incertocortical system was found to be significantly larger during early postnatal (2 to 3 weeks) development. The projection pattern of this newly discovered pathway resembles that of the monoaminergic and cholinergic systems, arising from the brainstem and forebrain, suggesting possible similarities of function.

Animals↗

Stereotyped position of local synaptic targets in neocortex.

The microcircuitry of the mammalian neocortex remains largely unknown. Although the neocortex could be composed of scores of precise circuits, an alternative possibility is that local connectivity is probabilistic or even random. To examine the precision and degree of determinism in the neocortical microcircuitry, we used optical probing to reconstruct microcircuits in layer 5 from mouse primary visual cortex. We stimulated "trigger" cells, isolated from a homogenous population of corticotectal pyramidal neurons, while optically detecting "follower" neurons directly driven by the triggers. Followers belonged to a few selective anatomical classes with stereotyped physiological and synaptic responses. Moreover, even the position of the followers appeared determined across animals. Our data reveal precisely organized cortical microcircuits.

Action Potentials↗

Hypothalamic gamma-aminobutyric acid neurons project to the neocortex.

Three groups of gamma-aminobutyric acid--containing neurons were found in the mammillary region of the posterior hypothalamus. The groups correspond to the tuberal, caudal, and postmammillary caudal magnocellular nuclei. Many cells in these nuclei were retrogradely labeled with fast blue after the injection of this fluorescent dye into the neocortex. Immunohistochemical experiments showed that these same neurons also contained the gamma-aminobutyric acid-synthesizing enzyme glutamate decarboxylase. These results provide morphological evidence for a gamma-aminobutyric acid pathway arising in magnocellular neurons of the posterior hypothalamus and innervating the neocortex.

Animals↗

Common forms of synaptic plasticity in the hippocampus and neocortex in vitro.

Activity-dependent synaptic plasticity in the superficial layers of juvenile cat and adult rat visual neocortex was compared with that in adult rat hippocampal field CA1. Stimulation of neocortical layer IV reliably induced synaptic long-term potentiation (LTP) and long-term depression (LTD) in layer III with precisely the same types of stimulation protocols that were effective in CA1. Neocortical LTP and LTD were specific to the conditioned pathway and, as in the hippocampus, were dependent on activation of N-methyl-D-aspartate receptors. These results provide strong support for the view that common principles may govern experience-dependent synaptic plasticity in CA1 and throughout the superficial layers of the mammalian neocortex.

Action Potentials↗

Periodicity and directionality in the propagation of epileptiform discharges across neocortex.

1. The horizontal propagation of epileptiform discharges has been studied in slices of neocortex treated with high concentrations of bicuculline methiodide, an antagonist of the inhibitory transmitter gamma-aminobutyric acid (GABA). The cortical areas examined were: primary somatosensory (SmI) and motor (MI), and primary (area 17) and secondary (area 18) visual areas of rats, and area 17 of cats. In all of these areas an electrical stimulus evoked single, all-or-none paroxysmal field potentials (PFPs) that propagated across the entire width of the slice without decrement. 2. The velocity of PFP propagation was approximately 0.06-0.09 m/s when averaged over cortical distances of several millimeters. PFP propagation occurred equally well in both directions across a slice. 3. Measurement of PFP propagation at higher spatial resolution (100-180 micron intervals) revealed that velocity was not homogeneous within rat SmI, rat area 18 and cat area 17, but instead varied manyfold as horizontal position changed. In these areas of cortex, propagation patterns were spatially periodic; power spectra reveal that the dominant spatial frequencies were centered about 1 mm-1, with negligible contributions above 2 mm-1. Occasionally PFP propagation was discontinuous, skipping over a small region of cortex and arriving distally before propagating into the more proximal region. 4. In those cortices with periodic propagation patterns, PFP velocity was also strongly direction-dependent. Propagation patterns measured in opposite directions across the same strip of cortex displayed similar periodicities, but in many slices they were negatively correlated, i.e., the propagation pattern in one direction was antiphasic compared to that in the other direction. 5. In contrast, propagation velocity across the center of area 17 of the rat was relatively constant and not directional. Near the boundaries of areas 17 and 18, however, PFP velocity changed abruptly and became periodic within area 18. Similarly, velocity within rat MI was more constant and less directional than in the adjacent SmI. 6. The patterns of PFP propagation velocity are often spatially periodic, directionally asymmetric, and depend upon cortical area. We suggest that the periodic patterns reflect systematic variations in the length or density of horizontal excitatory connections. Alternatively, or concurrently, periodicities could arise from the patchy distributions of intrinsic connections that have been observed anatomically in many areas of neocortex.

Animals↗

Laminar distribution of neuronal membrane properties in neocortex of normal and reeler mouse.

1. Reeler is an autosomal recessive mutation of mice that alters neuronal migration during development, yielding a general inversion of the laminae in the neocortex. We recorded in vitro from slices of normal and reeler neocortex to study the influence of neuron position and shape on membrane properties and synaptic responses. 2. The intrinsic firing patterns, action-potential shapes, resting membrane potentials, input resistances, and evoked excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) did not differ between reelers and controls when data were grouped. 3. The depth distribution of intrinsic firing patterns was inverted in the reeler: intrinsically bursting (IB) neurons were found only in layer 5 in the normal mouse, but they were found exclusively in supragranular layers of the reeler cortex. 4. The spatial distribution of synaptic responses in the reeler was also inverted: very prominent IPSPs were characteristic of upper layer neurons in the normal mouse, but in the reeler similar inhibitory responses were observed predominantly in deep infragranular layers. 5. Dye injections in reeler pyramidal neurons revealed atypical morphologies, including distorted apical dendrites and cell inversion. 6. The data imply that cortical neurons develop the membrane and synaptic properties appropriate to their function, despite being malformed and mispositioned.

Animals↗

Recruitment of GABAA inhibition in rat neocortex is limited and not NMDA dependent.

1. The recruitment of evoked fast inhibitory postsynaptic currents (IPSCs) and excitatory postsynaptic currents (EPSCs) was examined using whole cell voltage-clamp recordings from layer V pyramidal neurons in slices of rat somatosensory cortex. Synaptic currents were evoked with graded electrical stimulation to assess the relative activation of IPSCs and EPSCs. Fast GABAA ergic IPSCs were selectively recorded by holding cells at potentials equal to EPSC reversal (approximately 0 mV). EPSCs were likewise isolated by holding cells at IPSC reversal potential (about -75 mV). 2. As stimulus intensities were increased, the magnitude of the postsynaptic currents also increased. Over the range of stimuli applied (2-10 V), EPSCs did not exhibit an upper limit. However, fast gamma-aminobutyric acid-A (GABAA-mediated IPSCs reached a maximum at intensities approximately 2 times threshold. 3. The limit on fast inhibition was unresponsive to alterations in N-methyl-D-aspartate (NMDA)-mediated excitation. Exposure to nominally magnesium-free solutions or to the NMDA antagonist 3-[(RS)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid did not affect the fast IPSC maximum. Shifts in the input-output curves for submaximal activation of IPSCs were seen, which were attributed to polysynaptic excitation. 4. Blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate (non-NMDA) receptors with 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) completely abolished synaptically driven, fast GABAA-mediated inhibition. These findings suggested that neocortical inhibitory cells could be driven exclusively through non-NMDA transmission. 5. By comparison, in hippocampal CA1 pyramidal neurons maximal fast inhibition was sensitive to both NMDA and non-NMDA receptor blockade. 6. The results in neocortex were corroborated by direct intracellular recordings from layer V-VI interneurons. Non-NMDA receptor blockade with CNQX prevented synaptic activation of action potentials in these cells, even during cotreatment with magnesium-free solution. 7. Together, these results suggest that recruitment of GABA(A) ergic IPSCs in neocortex is ultimately driven via glutamatergic afferents arriving at non-NMDA receptors on interneurons. Properties limiting fast inhibition would favor the propagation of enhanced excitatory activity through the neuronal network.

Animals↗

Seizure-like discharges recorded in human dysplastic neocortex maintained in vitro.

Application of the convulsant drug 4-aminopyridine (50 to 100 microM) induced spontaneous seizure-like discharges (duration = 76.3 +/- 46.8 sec, mean +/- SD; interval of occurrence = 225.2 +/- 87.9 sec) in slices of neocortex obtained from patients with a diagnosis of focal neuronal migration disorders during neurosurgical procedures for relief of drug-resistant seizures. Similar epileptiform discharges could also be elicited in these slices by single-shock stimuli delivered in the underlying white matter or within the gray matter. By contrast, neocortical slices obtained from patients suffering from temporal lobe epilepsy (which is characterized by Ammon's horn sclerosis but relatively normal neocortex) did not generate any epileptiform activity during 4-aminopyridine application. Thus, our study is the first to provide experimental evidence for the intrinsic epileptogenicity that characterizes neuronal migration disorders.

4-Aminopyridine↗

Use of stimulation mapping and corticography in the excision of arteriovenous malformations in sensorimotor and language-related neocortex.

The excision of an arteriovenous malformation (AVM) located within eloquent neocortex presents a formidable neurosurgical challenge. Compromise of the vascular supply to normal surrounding brain or surgical trauma to essential neighboring neocortex may result in unacceptable postoperative neurological morbidity. In addition, successful removal of these lesions without the benefit of intraoperative corticography may leave in situ areas of highly epileptogenic brain, resulting in continued epilepsy. In this report, we describe eight patients who underwent craniotomy and excision of AVMs at our institutions. Six of these lesions were located in the dominant (left) hemisphere, and two were on the right. All patients underwent preoperative testing with Amytal administered via the carotid artery (Wada test). Subsequently, the patient was placed under local anesthesia, and we performed a craniotomy. Electrocorticography was used to identify epileptogenic brain in the region of the AVM and to establish after-discharge thresholds to electrical stimulation. Stimulation-mapping techniques were then used to delineate critical motor, sensory, and language areas. Trial occlusion of feeding vessels was also carried out to document postocclusion neurological deterioration, if any. At a later time, a second procedure was performed under general anesthesia to excise the lesion and any epileptogenic foci, using the cortical maps derived earlier. Using these techniques, it was possible to effect complete excision of these lesions in seven of eight patients without causing additional neurological deficits.

Adolescent↗

Enhanced excitatory synaptic connectivity in layer v pyramidal neurons of chronically injured epileptogenic neocortex in rats.

Formation of new recurrent excitatory circuits after brain injuries has been hypothesized as a major factor contributing to epileptogenesis. Increases in total axonal length and the density of synaptic boutons are present in layer V pyramidal neurons of chronic partial isolations of rat neocortex, a model of posttraumatic epileptogenesis. To explore the functional consequences of these changes, we used laser-scanning photostimulation combined with whole-cell patch-clamp recording from neurons in layer V of somatosensory cortex to map changes in excitatory synaptic connectivity after injury. Coronal slices were submerged in artificial CSF (23 degrees C) containing 100 microM caged glutamate, APV (2-amino-5-phosphonovaleric acid), and high divalent cation concentration to block polysynaptic responses. Focal uncaging of glutamate, accomplished by switching a pulsed UV laser to give a 200-400 micros light stimulus, evoked single- or multiple-component composite EPSCs. In neurons of the partially isolated cortex, there were significant increases in the fraction of uncaging sites from which EPSCs could be evoked ("hot spots") and a decrease in the mean amplitude of individual elements in the composite EPSC. When plotted along the cortical depth, the changes in EPSCs took place mainly between 150 and 200 microm above and below the somata, suggesting a specific enhancement of recurrent excitatory connectivity among layer V pyramidal neurons of the undercut neocortex. These changes may shift the balance within cortical circuits toward increased synaptic excitation and contribute to epileptogenesis.

2-Amino-5-phosphonovalerate↗

Archicortex and neocortex in the precocial murid Acomys cahirinus. A comparison with two altricial species: Mus musculus and Rattus norvegicus.

A morphological analysis of some structures of the archicortex and neocortex was performed in the Acomys cahirinus (spiny mouse), the only precocial murid. The data obtained indicate that the spiny mouse brain is an interesting case of a largely developed hippocampus with respect to the neocortex when compared to the brains of the mouse and rat. The precocious pups of the spiny mouse present the peculiarity among Murids of an early olfactory imprinting.

Animals↗

A hypothesis on the primate neocortex evolution: column-multiplication hypothesis.

A hypothesis is proposed, that the primate neocortex has evolved by the multiplication of cortical columns. As the column size is similar across primate species, it is considered that the columns have multiplied to expand the neocortex during primate evolution. This hypothesis would explain the expansion of neocortical sensory-motor-associational areas and multiple sensory and motor areas which had occurred during evolution. Further, the hypothesis predicts the existence of columns neutral for the fitness, genetic control upon the columns, and intraspecies variations of the columns.

Afferent Pathways↗

Asymmetrical modulation of immune reactivity in left- and right-biased rats after ipsilateral ablation of the prefrontal, parietal and occipital brain neocortex.

We report here on the lateralized brain immunomodulation in male Wistar rats, a phenomenon related to the rotational bias of animal and the site of cortical lesion. Rats assigned to left- and right-rotators in a cylindrical Plexiglass rotometer were subjected to the ablation of the ipsilateral prefrontal cortex (PFC), parietal cortex (PC) and occipital cortex (OC) and sensitized with bovine serum albumin (BSA) in complete Freund's adjuvant. Intact and sham-lesioned left-biased animals demonstrated increased Arthus and delayed hypersensitivity skin reactions and antibody production to BSA in comparison with corresponding right-biased animals. PFC ablation decreased humoral and cellular immune responses to BSA in left- but increased in right-biased rats. Lesioning of PC decreased humoral immune reactions in left- but increased in right-rotating animals. OC ablation failed to produce immunological abnormalities. These results suggest that immunopotentiation is associated with the left neocortex, and immunosuppression with the right neocortex. The prefrontal cortex appears to be particularly associated with immune reactions.

Animals↗

Immunoregulatory effect of neocortex in mice.

Immune responses were analyzed after neocortex ablation in mice. The neocortex ablations were performed in inbred mice on the left (ALN) or right hemisphere (ARN) separately. Two months later immunological parameters were tested. The results showed that the mitogenesis induced by Con A, natural killer cell (NK) cytotoxicity, production of IL-1 and IL-2 as well as the reactivity to IL-1 were all suppressed in ALN mice but stimulated in ARN mice compared to sham-operated controls. The primary antibody response to sheep red blood cells (SRBC) was also enhanced in ARN but not ALN mice. These results indicate that there may be a different regulatory effect on the immune system mediated by the different brain hemispheres, a phenomenon named lateralization of brain.

Animals↗

Brain neocortex and imuthiol regulate the expression of MHC antigens on mouse T lymphocytes.

The induction of T-cell responses involves the recognition of extrinsic antigens in association with antigens of the major histocompatibility complex (MHC). The present results demonstrate that the lateralized control exerted by the brain neocortex on T-cell activities extends to the expression of MHC antigens, yet differently on spleen or lymph node T cells. This study also shows that the neocortex influences the changes induced by an immunopotentiator, sodium diethyldithiocarbamate (imuthiol), on the MHC antigen content on mouse T cell-surface.

Animals↗

Action of phospholipases A2 and C on free fatty acid release during complete ischemia in rat neocortex. Effect of phospholipase C inhibitor and N-methyl-D-aspartate antagonist.

The levels of brain free fatty acids rapidly increase after the onset of ischemia. The purpose of this study was to investigate the action of phospholipases A2 and C during complete ischemia based on the effects of a phospholipase C inhibitor (phenylmethylsulfonyl fluoride) and the N-methyl-D-aspartate antagonist MK-801 on the release of free fatty acids in rat neocortex. Complete brain ischemia was induced in rats with cardiac arrest by intracardiac injection of KCl. Free fatty acid levels in the neocortex were measured 0, 2, 4, and 8 minutes after cardiac arrest. Phenylmethylsulfonyl fluoride inhibited the release of free fatty acids primarily from phosphatidylinositol during the first 2 minutes of ischemia and from phosphatidylcholine and phosphatidylethanolamine at 4 to 8 minutes of ischemia. Conversely, MK-801 inhibited free fatty acid release mainly from phosphatidylcholine and phosphatidylethanolamine at 2 to 4 minutes of ischemia. These results indicate that the release of free fatty acids during the first 2 minutes of ischemia can be attributed mostly to the action of phospholipase C, and that the activation of phospholipase C further influences the activation of phospholipase A2 in the subsequent course, while phospholipase A2 predominantly acts after 2 minutes of ischemia.

Animals↗

Shift from fibrillar to nonfibrillar Abeta deposits in the neocortex of subjects with Alzheimer disease.

A morphometric study of amyloid-beta-positive plaques in the neocortex of eight non-demented people from 68 to 82 years of age and 17 subjects with late-stage Alzheimer disease (GDS stage 7/FAST stages 7a-f) from 73 to 93 years of age shows a shift from prevalence of fibrillar plaques to prevalence of nonfibrillar plaques. In the aged, non-demented subjects, about 4/mm^2 plaques are detectable in the neocortex, and the majority are fibrillar plaques. Specifically, 64% found to be classical fibrillar and Thioflavin-S-positive bright primitive plaques. A lower percentage of pale primitive plaques (35%) relatively small proportion of plaques that are poor in thioflavin S-positive fibrils. The numerical density of plaques in the severe stage of AD increases to about 41/mm^2. Severely demented subjects appear to maintain an active process of fibrillar plaque formation. This is reflected in the presence of 3% bright primitive plaques. Severely demented subjects also manifest plaque degradation, reflected in the presence of 22% and 48% percentages of classical fibrillar plaques in non-demented subjects and in the end stage of disease suggest that once activated, the process of fibrillar plaque formation persists at a somewhat stable rate during the whole course of brain amyloidosis.

Journal Article↗

[Molecular mechanisms of the pathway formation in the fetal rat cerebral neocortex].

Neural cell adhesion molecules (NCAMs), L1 and TAG-1, which are prominently expressed in the developing nervous system, have been shown to promote axonal growth and bundle formation of central neurons in vitro. In the cerebral neocortex of fetal rats, immunoreactions of L1 and TAG-1 were specifically localized on thalamic afferent axons and cortical efferent axons, respectively. L1-bearing thalamocortical axons preferentially extended in the subplate of the cortical anlage where neurocan, a brain-specific chondroitin sulfate proteoglycan (CSPG), was prominently expressed. In contrast, cortical efferent axons immunoreactive for TAG-1 did not enter the subplate and run in the intermediate zone where neurocan expression was less abundant. In addition, TAG-1-bearing axons extensively invaded regions expressing another type of brain-specific CSPG, phosphacan. In the cell culture system, neurite outgrowth of TAG-1-transfected PC 12 D cells was remarkably inhibited on the neurocan substrate, while the outgrowth on phosphacan substrate was significantly promoted. Although both L1 and TAG-1 have been reported to bind both neurocan and phosphacan in vitro, interactions between NCAMs and CSPGs in vivo indicate more complicated patterns than previously thought. Thus, the present results suggest that various patterns of functional correlation between NCAMs and CSPGs play important roles in the pathway formation of the rat cerebral neocortex.

Animals↗