A neurofilament antibody recognizes a subset of pyramidal cells in the human neocortex that are preserved in Alzheimer's disease.
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Involvement of GABA(B) receptors in convulsant-induced epileptiform activity in rat neocortex in vitro.
The role of gamma-aminobutyric acid B (GABA(B)) receptors in the generation and maintenance of bicuculline-induced epileptiform activity in rat neocortical slices was studied using electrophysiological methods. A block of GABA(B) receptors in the presence of functional GABA(A) receptor-mediated inhibition was not sufficient to induce epileptiform activity. In the presence of the GABA(A) receptor antagonist bicuculline (10 microM) and at suprathreshold stimulation, the GABA(B) receptor antagonist CGP 35348 (10-300 microM) significantly potentiated epileptiform activity. With stimulation at threshold intensity, low concentrations of CGP 35348 (10-30 microM) potentiated bicuculline-induced activity, whereas higher concentrations (100-300 microM) invariably led to a reversible suppression of stimulus-evoked epileptiform discharges. CGP 35348 also enhanced picrotoxin-induced epileptiform activity, but at higher concentrations it was considerably less effective in suppressing such epileptiform discharges. The GABA uptake inhibitor nipecotic acid partially mimicked the actions of CGP 35348: with stimulation at threshold intensity, it reversibly suppressed bicuculline-induced epileptiform field potentials, but it did not influence epileptiform activity induced by picrotoxin. We conclude that a postsynaptic blockade of GABA(B) receptors induces an amplification of epileptiform activity in neocortical slices disinhibited by GABA(A) receptor antagonists. An additional blockade of presynaptic GABA(B) receptors, especially under conditions of weak stimulation of the neurons, reduces the inhibitory auto-feedback control of GABA release, leading to a displacement of competitive antagonists from the postsynaptic GABA(A) receptor and hence, to a suppression of epileptiform activity induced by competitive GABA(A) receptor antagonists.
Animals↗
Native human neocortex release-regulating dopamine D2 type autoreceptors are dopamine D2 subtype.
Dopamine (DA) autoreceptors expressed at DA nerve terminals regulate DA release. Considerable evidence has indicated that, in rodents, these autoreceptors belong to the D2 type of the DA receptor family, which, in turn, comprises the D2, D3 and D4 subtypes. We investigated here, for the first time, the subclassification of native human DA autoreceptors by studying the release of [3H]DA evoked by electrical stimulation in fresh human neocortical slices. The results have been compared with those obtained in three animal systems: rat neocortical and striatal slices and rat mesencephalic neuronal cultures. In human neocortical slices, the D2/D3 receptor agonist quinpirole (1 nM-10 microM) inhibited tritium release with a calculated EC50 of 17 nM and a maximal inhibition of approximately 75% reached at 1 microM. In the presence of the D2/D3 receptor antagonist (-)-sulpiride (0.1 and 1 microM), the concentration-response curve of quinpirole was shifted to the right, and the apparent pA2 mean value was 8.5 (8.14-8.77); on the other hand, the inhibitory effects of quinpirole were not affected by the D3 receptor-selective antagonist [7-N,N-dipropylamino-5,6,7, 8-tetrahydro-naphtho(2,3b) dihydro,2,3-furane] (S 14297) and the D4 receptor-selective antagonist 3-(4-[4-chlorophenyl]piperazin-1-yl)-methyl-1H-pyrrolo [2,3-b]pyridine (L-745,870) (0.01-1 microM in each case). Superimposable results have been obtained when the release was elicited from rat striatal slices or dopamine mesencephalic neurons in culture, whereas quantitative differences emerged in the case of rat cortical slices. It is concluded that in human brain, as well as in rat brain, the release of DA in the terminal region of midbrain dopaminergic neurons is regulated through autoreceptors of the D2 subtype.
Adult↗
Basal forebrain nitric oxide synthase (NOS)-containing neurons project to microvessels and NOS neurons in the rat neocortex: cellular basis for cortical blood flow regulation.
Stimulation of basal forebrain neurons results in local increases in cortical cerebral blood flow that are dependent upon cholinergic and nitrergic mechanisms. In the present study, we investigated the possibility that basal forebrain nitric oxide synthase (NOS)-containing neurons project to microvessels and NOS interneurons in the rat cerebral cortex. We performed quisqualic (QUIS) acid lesions of the basal forebrain and evaluated their effects on cortical NOS immunostained nerve terminals, with emphasis on those associated with microvessels and NOS interneurons, both at the light and/or electron microscopic levels. The results show that basal forebrain NOS neurons provide about one third of the overall cortical NOS innervation. Further, the data indicate that basalocortical NOS fibres establish privileged associations with microvessels and NOS neurons, as respective denervations of 60 and 45% were observed following lesion. At the electron microscopic level, most perivascular NOS neuronal elements corresponded to nerve terminals and a majority ( approximately 25%) of these were located in the immediate vicinity of the blood vessels, similar to the perivascular distribution reported previously for classic neurotransmitters/neuromediators. NOS terminals abutting on cortical NOS neurons were primarily nonjunctional. Altogether, these results raise the possibility that not only cholinergic but also nitrergic basal forebrain neurons are involved in the flow response observed following stimulation of the basal forebrain. Further, they suggest interactions between basalocortical and intracortical NOS neurons. We conclude that these interactions are involved in the spatial and temporal regulation of cortical perfusion following basal forebrain activation, and that they may become dysfunctional in pathologies such as Alzheimer's disease which affects both the basal forebrain and the cortical NOS neurons.
Acetylcholine↗
Innervation of interneurons immunoreactive for VIP by intrinsically bursting pyramidal cells and fast-spiking interneurons in infragranular layers of juvenile rat neocortex.
Cortical columns contain specific neuronal populations with characteristic sets of connections. This wiring forms the structural basis of dynamic information processing. However, at the single-cell level little is known about specific connectivity patterns. We performed experiments in infragranular layers (V and VI) of rat somatosensory cortex, to clarify further the input patterns of inhibitory interneurons immunoreactive (ir) for vasoactive intestinal polypeptide (VIP). Neurons in acute slices were electrophysiologically characterized using whole-cell recordings and filled with biocytin. This allowed us to determine their firing pattern as regular-spiking, intrinsically bursting and fast-spiking, respectively. Biocytin was revealed histochemically and VIP immunohistochemically. Sections were examined for contacts between the axons of the filled neurons and the VIP-ir targets. Twenty pyramidal cells and five nonpyramidal (inter)neurons were recovered and sufficiently stained for further analysis. Regular-spiking pyramidal cells displayed no axonal boutons in contact with VIP-ir targets. In contrast, intrinsically bursting layer V pyramidal cells showed four putative single contacts with a proximal dendrite of VIP neurons. Fast-spiking interneurons formed contacts with two to six VIP neurons, preferentially at their somata. Single as well as multiple contacts on individual target cells were found. Electron microscopic examinations showed that light-microscopically determined contacts represent sites of synaptic interactions. Our results suggest that, within infragranular local cortical circuits, (i) fast-spiking interneurons are more likely to influence VIP cells than are pyramidal cells and (ii) pyramidal cell input probably needs to be highly convergent to fire VIP target cells.
Action Potentials↗
Histaminergic facilitation of electrocorticographic activation: role of basal forebrain, thalamus, and neocortex.
The neuromodulator histamine plays an important role in the regulation of behavioural state and the neocortical electrocorticogram (ECoG). With the present experiments, we characterized the anatomical targets that mediate the cortical-activating effects of histamine. Urethane-anaesthetized rats displayed continuous large-amplitude, low-frequency oscillations with a maximal spectral power in the delta (0.5-3.9 Hz) frequency band. Electrical (100 Hz) stimulation of the pontine-tegmentum suppressed slow, large-amplitude oscillations and induced ECoG activation. Application of histamine (1 mm) into the basal forebrain cholinergic complex by reverse microdialysis enhanced ECoG activation elicited by tegmental stimulation without changing resting ECoG activity. Ventrolateral or central thalamic application of histamine had no effect on resting ECoG activity, and ventrolateral thalamic application produced only a slight enhancement of brainstem-induced activation. Neocortical application of histamine in close proximity (< 500 micro m) to the recording electrode reduced low-frequency delta power in the resting ECoG without affecting stimulation-induced ECoG activation. These data suggest that, under the present experimental conditions, histamine facilitates ECoG activation primarily by potentiating the excitatory influence of brainstem fibers at the level of the basal forebrain. Histamine release in some parts of the thalamus results in a minor enhancement of ECoG activation, and cortical histamine release produces a small but consistent suppression of slow delta oscillations in the resting ECoG. These concurrent subcortical and cortical actions probably permit histamine to effectively modulate cortical activation and excitability across different behavioural states.
Animals↗
[A new mechanism for memory: neuronal networks rewiring in the young rat neocortex].
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Animals↗
Communication between neocortex and hippocampus during sleep in rodents.
Both neocortical and hippocampal networks organize the firing patterns of their neurons by prominent oscillations during sleep, but the functional role of these rhythms is not well understood. Here, we show a robust correlation of neuronal discharges between the somatosensory cortex and hippocampus on both slow and fine time scales in the mouse and rat. Neuronal bursts in deep cortical layers, associated with sleep spindles and delta waves/slow rhythm, effectively triggered hippocampal discharges related to fast (ripple) oscillations. We hypothesize that oscillation-mediated temporal links coordinate specific information transfer between neocortical and hippocampal cell assemblies. Such a neocortical-hippocampal interplay may be important for memory consolidation.
Animals↗
Reciprocal evolution of the cerebellum and neocortex in fossil humans.
Human brain evolution involved both neurological reorganization and an increase in overall brain volume relative to body mass. It is generally difficult to draw functional inferences about the timing and nature of brain reorganization, given that superficial brain morphology recorded on fossil endocasts is functionally ambiguous. However, the cerebellum, housed in the clearly delineated posterior cranial fossa, is functionally and ontologically discrete. The cerebellum is reciprocally connected to each of 14 neocortical regions important to human cognitive evolution. Cerebellar volume varies significantly relative to overall brain volume among mammalian orders, as well as within the primate order. There is also significant diachronic variation among fossil human taxa. In the australopithecines and early members of the genus Homo, the cerebral hemispheres were large in proportion to the cerebellum, compared with other hominoids. This trend continued in Middle and Late Pleistocene humans, including Neandertals and Cro-Magnon 1, who have the largest cerebral hemispheres relative to cerebellum volume of any primates, including earlier and Holocene humans. In recent humans, however, the pattern is reversed; the cerebellum is larger with respect to the rest of the brain (and, conversely, the cerebral hemispheres are smaller with respect to the cerebellum) than in Late Pleistocene humans. The cerebellum and cerebral hemispheres appear to have evolved reciprocally. Cerebellar development in Holocene humans may have provided greater computational efficiency for coping with an increasingly complex cultural and conceptual environment.
Biological Evolution↗
Theory for normal and impaired experience-dependent plasticity in neocortex of adult rats.
We model experience-dependent plasticity in the cortical representation of whiskers (the barrel cortex) in normal adult rats, and in adult rats that were prenatally exposed to alcohol. Prenatal exposure to alcohol (PAE) caused marked deficits in experience-dependent plasticity in a cortical barrel-column. Cortical plasticity was induced by trimming all whiskers on one side of the face except two. This manipulation produces high activity from the intact whiskers that contrasts with low activity from the cut whiskers while avoiding any nerve damage. By a computational model, we show that the evolution of neuronal responses in a single barrel-column after this sensory bias is consistent with the synaptic modifications that follow the rules of the Bienenstock, Cooper, and Munro (BCM) theory. The BCM theory postulates that a neuron possesses a moving synaptic modification threshold, theta(M), that dictates whether the neuron's activity at any given instant will lead to strengthening or weakening of its input synapses. The current value of theta(M) changes proportionally to the square of the neuron's activity averaged over some recent past. In the model of alcohol impaired cortex, the effective theta(M) has been set to a level unattainable by the depressed levels of cortical activity leading to "impaired" synaptic plasticity that is consistent with experimental findings. Based on experimental and computational results, we discuss how elevated theta(M) may be related to (i) reduced levels of neurotransmitters modulating plasticity, (ii) abnormally low expression of N-methyl-d-aspartate receptors (NMDARs), and (iii) the membrane translocation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in adult rat cortex subjected to prenatal alcohol exposure.
Action Potentials↗
Amphetamine or cocaine limits the ability of later experience to promote structural plasticity in the neocortex and nucleus accumbens.
Drugs of abuse and many other kinds of experiences share the ability to alter the morphology of neuronal dendrites and spines, the primary site of excitatory synapses in the brain. We hypothesized, therefore, that exposure to psychostimulant drugs might influence later experience-dependent structural plasticity. We tested this hypothesis by treating rats repeatedly with amphetamine or cocaine and then housing them in either a complex environment or standard laboratory cages for 3-3.5 mo. The brains were processed for Golgi-Cox staining, and the number of dendritic branches and the density of dendritic spines on medium spiny neurons in the nucleus accumbens and pyramidal cells in the parietal cortex were quantified. On most measures, prior treatment with amphetamine or cocaine interfered with the ability of experience in a complex environment to increase dendritic arborization and spine density. We conclude that in some brain regions, repeated exposure to psychomotor-stimulant drugs limits the ability of later experience to produce this form of synaptic plasticity, which may contribute to the persistent behavioral and cognitive deficits associated with drug abuse.
Amphetamine↗
Electrical and chemical synapses among parvalbumin fast-spiking GABAergic interneurons in adult mouse neocortex.
Networks of gamma-aminobutyric acid (GABA)ergic interneurons connected via electrical and chemical synapses are thought to play an important role in detecting and promoting synchronous activity in the cerebral cortex. Although the properties of electrical and chemical synaptic interactions among inhibitory interneurons are critical for their function as a network, they have only been studied systematically in juvenile animals. Here, we have used transgenic mice expressing the enhanced green fluorescent protein in cells containing parvalbumin (PV) to study the synaptic connectivity among fast-spiking (FS) cells in slices from adult animals (2-7 months old). We have recorded from pairs of PV-FS cells and found that the majority of them were electrically coupled (61%, 14 of 23 pairs). In addition, 78% of the pairs were connected via GABAergic chemical synapses, often reciprocally. The average coupling coefficient for step injections was 1.5% (n = 14), a smaller value than that reported in juvenile animals. GABA-mediated inhibitory postsynaptic currents and potentials decayed with exponential time constants of 2.6 and 5.9 ms, respectively, and exhibited paired-pulse depression (50-ms interval). The inhibitory synaptic responses in the adult were faster than those observed in young animals. Our results indicate that PV-FS cells are highly interconnected in the adult cerebral cortex by both electrical and chemical synapses, establishing networks that can have important implications for coordinating activity in cortical circuits.
Action Potentials↗
Fluctuations and stimulus-induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex.
Cortical blood flow at the level of individual capillaries and the coupling of neuronal activity to flow in capillaries are fundamental aspects of homeostasis in the normal and the diseased brain. To probe the dynamics of blood flow at this level, we used two-photon laser scanning microscopy to image the motion of red blood cells (RBCs) in individual capillaries that lie as far as 600 micrometers below the pia mater of primary somatosensory cortex in rat; this depth encompassed the cortical layers with the highest density of neurons and capillaries. We observed that the flow was quite variable and exhibited temporal fluctuations around 0.1 Hz, as well as prolonged stalls and occasional reversals of direction. On average, the speed and flux (cells per unit time) of RBCs covaried linearly at low values of flux, with a linear density of approximately 70 cells per mm, followed by a tendency for the speed to plateau at high values of flux. Thus, both the average velocity and density of RBCs are greater at high values of flux than at low values. Time-locked changes in flow, localized to the appropriate anatomical region of somatosensory cortex, were observed in response to stimulation of either multiple vibrissae or the hindlimb. Although we were able to detect stimulus-induced changes in the flux and speed of RBCs in some single trials, the amplitude of the stimulus-evoked changes in flow were largely masked by basal fluctuations. On average, the flux and the speed of RBCs increased transiently on stimulation, although the linear density of RBCs decreased slightly. These findings are consistent with a stimulus-induced decrease in capillary resistance to flow.
Animals↗
Disfacilitation and active inhibition in the neocortex during the natural sleep-wake cycle: an intracellular study.
Earlier extracellular recordings during natural sleep have shown that, during slow-wave sleep (SWS), neocortical neurons display long-lasting periods of silence, whereas they are tonically active and discharge at higher rates during waking and sleep with rapid eye movements (REMs). We analyzed the nature of long-lasting periods of neuronal silence in SWS and the changes in firing rates related to ocular movements during REM sleep and waking using intracellular recordings from electrophysiologically identified neocortical neurons in nonanesthetized and nonparalyzed cats. We found that the silent periods during SWS are associated with neuronal hyperpolarizations, which are due to a mixture of K(+) currents and disfacilitation processes. Conventional fast-spiking neurons (presumably local inhibitory interneurons) increased their firing rates during REMs and eye movements in waking. During REMs, the firing rates of regular-spiking neurons from associative areas decreased and intracellular traces revealed numerous, short-lasting, low-amplitude inhibitory postsynaptic potentials (IPSPs), that were reversed after intracellular chloride infusion. In awake cats, regular-spiking neurons could either increase or decrease their firing rates during eye movements. The short-lasting IPSPs associated with eye movements were still present in waking; they preceded the spikes and affected their timing. We propose that there are two different forms of firing rate control: disfacilitation induces long-lasting periods of silence that occur spontaneously during SWS, whereas active inhibition, consisting of low-amplitude, short-lasting IPSPs, is prevalent during REMs and precisely controls the timing of action potentials in waking.
Animals↗
Gap junction proteins in inhibitory neurons of the adult barrel neocortex.
Recent studies indicate that electrical coupling among cortical neurons may persist throughout development; electrophysiological recordings made in cortical slices from young rats reveal that numerous GABAergic neurons are electrically coupled. To determine whether these in vitro findings reflect an inhibitory neural circuit that could be functionally relevant in vivo in adult rodents, we sought to identify whether inhibitory, parvalbumin-containing neurons of the mature cortex express gap junction proteins. Immunohistochemistry was used to examine the laminar distribution of the gap junction-forming proteins connexin 32 (Cx32), connexin 36 (Cx36) and connexin 43 (Cx43) in the somatosensory cortex of the adult mouse. Double labeling immunofluorescence identified Cx32, Cx36 and Cx43 in cortical neurons that were immunoreactive (-ir) for the neuronal markers neurofilament 145 kDa and neuronal nuclei (NeuN). Parvalbumin-ir neurons throughout the cortical laminae were labeled with Cx32-ir, Cx36-ir and Cx43-ir. Stereological methods were used to quantify the extent of parvalbumin colocalization with connexins. Analysis indicated that approximately 40% of parvalbumin-ir neurons were double labeled with either Cx32-ir or Cx43-ir, and approximately 50% of parvalbumin-ir neurons were double labeled with Cx36. These findings establish an anatomical substrate for widespread electrical coupling of neurons in somatosensory cortex and suggest that gap junctions among inhibitory interneurons may persist into adulthood, providing an important mechanism for neuronal communication.
Animals↗
Sensitivity to radiation-induced apoptosis and neuron loss declines rapidly in the postnatal mouse neocortex.
Therapeutic brain irradiation can cause progressive decline in cognitive function, particularly in children, but the reason for this effect is unclear. The study explored whether age-related differences in apoptotic sensitivity might contribute to the increased vulnerability of the young brain to radiation. Postnatal day 1 (P1) to P30 mice were treated with 0-16 Gy whole-body X-irradiation. Apoptotic cells were identified and quantified up to 48 h later using the TdT-UTP nick end-labelling method (TUNEL) and immunohistochemistry for activated caspase-3. The number of neuron-specific nuclear protein (NeuN)-positive and -negative cells were also counted to measure neuronal and non-neuronal cell loss. Significantly greater TUNEL labelling occurred in the cortex of irradiated P1 animals relative to the other age groups, but there was no difference among the P7, P14 and P30 groups. Irradiation decreased the %NeuN-positive cells in the mice irradiated on P1, whereas in P14 animals, irradiation led to an increase in the %NeuN-positive cells. These data demonstrate that neocortical neurons of very young mice are more susceptible to radiation-induced apoptosis. However, this sensitivity decreases rapidly after birth. By P14, acute cell loss due to radiation occurs primarily in non-neuronal populations.
Animals↗
Non-uniformity of neocortex: areal heterogeneity of NADPH-diaphorase reactive neurons in adult macaque monkeys.
We have examined the distribution of cortical neurons in adult monkey cortex which stain for nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), an enzyme which is involved in the synthesis of nitric oxide. In order to compare distributions across areas we employed a cortical unit defined as the radial column, which refers to the volume of cortex below 1 mm(2) of cortical surface. Numbers of labeled neurons per radial column generate areal density measurements either for the full thickness of the cortex or for individual layers. Measurements were made in six cortical regions (areas V1, V2, STS, auditory cortex, area 4 and area 6). NADPH-d stains nonpyramidal neurons which can be divided into two major groups. Type 1 neurons have large soma diameters, stain densely for NADPH-d and show few morphological variations both within and across areas. Type 2 neurons have small somata and short processes, and can be subdivided on the basis of soma size into dense and light staining categories. Both subcategories of type 2 neurons show significant areal variations in size. In each cortical area the majority of type 1 neurons are located in the white matter. Areal densities of type 1 neurons are minimal in areas V1 and V2, and twice as dense in the frontal cortex. Pairwise comparisons of areal densities among the six areas examined show that in a radial column throughout the full thickness of cortex, areas differ significantly from each other in 12/15 comparisons. Consideration of individual layers shows significant differences in 13/15 comparisons. Type 2 neurons are exclusively located in the cortical gray matter, and in all areas are considerably more numerous than type 1 neurons. Area V1 is unique it that it has up to three times the areal density found in any other cortical area. With reference to published laminar cell density counts our results show that the percentage of labeled NADPH-d neurons in individual layers of area V1 are significantly higher than in the other areas. The laminar distributions of type 1 and type 2 neurons show that each area has a unique profile of NADPH-d expression. The modular or columnar organization of the cortex, also referred to as the radial column hypothesis, is important for understanding both the development and function of the cortex. The present results show that radial columns in individual cortical areas possess distinctive patterns of NADPH-d expression. This important degree of areal heterogeneity of NADPH-d neurons has far reaching implications for both the development and functions of neocortical areas.
Animals↗
Cellular diversity in mouse neocortex revealed by multispectral analysis of amino acid immunoreactivity.
Cortical cells were classified using an unsupervised cluster analysis based upon their quantitative and combinatorial immunoreactivity for glutamate, gamma-aminobutyric acid (GABA), aspartate, glutamine and taurine. Overall, cell class-specific amino acid signatures were found for 12 cellular types; seven GABA-immunoreactive (GABA-IR) populations (GABA1--7), three classes containing high glutamate levels (GLUT1--3) and two putative glial (GLIA1, 2) cell types. From their large somata, associated vertical processes and high glutamate content, the GLUT classes most probably correspond to pyramidal neurons. Two of the GLUT classes demonstrated complementary distributions in different cortical layers, suggesting spatial separation of cells differing in amino acid immunoreactivity. Of the seven GABA classes, two comprised cells with large somata and displayed medium to low glutamate levels. On the basis of size, these two populations may correspond to large basket cell interneurons. Glial populations could be divided into two classes: GLIA1 cells were more frequently associated with blood vessels and GLIA2 cells were more commonly seen in the lower cortical layers. This work demonstrates that signature recognition based upon amino acid content can be used to separate cortical cells into different categories and reveal further subclasses within these categories. This approach is complementary to other methods using physiological and molecular tools and ultimately will enhance our understanding of neuronal heterogeneity.
Amino Acids↗