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PubMed2002

Glial and neuronal interactions during slow wave and paroxysmal activities in the neocortex.

Increasing evidence suggests that glial cells are endowed with the ability to externalize their activity to the extracellular space and to neurons. Since the same activity is influenced by the extracellular ionic concentrations and the neurotransmitters released by neurons, it is suggested that neurons and glia entertain a continuous exchange of information. This behavior might have a particular significance during cortical oscillations. In this study we analyzed the time and voltage relationships within simultaneously recorded neuron-glia pairs during normal states characterized by a slow (<1 Hz) sleep oscillation and during paroxysmal epileptic discharges. Our data show that cortical neurons and glia display coherent activities during the tested spontaneous oscillations. The onset of the depolarizing phase of the slow oscillation started in neurons and followed with a lag of 88 ms in nearby (1-2 mm) recorded glial cells. In contrast, the beginning of the hyperpolarizing phase was initiated in glial cells, and neurons followed after 79 ms, suggesting that glial activities are not exclusively the reflection of neuronal ones. Moreover, we tested neuronal excitability that resulted in phase opposition with the glial membrane potential, establishing that only the first 30% of the neuronal depolarization is efficient for synaptic volleys within cortical neuronal networks. Seizures were associated with shorter time lags at onset of depolarization (1.8 ms) and with delayed glial offset (102 ms). The voltage slope and amplitude at the onset of the paroxysmal depolarizations were higher than in the case of the slow oscillation. Together with the variation of neuronal excitability, these results suggest that the glial uptake of K(+) contributes to the abridged duration of the paroxysmal depolarization.

Animals↗
PubMed2002

Spaceflight induces changes in the synaptic circuitry of the postnatal developing neocortex.

The establishment of the adult pattern of neocortical circuitry depends on various intrinsic and extrinsic factors, whose modification during development can lead to alterations in cortical organization and function. We report the effect of 16 days of spaceflight [Neurolab mission; from postnatal day 14 (P14) to P30] on the neocortical representation of the hindlimb synaptic circuitry in rats. As a result, we show, for the first time, that development in microgravity leads to changes in the number and morphology of cortical synapses in a laminar-specific manner. In the layers II/III and Va, the synaptic cross-sectional lengths were significantly larger in flight animals than in ground control animals. Flight animals also showed significantly lower synaptic densities in layers II/III, IV and Va. The greatest difference was found in layer II/III, where there was a difference of 344 million synapses per mm(3) (15.6% decrease). Furthermore, after a 4 month period of re-adaptation to terrestrial gravity, some changes disappeared (i.e. the alterations were transient), while conversely, some new differences also appeared. For example, significant differences in synaptic density in layers II/III and Va after re-adaptation were no longer observed, whereas in layer IV the density of synapses increased notably in flight animals (a difference of 185 million synapses per mm(3) or 13.4%). In addition, all the changes observed only affected asymmetrical synapses, which are known to be excitatory. These results indicates that terrestrial gravity is a necessary environmental parameter for normal cortical synaptogenesis. These findings are fundamental in planning future long-term spaceflights.

Adaptation, Physiological↗
PubMed2003

Fast-spike interneurons and feedforward inhibition in awake sensory neocortex.

'Fast-spike' interneurons of layer 4 mediate thalamocortical feedforward inhibition and can, with some confidence, be identified using extracellular methods. In somatosensory barrel cortex of awake rabbits, these 'suspected inhibitory interneurons' (SINs) have distinct receptive field properties: they respond to vibrissa displacement with very high sensitivity and temporal fidelity. However, they lack the directional specificity that is clearly seen in most of their ventrobasal thalamocortical afferents. Several lines of evidence show that layer-4 SINs receive a potent and highly convergent and divergent functional input from topographically aligned thalamocortical neurons. Whereas the unselective pooling of convergent thalamocortical inputs onto SINs generates sensitive and broadly tuned inhibitory receptive fields, the potent divergence of single thalamocortical neurons onto many SINs generates sharply synchronous (+/-1 ms) activity (because of coincident EPSPs). Synchronous discharge of these interneurons following thalamocortical impulses will generate a synchronous feedforward release of GABA within the barrel. Thalamocortical impulses will, therefore, generate only a brief 'window of excitability' during which spikes can occur in the post-synaptic targets of fast-spike interneurons. This fast, synchronous, highly sensitive and broadly tuned feed-forward inhibitory network is well suited to suppress spike generation in spiny neurons following all but the most optimal feedforward excitatory inputs.

Action Potentials↗
PubMed2003

Voltage-gated currents, dye and electrical coupling in the embryonic mouse neocortex.

We measured dye coupling, electrical coupling, and voltage-gated currents using whole-cell voltage clamp in slices of mouse sensorimotor cortex at embryonic day 14 (E14). As in rat ventricular zone (VZ), cells of the VZ were extensively dye coupled, often in clusters of >100 cells. In mouse VZ, however, cells were much less electrically coupled, making measurement of voltage-gated currents more accurate. All VZ cells expressed delayed K(+) currents (I(K)), and 30%, including morphologically identified radial glia, also expressed inward Na(+) currents (I(Na)). This fraction is consistent with I(Na) expression being an early event following cell cycle exit. Intermediate zone (IZ) cells also expressed I(K) and I(Na). Na(+) current amplitude distributions indicated three populations of IZ cells: those without I(Na), those with I(Na) similar in amplitude to VZ cells, and those with I(Na) being almost 10 times larger than in VZ cells. Cells of the cortical plate (CP) expressed both I(K) and I(Na), with I(Na) being almost 10-fold larger than in VZ cells. No cell in any zone expressed detectable hyperpolarization-activated currents. Our data suggest that the distribution and density of I(Na) may be related to early events of cell cycle exit and migration.

Action Potentials↗
PubMedDate not supplied

Nitric oxide-producing neurons in the neocortex: morphological and functional relationship with intraparenchymal microvasculature.

Nitric oxide is a ubiquitous intercellular messenger involved in particular functions in the cardiovascular, immunological and nervous systems. In the cerebral cortex, nitric oxide is synthetized by endothelial cells and by a discrete population of neurons and glial cells expressing nitric oxide synthase. Nitric oxide of endothelial and neuronal origin is involved in the regulation of cerebral blood flow. In this review, we have tried to combine morphological data providing information on the chemical nature of nitric oxide synthase-containing neurons and their arrangement, especially in relation to intracortical blood vessels, with functional results suggesting the participation of these neurons in the coupling between local cortical blood flow and synaptic activity.

Animals↗
PubMed1998

Effects of neonatal freeze lesions on expression of parvalbumin in rat neocortex.

Neonatal freeze lesions to the cortical plate result in focal malformations of the cerebral cortex that resemble four-layered microgyria. These malformations have been associated with local and distant changes in neuronal architecture, and have been implicated in the neocortical epileptiform discharges that can spread up to 4 mm away from the malformation itself. In an effort to assess potential changes in the development of one population of inhibitory interneurons in this malformation, we measured the density of parvalbumin-immunoreactive (ParvIR) neurons in microgyric and control cerebral cortex on postnatal days 13, 15, 21 and 64. In comparison to controls, microgyric animals exhibited a transient decrease in the expression of parvalbumin immunoreactivity in supragranular neurons, both within the malformation itself and in normal six-layered cortex up to 2 mm adjacent to it. This difference disappeared by P21. In addition, there was a permanent diminution of the density of ParvIR neurons in infragranular layers both within and immediately adjacent to the microgyrus. These results indicate that early injury to the cortical plate gives rise to both focal and more widespread changes in cortical architecture.

Animals↗
PubMed2004

Long-term potentiation induces expanded movement representations and dendritic hypertrophy in layer V of rat sensorimotor neocortex.

While long-term potentiation (LTP) is currently the most widely investigated model of the synaptic mechanisms underlying learning, there is a paucity of reports on the direct effects of LTP on cortical organization. Here we show that strengthening polysynaptic potentiation correlates with an expanded neocortical area that responds to intracortical microstimulation-induced movements of rat forelimb and increased dendritic material in layer V pyramidal cells. Rats carried a stimulating electrode in the corpus callosum (midline), and a recording electrode in the right caudal forelimb area (CFA). Each rat received 15 days of either high frequency stimulation (HFS) or handling. Evoked potentials of the transcallosal pathway were recorded in the right hemisphere before and after 15 days of stimulation or handling. Following the last stimulation, movement representations were determined in the left CFA using high-resolution intracortical microstimulation (ICMS) and then the brains were processed for Golgi-Cox staining. Our results show that synaptic modification results in a recruitment of more neocortical area into movement representations and increases in several measures of dendritic morphology in layers III and V. This study sheds light on the interaction between artificial models of learning, receptive field characteristics and dendritic morphology in the sensorimotor cortex.

Adaptation, Physiological↗
PubMed2004

Nootropic agents enhance the recruitment of fast GABAA inhibition in rat neocortex.

It is widely believed that nootropic (cognition-enhancing) agents produce their therapeutic effects by augmenting excitatory synaptic transmission in cortical circuits, primarily through positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors (AMPARs). However, GABA-mediated inhibition is also critical for cognition, and enhanced GABA function may be likewise therapeutic for cognitive disorders. Could nootropics act through such a mechanism as well? To address this question, we examined the effects of nootropic agents on excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) recorded from layer V pyramidal cells in acute slices of somatosensory cortex. Aniracetam, a positive modulator of AMPA/kainate receptors, increased the peak amplitude of evoked EPSCs and the amplitude and duration of polysynaptic fast IPSCs, manifested as a greater total charge carried by IPSCs. As a result, the EPSC/IPSC ratio of total charge was decreased, representing a shift in the excitation-inhibition balance that favors inhibition. Aniracetam did not affect the magnitude of either monosynaptic IPSCs (mono-IPSCs) recorded in the presence of excitatory amino acid receptor antagonists, or miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin. However, the duration of both mono-IPSCs and mIPSCs was prolonged, suggesting that aniracetam also directly modulates GABAergic transmission. Cyclothiazide, a preferential modulator of AMPAR function, enhanced the magnitude and duration of polysynaptic IPSCs, similar to aniracetam, but did not affect mono-IPSCs. Concanavalin A, a kainate receptor modulator, had little effect on EPSCs or IPSCs, suggesting there was no contribution from kainate receptor activity. These findings indicate that AMPAR modulators strengthen inhibition in neocortical pyramidal cells, most likely by altering the kinetics of AMPARs on synaptically connected interneurons and possibly by modulating GABA(A) receptor responses in pyramidal cells. This suggests that the therapeutic actions of nootropic agents may be partly mediated through enhanced cortical GABAergic inhibition, and not solely through the direct modification of excitation, as previously thought.

Animals↗
PubMed2005

Excitatory connections made by presynaptic cortico-cortical pyramidal cells in layer 6 of the neocortex.

Paired intracellular recordings with biocytin labelling were made in slices of adult rat somatosensory and visual cortex and in cat visual cortex to examine the properties of synaptic connections made by layer 6 pyramidal cells, to determine whether cortico-cortical pyramids more commonly provide input to other layer 6 pyramids than cortico-thalamic cells, and whether these connections exhibit paired pulse and brief train depression. Pyramidal cells with cortico-cortical like morphology were 2-4 times more likely to innervate other pyramidal cells than were cortico-thalamic like cells, but less likely to innervate inhibitory interneurons. The excitatory postsynaptic potentials elicited by presynaptic, phasically firing cortico-cortical pyramids in all classes of postsynaptic infragranular layer pyramidal cells exhibited strong, presynaptically mediated paired pulse and brief train depression. Those with larger paired pulse ratios also exhibited post-tetanic potentiation, but this was accompanied by stronger paired pulse and brief train depression. Both the firing characteristics and the outputs of cortico-cortical pyramidal cells display pronounced phasic characteristics, indicating that these cells respond most effectively to and preferentially pass on information related to novelty.

Animals↗
PubMed2005

Distinct Ca2+ channels mediate transmitter release at excitatory synapses displaying different dynamic properties in rat neocortex.

To study the type of presynaptic calcium channels controlling transmitter release at synaptic connections displaying depression or facilitation, dual whole cell recordings combined with biocytin labelling were performed in acute slices from motor cortex of 17- to 22-day-old rats. Layer V postsynaptic interneurons displayed either fast spiking (FS) (n = 12) or burst firing (BF) (n = 12) behaviour. The axons of FS cells ramified preferentially around pyramidal cell somata, while BF cell axons ramified predominately around pyramidal cell dendrites. Synapses between pyramidal cells and FS cells displayed brief train depression (n = 12). Bath application of omega-Agatoxin IVA (0.5 microM), blocking P/Q-type calcium channels, decreased mean peak amplitudes of the EPSPs to 40% of control EPSPs (n = 8). Failure rate of the EPSPs after the first presynaptic action potential increased from 9 +/- 11 to 28 +/- 15%. This was associated with an increase in paired pulse ratio of 152 +/- 44%. Omega-conotoxin GVIA (1-10 microM), selectively blocking N-type calcium channels, had no effect on peak amplitudes or frequency dependent properties of these connections (n = 5). Synapses from pyramidal cells to BF cells displayed brief train facilitation (n = 8). Application of omega-Conotoxin in these connections decreased peak amplitudes of the EPSPs to 15% of control EPSPs (n = 6) and decreased the paired pulse ratio by 41 +/- 30%. Omega-agatoxin did not have any significant effect on the EPSPs elicited in BF cells. This study indicates that P/Q-type calcium channels are associated with transmitter release at connections displaying synaptic depression, whereas N-type channels are predominantly associated with connections displaying facilitation.

Animals↗
PubMed2005

Heterotopia formation in rat but not mouse neocortex after RNA interference knockdown of DCX.

Subcortical band heterotopia (SBH) or double cortex is associated with significant impairments in neocortical function including mental retardation and epilepsy. Mutant alleles of DCX in humans typically cause SBH in females and lissencephaly in males, whereas Dcx null mutations in mice neither disrupt neocortical neuronal migration nor cause SBH formation. In utero RNA interference (RNAi) of Dcx in rats, in contrast, creates an animal model of SBH. Possible explanations for the discrepancies in results following loss of Dcx function include species differences and/or differences between RNAi knockdown and genetic deletion. We have carried out a series of in utero RNAi experiments to investigate possible species differences between rat and mouse to determine the molecular specificity of RNAi against Dcx and to identify the cellular constituents of SBH in the rat model. In utero RNAi in the rat consistently leads to both the formation of SBH and laminar displacement of transfected cells in normotopic cortex, whereas the same treatment in mouse fails to induce SBH but does create laminar displacement. Induction of SBH and impaired radial migration following RNAi against Dcx is rescued by overexpression of Dcx. Thus, both disruptions induced by RNAi are specific to interference of Dcx. SBHs contain transfected pyramidal cells as well as nontransfected cell types, including neocortical interneurons and glia. Together these results indicate that there is a species difference between rat and mouse with respect to RNAi-induced SBH formation and that SBH formation involves the recruitment of several unaltered cell types.

Animals↗
PubMed2006

Comparative analysis of layer-specific genes in Mammalian neocortex.

We examined the expression patterns of 4 layer-specific genes in monkey and mouse cortices by fluorescence double in situ hybridization. Based on their coexpression profiles, we were able to distinguish several subpopulations of deep layer neurons. One group was characterized by the expression of ER81 and the lack of Nurr1 mRNAs and mainly localized to layer 5. In monkeys, this neuronal group was further subdivided by 5-HT2C receptor mRNA expression. The 5-HT2C(+)/ER81(+) neurons were located in layer 5B in most cortical areas, but they intruded layer 6 in the primary visual area (V1). Another group of neurons, in monkey layer 6, was characterized by Nurr1 mRNA expression and was further subdivided as Nurr1(+)/connective tissue growth factor (CTGF)(-) and Nurr1(+)/CTGF(+) neurons in layers 6A and 6B, respectively. The Nurr1(+)/CTGF(+) neurons coexpressed ER81 mRNA in monkeys but not in mice. On the basis of tracer injections in 3 monkeys, we found that the Nurr1(+) neurons in layer 6A send some corticocortical, but not corticopulvinar, projections. Although the Nurr1(+)/CTGF(-) neurons were restricted to lateral regions in the mouse cortex, they were present throughout the monkey cortex. Thus, an architectonic heterogeneity across areas and species was revealed for the neuronal subpopulations with distinct gene expression profiles.

Animals↗
PubMed2006

Morphological, electrophysiological, and synaptic properties of corticocallosal pyramidal cells in the neonatal rat neocortex.

Neocortical pyramidal cells (PCs) project to various cortical and subcortical targets. In layer V, the population of thick tufted PCs (TTCs) projects to subcortical targets such as the tectum, brainstem, and spinal cord. Another population of layer V PCs projects via the corpus callosum to the contralateral neocortical hemisphere mediating information transfer between the hemispheres. This subpopulation (corticocallosally projecting cells [CCPs]) has been previously described in terms of their morphological properties, but less is known about their electrophysiological properties, and their synaptic connectivity is unknown. We studied the morphological, electrophysiological, and synaptic properties of CCPs by retrograde labeling with fluorescent microbeads in P13-P16 Wistar rats. CCPs were characterized by shorter, untufted apical dendrites, which reached only up to layers II/III, confirming previous reports. Synaptic connections between CCPs were different from those observed between TTCs, both in probability of occurrence and dynamic properties. We found that the CCP network is about 4 times less interconnected than the TTC network and the probability of release is 24% smaller, resulting in a more linear synaptic transmission. The study shows that layer V pyramidal neurons projecting to different targets form subnetworks with specialized connectivity profiles, in addition to the specialized morphological and electrophysiological intrinsic properties.

Action Potentials↗
PubMed1997

Multiple olfactory activity in the human neocortex identified by magnetic source imaging.

To date, cortical regions activated by olfactory stimulation have not been identified precisely in humans. In this study we used magnetic source imaging to localize neuronal activity following olfactory stimulation with two odorants, hydrogen sulphide and vanillin. Peak latencies of the olfactory event-related magnetic fields corresponded to the ascending and descending slopes of the major deflections of the olfactory event-related potentials (OERP). At these latencies we obtained consistent activation of the anterior-central parts of the insula (agranular-periallocortical and dysgranular regions) the parainsular cortex and the superior temporal sulcus. No reproducible equivalent current dipoles were found in other brain areas, including the orbitofrontal cortex. For the first time, brain areas were identified that generate most components of olfactory bioresponses (OERPs) in humans.

Adult↗
PubMed2001

Methamphetamine causes differential regulation of pro-death and anti-death Bcl-2 genes in the mouse neocortex.

Bcl-2, an inner mitochondrial membrane protein, inhibits apoptotic neuronal cell death. Expression of Bcl-2 inhibits cell death by decreasing the net cellular generation of reactive oxygen species. Studies by different investigators have provided unimpeachable evidence of a role for oxygen-based free radicals in methamphetamine (METH) -induced neurotoxicity. In addition, studies from our laboratory have shown that immortalized rat neuronal cells that overexpress Bcl-2 are protected against METH-induced apoptosis in vitro. Moreover, the amphetamines can cause differential changes in the expression of Bcl-X splice variants in primary cortical cell cultures. These observations suggested that METH might also cause perturbations of Bcl-2-related genes when administered to rodents. Thus, the present study was conducted to determine whether the use of METH might indeed be associated with transcriptional and translational changes in the expression of Bcl-2-related genes in the mouse brain. Here we report that a toxic regimen of METH did cause significant increases in the pro-death Bcl-2 family genes BAD, BAX, and BID. Concomitantly, there were significant decreases in the anti-death genes Bcl-2 and Bcl-XL. These results thus support the notion that injections of toxic doses of METH trigger the activation of the programmed death pathway in the mammalian brain.

Animals↗
PubMed2000

Evidence for proportional synaptic scaling in neocortex of intact animals.

Neocortical neurons in culture can modify their global synaptic strength according to their recent activity level. This process has been termed synaptic scaling. We explored possible effects of synaptic scaling in intact animals by comparing EPSPs of two identified synaptic tracts on single cortical neurons in acute slices. We show that the amplitude and rise-time of unitary thalamocortical and intracortical EPSPs vary among different neurons, but are highly correlated on single cells. Likewise, the AMPA-to-NMDA receptor ratio in EPSPs evoked from the two tracts is correlated in single neurons, although intracortical pathways within layer 5 exhibit a significantly larger NMDA component. These findings demonstrate that, under physiological conditions, cortical neurons actively regulate their own response magnitude, regardless of the input source.

Animals↗