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PubMedDate not supplied

Metastability, instability, and state transition in neocortex.

Mesoscopic patterns of neural activity were sought in multichannel EEGs of rabbits that were trained to respond to conditioned stimuli (CSs) in visual, auditory and somatic modalities. Spatiotemporal patterns were sought of oscillations in the beta and gamma ranges. The techniques required for preprocessing EEGs in search of global patterns were diametrically opposed to those needed for localization of modular EEG signals. Frames were found in the form of intermittent spatial patterns of phase and amplitude modulation (AM and PM) of carrier waves in beta and gamma ranges that served to classify EEG frames with respect to CSs. A model based on the intentional action-perception cycle is proposed to complement the information processing model.

Animals↗
PubMedDate not supplied

Ovarian cancer diagnosis by hippocampus and neocortex-inspired learning memory structures.

Early detection and accurate staging of ovarian cancer are the keys to improving survival rate. However, at present there is no single diagnosis modality that is sufficiently sensitive. DNA microarray analysis is an emerging technique that has potential for ameliorating the hardship in early detection and staging of ovarian disease. However, microarray data is ultra-huge and difficult to analyze. Hence, computational intelligence methods are often utilized to assist in the diagnosis and analysis process. Fuzzy Neural Networks (FNN) are more suitable for this task as FNN provides not only the accuracy, but also the interpretability of its reasoning process. Hippocampus-inspired Complementary Learning FNN (CLFNN) is able to rapidly derive fuzzy sets and formulate fuzzy rules. CLFNN uses positive and negative learning, and hence it reduces the effect of the curse of dimensionality and is capable of modeling the dynamics of the problem space with relatively good classification performance. One of its successors, a hybrid of complementary hippocampal learning and associative neocortical learning called Pseudo Associative Complementary Learning (PACL), is a structure that seeks to functionally model the memory consolidation process. Both PACL and CLFNN have human-like reasoning that allows physicians to examine their computation using familiar terms. They can construct intuitive fuzzy rules autonomously to justify their reasoning, which is important to generate trust among the users. Hence, CLFNN and PACL are applied as a diagnostic decision support system in ovarian cancer diagnosis. The experimental results are encouraging.

Algorithms↗
PubMed2005

Inter- and intra-laminar connections of pyramidal cells in the neocortex.

The flow of excitation through cortical columns has long since been predicted by studying the axonal projection patterns of excitatory neurones situated within different laminae. In grossly simplified terms and assuming random connectivity, such studies predict that input from the thalamus terminates primarily in layer 4, is relayed 'forward' to layer 3, then to layers 5 and 6 from where the modified signal may exit the cortex. Projection patterns also indicate 'back' projections from layer 5 to 3 and layer 6 to 4. More recently it has become clear that the interconnections between these layers are not random; forward projections primarily contact specific pyramidal subclasses and intracortical back projections innervate interneurones. This indicates that presynaptic axons or postsynaptic dendrites are capable of selecting their synaptic partners and that this selectivity is layer dependent. For the past decade, we and others have studied pyramidal cell targeting in circuits both within, and between laminae using paired intracellular recordings with biocytin filling and have begun to identify further levels of selectivity through the preferential targeting of electrophysiologically and/or morphologically distinct pyramidal subtypes. Presented here, therefore, is a brief overview of current thinking on the layer and subclass specific connectivity of neocortical principle excitatory cells.

Animals↗
PubMed2006

Transcription factors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus.

Glutamatergic, pyramidal-projection neurons are produced in the embryonic cerebral cortex by a series of genetically programmed fate choices, implemented in large part by developmental transcription factors. Our work has focused on Pax6, Tbr2/Eomes, NeuroD, and Tbr1, which are expressed sequentially during the neurogenesis of pyramidal-projection neurons. Recently, we have found that the same transcription factors are expressed, in the same order, during glutamatergic neurogenesis in the adult dentate gyrus, and (with modifications) in the developing cerebellum. While the precise functional significance of this transcription factor expression sequence is unknown, its common appearance in embryonic and adult neurogenesis, and in different brain regions, suggests it is part of a conserved genetic program that specifies general properties of glutamatergic neurons in these regions. Subtypes of glutamatergic neurons (e.g., layer-specific fates in the cortex) are further determined by combinations of transcription factors, superimposed on general sequential programs. These new perspectives on neurogenesis add to the conceptual framework for strategies to engineer neural stem cells for the repair of specific brain circuits.

Animals↗
PubMed2006

Early alpha-synuclein lipoxidation in neocortex in Lewy body diseases.

Previous studies in Lewy body diseases (LBDs), including Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), have shown oxidative stress damage more extended than the expected for the distribution of Lewy pathology. Since malondialdehyde (MDA) can form adducts with lysine residues of proteins, MDA-Lys immunoprecipitation and alpha-synuclein immunoblotting has been carried out in frontal cortex and substantia nigra homogenates from five patients with PD, five DLB, three iPD and seven aged-matched controls to decipher the extent of lipoxidized alpha-synuclein in LBDs. MDA-Lys-lipoxidation of alpha-synuclein in the substantia nigra and frontal cortex has been found in all DLB and PD cases examined, but also in the frontal cortex in 3/3 and in the substantia nigra in 2/3 cases with iPD. In addition, one control case had MDA-Lys-modified alpha-synuclein in the frontal cortex, and another in the substantia nigra. This work provides evidence of extended lipoxidative modification of alpha-synuclein in LBDs. Moreover, it demonstrates that alpha-synuclein lipoxidation is an early event in LBDs which precedes alpha-synuclein solubility modification and aggregation, and formation of Lewy bodies and neurites.

Aged↗
PubMed2006

Imaging the neocortex in epilepsy with double inversion recovery imaging.

The neocortices of 10 patients with partial seizures and acquired lesions, 14 patients with malformations of cortical development (MCD) and 33 patients with partial seizures and normal conventional MRI were quantitatively evaluated using whole brain double inversion recovery imaging (DIR) and Statistical Parametric Mapping (SPM). Compared to a group of 30 control subjects, DIR and objective voxel-by-voxel statistical comparison identified regions of significantly abnormal DIR signal intensity (DSI) in 9 out of 10 patients with acquired nonprogressive cerebral lesions and partial seizures. In all 9 patients, the areas of abnormal DSI concurred with abnormalities identified on visual inspection of conventional MRI. In all 14 patients with MCD, SPM detected regions of significantly abnormal DSI; all of which corresponded to abnormalities identified on visual inspection of conventional MRI. In addition, in both groups, there were areas that were normal on conventional imaging, which demonstrated abnormal DSI. Voxel-by-voxel statistical analysis identified significantly abnormal DSI in 15 of the 33 patients with cryptogenic focal epilepsy. In 10 of these, the areas of abnormal DSI concurred with epileptic EEG abnormality and clinical seizure semiology. Group analysis of MRI-negative patients with electroclinical seizure onset localising to the left temporal and left and right frontal regions revealed significantly abnormal DSI within the white matter of each respective lobe. DIR analysed using SPM was sensitive in patients with MCDs and acquired cerebral damage. Significant abnormalities in DSI in individual and grouped MRI-negative patients suggest that occult epileptogenic cerebral lesions are associated with subtle structural abnormalities. DIR is, therefore, a useful quantitative MRI technique for characterising epileptic foci and may contribute to presurgical evaluation.

Adult↗
PubMed2004

Precise development of functional and anatomical columns in the neocortex.

Sensory cortex is ordered into columns, each tuned to a subset of peripheral stimuli. To identify the principles underlying the construction of columnar architecture, we monitored the development of circuits in the rat barrel cortex, using laser-scanning photostimulation analysis of synaptic connectivity, reconstructions of axonal arbors, and in vivo whole-cell recording. Circuits impinging onto layer 2/3 neurons from layers 4 and 2/3 developed in a monotonic, precise progression, with little evidence for transient hyperinnervation at the level of cortical columns. Consistent with this, synaptic currents measured in layer 2/3 neurons at PND 8, just after these neurons ceased to migrate, revealed already spatially well-tuned receptive fields.

Action Potentials↗
PubMed2004

EMX2 regulates sizes and positioning of the primary sensory and motor areas in neocortex by direct specification of cortical progenitors.

Genetic studies of neocortical area patterning are limited, because mice deficient for candidate regulatory genes die before areas emerge and have other complicating issues. To define roles for the homeodomain transcription factor EMX2, we engineered nestin-Emx2 transgenic mice that overexpress Emx2 in cortical progenitors coincident with expression of endogenous Emx2 and survive postnatally. Cortical size, lamination, thalamus, and thalamocortical pathfinding are normal in homozygous nestin-Emx2 mice. However, primary sensory and motor areas are disproportionately altered in size and shift rostrolaterally. Heterozygous transgenics have similar but smaller changes. Opposite changes are found in heterozygous Emx2 knockout mice. Fgf8 expression in the commissural plate of nestin-Emx2 mice is indistinguishable from wild-type, but Pax6 expression is downregulated in rostral cortical progenitors, suggesting that EMX2 repression of PAX6 specification of rostral identities contributes to reduced rostral areas. We conclude that EMX2 levels in cortical progenitors disproportionately specify sizes and positions of primary cortical areas.

Animals↗
PubMed2004

New circuits for old memories: the role of the neocortex in consolidation.

Studies of learning and memory have provided a great deal of evidence implicating hippocampal mechanisms in the initial storage of facts and events. However, until recently, there were few hints as to how and where this information was permanently stored. A recent series of rodent molecular and cellular cognition studies provide compelling evidence for the involvement of specific neocortical regions in the storage of information initially processed in the hippocampus. Areas of the prefrontal cortex, including the anterior cingulate and prelimbic cortices, and the temporal cortex show robust increases in activity specifically following remote memory retrieval. Importantly, damage to or inactivation of these areas produces selective remote memory deficits. Additionally, transgenic studies provide glimpses into the molecular and cellular mechanisms underlying cortical memory consolidation. The studies reviewed here represent the first exciting steps toward the understanding of the molecular, cellular, and systems mechanisms of how the brain stores our oldest and perhaps most defining memories.

Animals↗
PubMed2005

Transient and persistent dendritic spines in the neocortex in vivo.

Dendritic spines were imaged over days to months in the apical tufts of neocortical pyramidal neurons (layers 5 and 2/3) in vivo. A fraction of thin spines appeared and disappeared over a few days, while most thick spines persisted for months. In the somatosensory cortex, from postnatal day (PND) 16 to PND 25 spine retractions exceeded additions, resulting in a net loss of spines. The fraction of persistent spines (lifetime > or = 8 days) grew gradually during development and into adulthood (PND 16-25, 35%; PND 35-80, 54%; PND 80-120, 66%; PND 175-225, 73%), providing evidence that synaptic circuits continue to stabilize even in the adult brain, long after the closure of known critical periods. In 6-month-old mice, spines turn over more slowly in visual compared to somatosensory cortex, possibly reflecting differences in the capacity for experience-dependent plasticity in these brain regions.

Aging↗
PubMed2005

Phosphorylation of Neurogenin2 specifies the migration properties and the dendritic morphology of pyramidal neurons in the neocortex.

The molecular mechanisms specifying the dendritic morphology of different neuronal subtypes are poorly understood. Here we demonstrate that the bHLH transcription factor Neurogenin2 (Ngn2) is both necessary and sufficient for specifying the dendritic morphology of pyramidal neurons in vivo by specifying the polarity of its leading process during the initiation of radial migration. The ability of Ngn2 to promote a polarized leading process outgrowth requires the phosphorylation of a single tyrosine residue at position 241, an event that is neither involved in Ngn2 direct transactivation properties nor its proneural function. Interestingly, the migration defect observed in the Ngn2 knockout mouse and in progenitors expressing the Ngn2(Y241F) mutation can be rescued by inhibiting the activity of the small-GTPase RhoA in cortical progenitors. Our results demonstrate that Ngn2 coordinates the acquisition of the radial migration properties and the unipolar dendritic morphology characterizing pyramidal neurons through molecular mechanisms distinct from those mediating its proneural activity.

Age Factors↗
PubMed2006

Cell type-specific structural plasticity of axonal branches and boutons in the adult neocortex.

We imaged axons in layer (L) 1 of the mouse barrel cortex in vivo. Axons from thalamus and L2/3/5, or L6 pyramidal cells were identified based on their distinct morphologies. Their branching patterns and sizes were stable over times of months. However, axonal branches and boutons displayed cell type-specific rearrangements. Structural plasticity in thalamocortical afferents was mostly due to elongation and retraction of branches (range, 1-150 microm over 4 days; approximately 5% of total axonal length), while the majority of boutons persisted for up to 9 months (persistence over 1 month approximately 85%). In contrast, L6 axon terminaux boutons were highly plastic (persistence over 1 month approximately 40 %), and other intracortical axon boutons showed intermediate levels of plasticity. Retrospective electron microscopy revealed that new boutons make synapses. Our data suggest that structural plasticity of axonal branches and boutons contributes to the remodeling of specific functional circuits.

Analysis of Variance↗
PubMed2006

The H current blocker ZD7288 decreases epileptiform hyperexcitability in the rat neocortex by depressing synaptic transmission.

Neurons respond to intracellular injection of hyperpolarizing current pulses by generating depolarizing sags contributed by a cation current termed Ih. Ih modulates neuron excitability and rhythmicity. It is, however, unclear whether the net effect of changing Ih leads to facilitation or depression of cortical epileptiform activity. Here, we addressed this issue by using field and intracellular recordings to study the effects of ZD7288 (10-100 microM), a bradycardic agent known to abolish Ih, on the epileptiform discharges (duration = 2.5 +/- 0.3 s, mean +/- SEM; interval of occurrence = 34.2 +/- 3.3 s, n = 30 slices) induced in rat neocortical slices by 4-aminopyridine and GABA receptor antagonists. ZD7288 abolished the depolarizing sags seen during injection of intracellular hyperpolarizing current pulses while increasing resting membrane potential and apparent input resistance. These effects, which were fully established with 10 microM ZD7288, were associated with a dose-dependent decrease in the occurrence of spontaneous epileptiform events and a reduction in their duration (the latter change occurring at doses > 20 microM). ZD7288 also caused a dose-dependent decrease of background postsynaptic potentials. Finally, ZD7288 could depress epileptiform activity during Cs+ pre-treatment, a procedure known to block Ih. These data indicate that ZD7288 hampers neocortical epileptiform synchronization, but also suggest that most of this action reflects the ability of ZD7288 to decrease synaptic transmission.

4-Aminopyridine↗
PubMed2004

Sequential activation of microcircuits underlying somatosensory-evoked potentials in rat neocortex.

Evoked cortical field potentials are widely used in neurophysiological studies into cortical functioning, but insight in the underlying neural mechanisms is severely hampered by ambiguities in the interpretation of the field potentials. The present study aimed at identifying the precise relationships between the primary evoked cortical field potential (the positive-negative [P1-N1]response) and the temporal and spatial sequence in which different local cortical micro-circuits are recruited. We electrically stimulated the median nerve and recorded field potentials using a 12-channel depth probe in somatosensory cortex of ketamine anesthetized rats. Current source density analysis was used and a grand average was constructed based on all individual animals taking into account individual differences in cortical layering. Manipulation of stimulus strength, selective averaging of single trial responses, and double-pulse stimulation, were used to help disentangle overlapping dipoles and to determine the sequence of neuronal events. We discriminated three phases in the generation of the P1-N1 wave. In the first phase, specific thalamic afferents depolarize both layer III and layer V pyramidal cells. In the second phase, superficial pyramidal cells are depolarized via supragranular intracortical projections. In the third phase, population spikes are generated in layer Vb pyramidal cells, associated with a distinct fast (approximately 1 ms) sink/source configuration. Axon-collaterals of layer Vb pyramidal cells produce an enhanced activation of the supragranular pyramidal cells in layer I-II, which generates N1.

Algorithms↗
PubMed2005

Evidence for neurogenesis within the white matter beneath the temporal neocortex of the adult rat brain.

Persistent neuron production in the adult CNS (adult neurogenesis) has been implicated in various brain functions such as learning/memory and mood control. Despite the widespread occurrence of neural stem/progenitor cells, active adult neurogenesis has been established only in two restricted regions. We explored in this study a previously overlooked neurogenic region in the adult rat brain and detected the evidence of neuron production within the subcortical white matter. Dividing Pax6- and Olig2-positive neural progenitor cells continually gave rise to doublecortin-positive new neurons in this region. However, the vast majority of newborn neurons were lost within a week of their birth. Accumulated apoptotic cells indicated the ongoing cell death in this area. In addition to providing the evidence of newborn cell migration to the hippocampus, these results suggest that cell genesis, death, and migration persist in a restricted subregion of the adult white matter.

Animals↗
PubMed2006

Density and morphology of dendritic spines in mouse neocortex.

Dendritic spines of pyramidal cells are the main postsynaptic targets of cortical excitatory synapses and as such, they are fundamental both in neuronal plasticity and for the integration of excitatory inputs to pyramidal neurons. There is significant variation in the number and density of dendritic spines among pyramidal cells located in different cortical areas and species, especially in primates. This variation is believed to contribute to functional differences reported among cortical areas. In this study, we analyzed the density of dendritic spines in the motor, somatosensory and visuo-temporal regions of the mouse cerebral cortex. Over 17,000 individual spines on the basal dendrites of layer III pyramidal neurons were drawn and their morphologies compared among these cortical regions. In contrast to previous observations in primates, there was no significant difference in the density of spines along the dendrites of neurons in the mouse. However, systematic differences in spine dimensions (spine head size and spine neck length) were detected, whereby the largest spines were found in the motor region, followed by those in the somatosensory region and those in visuo-temporal region.

Animals↗
PubMed2005

Does inhibition balance excitation in neocortex?

The distribution of inhibitory and excitatory synapses on neocortical neurons is at odds with a simple view that cortical functioning can persist by maintaining a balance between inhibitory and excitatory drives. Pyramidal cells can potentially be shut down by very powerful proximal inhibitory synapses, despite these accounting for perhaps less than 1% of their total number of synaptic inputs. Interneurons in contrast are dominated by excitatory inputs. These may be powerful enough to effect an apparent depolarizing block at the soma. In this extreme case though, models suggest that action potentials are generated down the axon, and the cells behave like integrate-and-fire neurons. We discuss possible network implications of these modelling studies.

Animals↗
PubMed2005

Mean cell spacing abnormalities in the neocortex of patients with schizophrenia.

It has been postulated that the prefrontal cortices of schizophrenic patients have significant alterations in their interneuronal (neuropil) space. The present study re-examines this finding based on measurements of mean cell spacing within the cell minicolumn. The population studied consisted of 13 male schizophrenic patients (DSM-IV criteria) and 13 age-matched controls. Photomicrographs of Brodmann's areas 9, 4 (M1), 3b (S1), and 17 (V1) were analyzed with computerized image analysis to measure parameters of minicolumnar morphometry, i.e., columnarity index (CI), minicolumnar width (CW), dispersion of minicolumnar width (V(CW)), and mean interneuronal distance (MCS). The results indicate alterations in the mean cell spacing of schizophrenic patients according to both the lamina and cortical area examined. The lack of variation in the columnarity index argues in favor of a defect postdating the formation of the cell minicolumn.

Adult↗