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PubMed2006

Enriched environment after focal cortical ischemia enhances the generation of astroglia and NG2 positive polydendrocytes in adult rat neocortex.

Environmental enrichment (EE) alleviates sensorimotor deficits after brain infarcts but the cellular correlates are not well-known. This study aimed to test the effects of postischemic EE on neocortical cell genesis. A neocortical infarct was caused by distal ligation of the middle cerebral artery in adult spontaneously hypertensive rats, subsequently housed in standard environment or EE. Bromodeoxyuridine (BrdU) was administered during the first postischemic week to label proliferating cells and BrdU incorporation was quantified 4 weeks later in the periinfarct, ipsilateral medial and contralateral cortex. Immunohistochemistry and confocal microscopy were used to analyze co-localization of BrdU with neuronal (calbindin D28k, calretinin, parvalbumin, glutamic acid decarboxylase, tyrosine hydroxylase), astrocytic (glial fibrillary acidic protein, glutamine synthetase, vimentin, nestin), microglia/macrophage (CD11b/Ox-42, CD68/ED-1), oligodendrocyte progenitor/polydendrocyte (NG2, platelet-derived growth factor alpha receptor) or mature oligodendrocyte (myelin basic protein) markers. BrdU positive cells were increased in all analyzed cortical regions in stroke EE rats compared with stroke standard environment rats. Newly born cells in the periinfarct cortex were mostly reactive astroglia. Occasionally, BrdU positive cells in the periinfarct cortex that were negative for glial or microglia/macrophage markers co-expressed markers typical for interneurons but did not express appropriate functional markers. The majority of BrdU positive cells in intact cortical regions, ipsi- and contralaterally, were identified as NG2 positive polydendrocytes. Perineuronally situated newly born cells and polydendrocytes were found to be brain-derived neurotrophic factor immunoreactive. In conclusion, EE enhanced newborn glial scar astroglia and NG2+ polydendrocytes in the postischemic neocortex which might be beneficial for brain repair and poststroke plasticity.

Animals↗
PubMed2024

Molecular mechanisms of the specialization of human synapses in the neocortex.

Synapses of the neocortex specialized during human evolution to develop over extended timescales, process vast amounts of information and increase connectivity, which is thought to underlie our advanced social and cognitive abilities. These features reflect species-specific regulations of neuron and synapse cell biology. However, despite growing understanding of the human genome and the brain transcriptome at the single-cell level, linking human-specific genetic changes to the specialization of human synapses has remained experimentally challenging. In this review, we describe recent progress in characterizing divergent morphofunctional and developmental properties of human synapses, and we discuss new insights into the underlying molecular mechanisms. We also highlight intersections between evolutionary innovations and disorder-related dysfunctions at the synapse.

Humans↗
PubMed2005

Theta phase locking across the neocortex reflects cortico-hippocampal recursive communication during goal conflict resolution.

EEG theta coherence, EEG theta power and subjective levels of response were examined in a continuous monitoring target detection task where periodic goal conflicts were introduced as 34 participants progressed through a stimulus sequence leading to response. EEG theta coherence revealed increases in phase locking between cortical areas at specific task stages involving goal conflict. Theta power also increased at points of goal conflict. The temporal characteristics of subjective response (measured continuously throughout the task) indicated a delay between participants actually experiencing goal conflict and overt indications of conflict. The starting point for the study was based on a specific aspect of Gray and McNaughton's [Gray, J.A., McNaughton, N., 2000. The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo-Hippocampal System, 2nd ed. Oxford University Press, Oxford] behavioural inhibition system model-namely, septo-hippocampal system involvement in the resolution of goal conflicts. We drew on Gray and McNaughton's [Gray, J.A., McNaughton, N., 2000. The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo-Hippocampal system, 2nd ed. Oxford University Press, Oxford] suggestion that septo-hippocampal involvement in this process is reflected by EEG theta. While their theory explains many of our findings, we also drew upon Given's [Givens, B., 1996. Stimulus-evoked reseting of the dentate theta rhythm: relation to working memory. Neuroreport 8 (1), 159-163] proposal that the dentate theta rhythm is reset by behaviourally relevant stimuli. We made further proposals based on Makeig et al.'s [Makeig, S., Westerfield, M., Jung, T.-P., Enghoff, S., Townsend, J., Courchesne, E., Sejnowski, T.J., 2002. Dynamic brain sources of visual evoked responses. Science 295, 690-694] view that specific stimulus events invoke concurrent phase resetting and transient frequency domain coherence across different areas of neocortex. Relations with Go/NoGo event related potentials (P300 and N2; e.g., [Bokura, H., Yamaguchi, S., Kobayashi, S., 2001. Electrophysiological correlates of response inhibition in a Go/NoGo task. Clin. Neurophysiol. 112 (12), 2224-2232]) were also discussed, as well as parallels between our data and interpretation, and other theoretical models of theta (e.g., [Kahana, M.J., Selig, D., Madsen, J.R., 2001. Theta returns. Curr. Opin. Neurobiol. 11, 739-744]). Suggestions for further research were made.

Adolescent↗
PubMed2005

Optimized protocols for the simultaneous preparation of primary neuronal cultures of the neocortex, hippocampus and cerebellum from individual newborn (P0.5) C57Bl/6J mice.

Knockout mouse models allow preparation of primary neuronal cultures from distinct brain regions in order to investigate the underlying neuronal pathomechanisms of human metabolic diseases associated with severe, regionally distinct brain pathologies (e.g. Zellweger syndrome, the most severe form of a peroxisomal biogenesis disorder). However, homozygous mouse pups with Zellweger syndrome usually die shortly after birth. Therefore, in this study, we established optimized protocols for the simultaneous preparation and cultivation of serum-free primary neuronal cultures from distinct brain regions (medial neocortex, hippocampus and cerebellum) from individual newborn (P0.5) C57Bl/6J mice. For each of the three types of neuronal cultures, we have optimized the isolation procedures and cultivation conditions including coating substrates, enzyme digestion, mode of trituration, seeding density and composition of the culture medium. As indicated by indirect immunofluorescence using antibodies against NeuN, GFAP and CNPase, the purity of the distinct neuronal cultures was high. The percentage of oligodendrocytes was less than 1% in all neuronal cultures. Only 5% astrocytes were present in cortical, 7% in hippocampal and 10% in cerebellar cultures. Cytosine arabinofuranoside (AraC) treatment reduced the percentage of astrocytes only significantly in hippocampal cultures, however, increased the percentage of apoptotic neurons in hippocampal and cortical cultures.

Animals↗
PubMed2004

A computational model for the primate neocortex based on its functional architecture.

Experimental evidence has shown that the primate neocortex consists in the main of a set of cortical regions which form a perception hierarchy, an action hierarchy and connections between them. By using a computer science analysis, we develop a computational architecture for the brain in which each cortical region is represented by a computational module with processing and storage abilities. Modules are interconnected according to the connectivity of the corresponding cortical regions. We develop computational principles for designing such a hierarchical and parallel computing system. We demonstrate this approach by proposing a causal functioning model of the brain. We report on results obtained with an implementation of this model. We conclude with a brief discussion of some consequences and predictions of our work.

Animals↗
PubMed2006

Scaling properties of pyramidal neurons in mice neocortex.

Dendritic morphology is the structural correlate for receiving and processing inputs to a neuron. An interesting question then is what the design principles and the functional consequences of enlarged or shrinked dendritic trees might be. As yet, only a few studies have examined the effects of neuron size changes. Two theoretical scaling modes have been analyzed, conservative (isoelectrotonic) scaling (preserves the passive and active response properties) and isometric scaling (steps up low pass-filtering of inputs). It has been suggested that both scaling modes were verified in neuroanatomical studies. To overcome obvious limitations of these studies like small size of analyzed samples and restricted validity of utilized scaling measures, we considered the scaling problem of neurons on the basis of large sample data and by employing a more general method of scaling analysis. This method consists in computing the morphoelectrotonic transform (MET) of neurons. The MET maps the neuron from anatomical space into electrotonic space using the logarithm of voltage attenuation as the distance metric. The theory underlying this approach is described and then applied to two samples of morphologically reconstructed pyramidal neurons (cells from neocortex of wildtype and synRas transgenic mice) using the NEURON simulator. In a previous study, we could verify a striking increase of dendritic tree size in synRas pyramidal neurons. Surprisingly, in this study the statistical analysis of the sample MET dendrograms revealed that the electrotonic architecture of these neurons scaled roughly in a MET-conserving mode. In conclusion, our results suggest only a minor impact of the Ras protein on dendritic electroanatomy, with non-significant changes of most regions of the corresponding METs.

Algorithms↗
PubMed2006

Selective effects of the APOE epsilon4 allele on presynaptic cholinergic markers in the neocortex of Alzheimer's disease.

The effects of the APOE epsilon4 allele on a range of pre- and postsynaptic cholinergic markers were studied in a cohort of community-based Alzheimer's disease (AD) patients. Compared with age-matched controls, the postmortem AD neocortex showed decreased choline acetyltransferase (ChAT) and acetyl cholinesterase activities, lower muscarinic M2, and nicotinic alpha4beta2 receptor densities, as well as reduced M1 receptor coupling to G-proteins. However, the epsilon4 allele was dose-dependently correlated only with higher losses of ChAT activities. AD patients with two epsilon4 alleles also had more beta-amyloid containing senile plaques in the temporal cortex compared to patients with 0/1 epsilon4. This study suggests that APOE epsilon4 selectively affects presynaptic cholinergic function which may contribute to the clinical and neuropathological features of AD.

Acetylcholine↗
PubMed2004

Inducible nitric oxide synthase is involved in the mechanisms of cocaine enhanced neuronal apoptosis induced by HIV-1 gp120 in the neocortex of rat.

Cocaine, often abused by human immunodeficiency virus (HIV) infected patients, has been suggested to worsen the HIV associated dementia via unknown mechanisms. Here we report that subchronic treatment with a dose of cocaine (30 mg/kg i.p.), unable per se to cause neuronal death, increases the number of apoptotic cells typically observed in the neocortex of rats treated with HIV-1 gp120 (100 ng given i.c.v.). A pre-treatment with MK801 (0.3 mg/kg i.p.), a NMDA receptor antagonist, L-NAME (10 mg/kg i.p.) and 7-nitroindazole (50 mg/kg i.p.), two specific inhibitors of NOS, or with 1400 W (1 mg/kg s.c.), a selective inhibitor of inducible NOS (iNOS), minimized neurotoxicity by combined administration of cocaine and gp120 thus implicating iNOS. This conclusion is supported by the evidence that cocaine increases brain neocortical citrulline, the co-product of NO synthesis.

Anesthetics, Local↗
PubMed2006

Effects of quetiapine on the brain-derived neurotrophic factor expression in the hippocampus and neocortex of rats.

The effects of antipsychotics on the brain-derived neurotrophic factor (BDNF) expression have been controversial. This study aimed to investigate the effects of chronic quetiapine administration on the BDNF mRNA expression in hippocampus and neocortex of rats with or without immobilization stress. The chronic administration (21 days) of quetiapine (10 mg/kg) significantly attenuated the decreased BDNF mRNA expression in the both hippocampal and cortical regions of rats caused by immobilization stress, and significantly increased the BDNF mRNA expression in the dentate gyrus of rats even without the immobilization stress. These results could add some theoretical bases to explain why quetiapine may improve cognitive symptoms of schizophrenia by stimulating BDNF mRNA expression.

Analysis of Variance↗
PubMed2005

Impaired coupling of muscarinic M1 receptors to G-proteins in the neocortex is associated with severity of dementia in Alzheimer's disease.

Impaired transmission of acetylcholine-mediated signaling by postsynaptic muscarinic M1 receptors has been postulated to underlie the limited efficacy of cholinergic replacement therapies in Alzheimer's disease (AD). However, a clear relationship between the functionality of M1 receptors and dementia severity has not been demonstrated. The present study aims to measure M1 coupling to its nucleotide binding (G-) protein in the AD neocortex, and to correlate neurochemical findings with clinical features. A cohort of dementia patients was longitudinally assessed for cognitive decline, with postmortem neuropathological confirmation of AD diagnosis. Measures of M1 receptor density, M1/G-protein coupling and choline acetyltransferase (ChAT) activities were performed in the frontal and temporal cortex of 24 AD patients as well as in 12 age-matched controls. We found that M1 receptor densities were unchanged in AD, which contrasted with significantly reduced M1 coupling to G-proteins in severely demented AD patients. Loss of M1/G-protein coupling in the frontal cortex, but not the temporal cortex, also correlated with the rate of cognitive decline. Additionally, correlations between M1/G-protein coupling and ChAT activities were demonstrated in both regions. These results suggest that defective coupling of neocortical M1 receptors to G-proteins is a neurochemical substrate of cognitive decline in AD. Based on its associations with ChAT deficits and dementia severity, we propose that M1/G-protein uncoupling may have a significant role in the disease mechanism of AD and thus may be considered to be a potential therapeutic target.

Aged↗
PubMed2004

Local and remote functional connectivity of neocortex under the inhibition influence.

The current paper focuses on a relatively new and promising area of the study of EEG transformations during brain information processing based on the reduction of the signal to the discrete quasi-stationary segment sequences which may reflect individual brain microstates or discrete operations. In this framework, the complex brain functions require integration of several operations throughout the whole neocortex. However, the role of inhibitory brain systems in such processes is still unsettled. The effects of a single dose (30 microg/kg) of lorazepam on the operational activity of neuronal populations and on the temporal binding between them were examined in a double-blind randomized crossover placebo-controlled study with eight healthy volunteers. EEG measures at 20 channels were evaluated on two occasions: (1) eyes closed, (2) eyes open. In short, we conducted a two-by-two factorial study where one factor manipulated GABAergic neurotransmission (lorazepam vs. placebo), and the other factor was simply brain state (eyes closed vs. eyes opened). We were primarily interested in the main effect of lorazepam. In the present study, a connection between the mesoscopic level, described by the local functional processes (neuronal assemblies or populations) and the macroscopic level, described as a sequence of metastable brain states (remote functionally synchronized neuronal populations) was established. The role of inhibitory brain systems facilitated by lorazepam in the operational dynamics of neuronal populations and in the process of EEG structural synchrony (SS) (topological peculiarities) was addressed for the first time. It was shown that GABA signaling reorganized the dynamics of local neuronal populations and the remote functional connectivity between them.

Adult↗
PubMed2004

Calcium waves propagate through radial glial cells and modulate proliferation in the developing neocortex.

The majority of neurons in the adult neocortex are produced embryonically during a brief but intense period of neuronal proliferation. The radial glial cell, a transient embryonic cell type known for its crucial role in neuronal migration, has recently been shown to function as a neuronal progenitor cell and appears to produce most cortical pyramidal neurons. Radial glial cell modulation could thus affect neuron production, neuronal migration, and overall cortical architecture; however, signaling mechanisms among radial glia have not been studied directly. We demonstrate here that calcium waves propagate through radial glial cells in the proliferative cortical ventricular zone (VZ). Radial glial calcium waves occur spontaneously and require connexin hemichannels, P2Y1 ATP receptors, and intracellular IP3-mediated calcium release. Furthermore, we show that wave disruption decreases VZ proliferation during the peak of embryonic neurogenesis. Taken together, these results demonstrate a radial glial signaling mechanism that may regulate cortical neuronal production.

Animals↗
PubMed2005

Differential encoding of behavior and spatial context in deep and superficial layers of the neocortex.

Rodent hippocampal activity is correlated with spatial and behavioral context, but how context affects coding in association neocortex is not well understood. The cellular distribution of the neural activity-regulated immediate-early gene Arc was used to monitor the activity history of cells in CA1, and in deep and superficial layers of posterior parietal and gustatory cortices (which encode movement and taste, respectively), during two behavioral epochs in which spatial and behavioral context were independently manipulated while gustatory input was held constant. Under conditions in which the hippocampus strongly differentiated behavioral and spatial contexts, deep parietal and gustatory layers did not discriminate between spatial contexts, whereas superficial layers in both neocortical regions discriminated well. Deep parietal cells discriminated behavioral context, whereas deep gustatory cortex neurons encoded the two conditions identically. Increased context sensitivity of superficial neocortical layers, which receive more hippocampal outflow, may reflect a general principle of neocortical organization for memory retrieval.

Animals↗
PubMed2005

Modeling depression: social dominance-submission gene expression patterns in rat neocortex.

Gene expression profiles in the cortex of adult Long-Evans rats as a function of a stressful social loss and victory in inter-male fighting encounters were examined. This social dominance and subordination model has been postulated to simulate early changes in the onset of depression in the losers. Microarrays were fabricated containing 45mer oligonucleotides spotted in quadruplicate and representing 1178 brain-associated genes. Dynamic range, discrimination power, accuracy and reproducibility were determined with standard mRNA "spiking" studies. Gene expression profiles in dominant and subordinate animals were compared using a "universal" reference design [Churchill GA (2002) Fundamentals of experimental design for cDNA microarrays. Nat Genet 32 (Suppl):490-495]. Data were analyzed by significance analysis of microarrays using rank scores [Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 98:5116-5121; van de Wiel MA (2004) Significance analysis of microarrays using rank scores. Kwantitatieve Methoden 71:25-37]. Ontological analyses were then performed using the GOMiner algorithm [Zeeberg BR, Feng W, Wang G, Wang MD, Fojo AT, Sunshine M, Narasimhan S, Kane DW, Reinhold WC, Lababidi S, Bussey KJ, Riss J, Barrett JC, Weinstein JN (2003) GoMiner: a resource for biological interpretation of genomic and proteomic data. Genome Biol 4(4):R28]. And finally, genes of special interest were further studied using quantitative reverse transcriptase polymerase chain reaction. Twenty-two transcripts were statistically significantly differentially expressed in the neocortex between dominant and subordinate animals. Ontological analyses revealed that significant gene changes were clustered primarily into functional neurochemical pathways associated with protein biosynthesis and cytoskeletal dynamics. The most robust of these were the increased expression of interleukin-18, heat shock protein 27, beta3-tubulin, ribosome-associated membrane protein 4 in subordinate animals. Interleukin-18 has been found to be over-expressed in human depression and panic disorder as well as other physiological stress paradigms [Takeuchi M, Okura T, Mori T, Akita K, Ohta T, Ikeda M, Ikegami H, Kurimoto M (1999) Intracellular production of interleukin-18 in human epithelial-like cell lines is enhanced by hyperosmotic stress in vitro. Cell Tissue Res 297(3):467-473] and heat shock proteins have been shown to be involved in the pathogenesis of many neurodegenerative and psychiatric disorders [Iwamoto K, Kakiuchi C, Bundo M, Ikeda K, Kato T (2004) Molecular characterization of bipolar disorder by comparing gene expression profiles of postmortem brains of major mental disorders. Mol Psychiatry 9(4):406-416; Pongrac JL, Middleton FA, Peng L, Lewis DA, Levitt P, Mirnics K (2004) Heat shock protein 12A shows reduced expression in the prefrontal cortex of subjects with schizophrenia. Biol Psychiatry 56(12):943-950]. Thus, the gene expression changes that we have observed here are consistent with and extend the observations found in the clinical literature and link them to the animal model used here thereby reinforcing its use to better understand the genesis of depression and identify novel therapeutic targets for its treatment.

Animals↗
PubMed2004

High-resolution functional optical imaging: from the neocortex to the eye.

Much work remains to be done to establish the clinical usefulness of the RFI for early diagnosis and treatment guidance. The discoveries obtained by functional optical imaging of the neocortex in the last 15 years and the recent RFI studies of the eyes of normal subjects and patients with diabetic retinopathy, glaucoma, and age-related macular degeneration suggest that functional optical imaging of the retina is likely to become a multi-modality powerful clinical tool.

Animals↗
PubMed2005

Primary central white matter hypoplasia of the neocortex.

Leukodystrophies, or diseases of the white matter, represent acute or ongoing damage to the oligodendrocytes of the central nervous system. Early childhood white matter disease is most commonly observed after hypoxic ischemic insults, with acute magnetic resonance imaging changes followed by atrophy or periventricular leukomalacia. Dysmyelination occurring in the setting of inborn errors of metabolism is characterized by progressive changes with high signal intensity in white matter on magnetic resonance imaging. This report presents a patient whose magnetic resonance imaging scans demonstrated hypoplasia of myelin in the telencephalon, without clinical or magnetic resonance imaging evidence of inflammatory dysmyelination. Clinical features included intractable seizures, severe hypotonia, and dysmorphic facial features coupled with a static failure to gain developmental milestones. Together, the clinical and magnetic resonance imaging findings are evidence of a primary failure of myelination in the neocortex.

Abnormalities, Multiple↗
PubMed2006

Is neocortex essentially multisensory?

Although sensory perception and neurobiology are traditionally investigated one modality at a time, real world behaviour and perception are driven by the integration of information from multiple sensory sources. Mounting evidence suggests that the neural underpinnings of multisensory integration extend into early sensory processing. This article examines the notion that neocortical operations are essentially multisensory. We first review what is known about multisensory processing in higher-order association cortices and then discuss recent anatomical and physiological findings in presumptive unimodal sensory areas. The pervasiveness of multisensory influences on all levels of cortical processing compels us to reconsider thinking about neural processing in unisensory terms. Indeed, the multisensory nature of most, possibly all, of the neocortex forces us to abandon the notion that the senses ever operate independently during real-world cognition.

Animals↗
PubMed2004

Widespread tangential dispersion and extensive cell death during early neurogenesis in the mouse neocortex.

The development of the mammalian neocortex requires radial and tangential migration of cells. Radial migration of differentiated neurons from the ventricular zone (VZ) is well established. It is hypothesised that an earlier phase of tangential migration of mitotically active cells lays down a widespread periodically spaced set of progenitors that generate radial arrays of postmitotic neurons. We use a transgenic cell lineage marker to label and observe the behaviour of progenitors before and during the early stages of neurogenesis. Using optical projection tomography (OPT), we show that individual progenitor cells generate many radially arrayed columns of periodically spaced cells. Column positions indicate the paths taken by these progenitor cells as they migrate, often over long distances, through the proliferative zone. Clonally related cells can be distributed in both hemispheres, suggesting progenitor cells cross the midline in the anterior neural plate. We observe a dramatic and rapid decline in the number of labelled clones after E13.5, indicating that there is extensive cell death at this time.

Animals↗