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PubMed2006

Severe alcohol-induced neuronal deficits in the hippocampus and neocortex of neonatal mice genetically deficient for neuronal nitric oxide synthase (nNOS).

Alcohol can severely damage the developing brain, and neuronal loss is a critical component of this injury. Thus, identification of molecular factors that ameliorate alcohol-induced neuronal loss is of great importance. Previous in vitro work has demonstrated that nitric oxide (NO) protects neurons against alcohol toxicity. We tested the hypothesis that neonatal mice carrying a null mutation for neuronal nitric oxide synthase (nNOS), the enzyme that synthesizes NO in neurons, have an increased vulnerability to alcohol-induced neuronal loss in the neocortex and hippocampus. Wildtype mice and nNOS-/- mice received ethanol (0.0, 2.2, 3.3, or 4.4 g/kg) daily over postnatal days (P) 4-9 and were sacrificed on P10. The number of hippocampal CA1 and CA3 pyramidal cells, dentate gyrus granule cells, and neocortical neurons were determined using stereological methods. Alcohol pharmacokinetics did not differ between wildtype and nNOS-/- strains. Alcohol induced dose-dependent reductions in all four neuronal populations, and the losses were substantially more severe in the nNOS-/- mice than in wildtype. Furthermore, the threshold dose of alcohol to induce cell death was lower in the nNOS-/- mice than in the wildtype mice for all neuronal populations. While nNOS deficiency worsened alcohol-induced neuronal losses, the magnitude of this exacerbation varied among brain regions and depended on alcohol dose. These results demonstrate that nNOS deficiency decreases the ability of developing neurons in vivo to survive the toxic effects of alcohol and strengthen the hypothesis that NO exerts a neuroprotective effect against alcohol toxicity in the developing brain.

Analysis of Variance↗
PubMed2006

Estradiol-induced modulation of estrogen receptor-beta and GABA within the adult neocortex: a potential transsynaptic mechanism for estrogen modulation of BDNF.

Estrogen influences brain-derived neurotrophic factor (BDNF) expression in the neocortex. However, BDNF-producing cortical neurons do not express detectable levels of nuclear estrogen receptors; instead, the most abundant cortical nuclear estrogen receptor, ER-beta, is present in GABAergic neurons, prompting us to test the hypothesis that estrogen effects on BDNF are mediated via cortical inhibitory interneurons. Adult female ovariectomized rats were provided acute estrogen replacement and the number of cortical GABA, ER-beta, and ER-beta/GABA double-labeled neurons was examined. Within 48 hours of injection of 17-beta-estradiol, the number of perirhinal neurons double-labeled for ER-beta/GABA was reduced by 28% (P<0.01 compared to vehicle-treated ovariectomized controls), and all cells expressing detectable levels of GABA were reduced by 19% (P<0.01). To investigate potential relationships between estrogen receptors, GABAergic neurons, and BDNF-expressing cells, brain sections were double- or triple-labeled for ER-beta, GABAergic, and BDNF immunomarkers. The findings indicated that ER-beta-bearing inhibitory neurons project onto other GABAergic neurons that lack nuclear estrogen receptors; these inhibitory neurons in turn innervate BDNF-expressing excitatory cells. High estrogen states reduce cortical GABA levels, presumably releasing inhibition on BDNF-expressing neurons. This identifies a putative two-step transsynaptic mechanism whereby estrogen availability modulates expression of inhibitory transmitters, resulting in increased BDNF expression.

Animals↗
PubMed2002

Cre/loxP recombination-activated neuronal markers in mouse neocortex and hippocampus.

A new strategy for visualizing neuronal cell morphology of mouse brain based on Cre/loxP recombination-activated gene expression is described. A "reporter" transgenic line was generated which expressed a fusion gene encoding a dendrite-targeted green fluorescent protein (MAP2-GFP) upon deletion of a transcription/translation STOP (transcription and translation stop signal) cassette. Cre transgenic "deleter" lines were established that activated reporter gene expression at various frequencies in pyramidal neurons in the forebrain. A deleter line was identified which activated a MAP2-GFP reporter gene at very low frequency (less than 0.1% of pyramidal neurons) and allowed the visualization of dendritic structures of individual neocortical and hippocampal pyramidal neurons. In addition, vertical "columns" of pyramidal neurons in the neocortex were labeled in these mice. In a second deleter line, a MAP2-GFP reporter gene was selectively activated in pyramidal neurons of the CA-1 subregion of the hippocampus in young mice. With its combinatorial property, this binary recombination-activated neuronal marker system should facilitate the study of detailed morphology, connectivity, and plasticity of defined classes of live neurons in vitro and in vivo.

Animals↗
PubMed2005

Enhanced proliferation of progenitor cells in the subventricular zone and limited neuronal production in the striatum and neocortex of adult macaque monkeys after global cerebral ischemia.

Cerebral ischemia in adult rodent models increases the proliferation of endogenous neural progenitor cells residing in the subventricular zone along the anterior horn of the lateral ventricle (SVZ a) and induces neurogenesis in the postischemic striatum and cortex. Whether the adult primate brain preserves a similar ability in response to an ischemic insult is uncertain. We used the DNA synthesis indicator bromodeoxyuridine (BrdU) to label newly generated cells in adult macaque monkeys and show here that the proliferation of cells with a progenitor phenotype (double positive for BrdU and the markers Musashi 1, Nestin, and beta III-tubulin) in SVZ a increased during the second week after a 20-min transient global brain ischemia. Subsequent progenitor migration seemed restricted to the rostral migratory stream toward the olfactory bulb and ischemia increased the proportion of adult-generated cells retaining their location in SVZ a with a progenitor phenotype. Despite the lack of evidence for progenitor cell migration toward the postischemic striatum or prefrontal neocortex, a small but sustained proportion of BrdU-labeled cells expressed features of postmitotic neurons (positive for the protein Neu N and the transcription factors Tbr 1 and Islet 1) in these two regions for at least 79 days after ischemia. Taken together, our data suggest an enhanced neurogenic response in the adult primate telencephalon after a cerebral ischemic insult.

Animals↗
PubMed2004

Optimized interleaved whole-brain 3D double inversion recovery (DIR) sequence for imaging the neocortex.

For a substantial number of individuals with neurological disorders, a conventional MRI scan does not reveal any obvious etiology; however, it is believed that abnormalities in the neocortical gray matter (GM) underlie many of these disorders. Attempts to image the neocortex are hindered by its thin, convoluted structure, and the partial volume (PV) effect. Therefore, we developed a 3D version of the double inversion recovery (DIR) sequence that incorporates an optimized interleaved (OIL) strategy to improve efficiency and allow high-quality, high-resolution imaging of GM.

Brain↗
PubMed2004

Induction of long-term depression is associated with decreased dendritic length and spine density in layers III and V of sensorimotor neocortex.

Long-term potentiation (LTP) and long-term depression (LTD) are currently the most widely investigated models of the synaptic mechanisms underlying learning and memory. Previous research has shown that induction of LTP increases measures of pyramidal cell dendritic morphology in the hippocampus and layers III and V of the neocortex. However, to date there are no reports on the direct effects of LTD induction on dendritic morphology. Here, we investigated the effects of LTD induction on sensorimotor pyramidal cell dendritic morphology. Rats carried a stimulating electrode in the corpus callosum (midline) and a recording electrode in the right sensorimotor cortex. Each rat received low-frequency stimulation composed of 900 pulses at 1 Hz or handling daily for a total 15 days. Evoked potentials (EPs) of the transcallosal pathway were recorded in the right hemisphere before and after the 15 days of stimulation or handling. The rats were then perfused with saline and the brains were immediately processed for Golgi-Cox staining. Our results show that LTD induction is related to decreases in dendritic length and spine density both in layers III and V as well as a decrease in dendritic branch complexity in layer V of the sensorimotor cortex. Thus, neuronal alterations following modifications in neocortical synaptic efficacy may provide a general mechanism for the physical instantiation of learning and memory.

Animals↗
PubMed1998

HIV-1 gp120-induced apoptosis in the rat neocortex involves enhanced expression of cyclo-oxygenase type 2 (COX-2).

The effect of subchronic intracerebroventricular (i.c.v.) injection of the human immunodeficiency virus type 1 (HIV-1) recombinant protein gp120 (100 ng, given daily for up to 7 consecutive days) on cyclooxygenase type 2 (COX-2) expression was studied by immunohistochemistry in the brain of adult rats. In comparison to control, bovine serum albumin (100 ng, given i.c.v. for up to 7 days) treated animals (n = 6), a single daily injection of the viral protein for 7 consecutive days enhanced the number of COX-2 immunoreactive cells in the brain cortex of rats (n = 6 per group) and this was accompanied by a 50% increase over control PGE2 content in whole brain tissue homogenates (n = 6). In another series of experiments, pretreatment of rats (n = 6) with indomethacin (6.0 mg/kg given i.p. 1 h before gp120 injection), an inhibitor COX activity, prevented apoptotic death typically produced by gp120 in the neocortex of rat suggesting that enhancement of COX-2 expression may be involved in the mechanisms of apoptosis yielded by the HIV-1 coat protein.

Animals↗
PubMed2000

Apoptosis induced by gp120 in the neocortex of rat involves enhanced expression of cyclooxygenase type 2 and is prevented by NMDA receptor antagonists and by the 21-aminosteroid U-74389G.

The effects of a single dose of the HIV-1 coat protein gp120 given into one lateral cerebral ventricle (i.c.v.) on the expression of cyclooxygenase type 2 (COX-2) and PGE(2) levels have been studied using Western blotting and ELISA techniques applied to brain tissue extracts obtained from the neocortex of individual rats, one of the regions of the central nervous system where the viral protein causes apoptosis. The results demonstrate that COX-2 expression is almost doubled 6 h after a single dose (100 ng) of gp120 and this is paralleled by a statistically significant elevation of PGE(2). Enhanced COX-2 expression is implicated in the mechanisms of apoptosis evoked by gp120 because the latter is prevented by NS398 (10 mg/kg i.p.), a selective inhibitor of COX-2 activity. Protection is also afforded by NMDA receptor antagonists, such as MK801 (0.3 mg/kg i.p.) and CGP040116 (10 mg/kg i.p.), and by the free radical scavenger, U-74389G (10 mg/kg i.p.), supporting a glutamate-mediated, excitotoxic, mechanism of apoptotic death induced by gp120. These data together with the observation that MK801 failed to prevent gp120-enhanced COX-2 expression indicate that products of the arachidonic cascade may be responsible for elevation of synaptic glutamate leading neocortical cells to oxidative stress and excitotoxic apoptosis.

Animals↗
PubMed1997

Transplantation of fetal neocortex ameliorates sensorimotor and locomotor deficits following neonatal ischemic-hypoxic brain injury in rats.

Ischemic brain injury in neonates can result in the degeneration of cortical and subcortical areas of brain and is associated with neurologic deficits. One approach to restoring function in conditions of ischemic brain injury is the use of neural transplants to repair damaged connections. This approach has been shown to reestablish neural circuitry and to ameliorate associated motor deficits in models of neonatal sensorimotor cortex damage. In this study, we utilized the Rice et al. rodent model of neonatal ischemic-hypoxic (IH) brain injury to assess whether transplantation of fetal neocortical tissue can promote functional recovery in tests of sensorimotor and locomotor ability throughout development and as adults. We show that animals that received neocortical grafts 3 days following the IH injury performed significantly better as adults on two measures of motor ability, the Rota-Rod treadmill and apomorphine-induced rotations, than did control animals that received sham transplants after the IH injury. Transplants were identifiable in 72% of the animals 10-12 weeks after implantation. Histochemical studies revealed that while the transplanted tissue did not establish normal cortical cytoarchitecture, cells and fibers within the grafts stained for nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d), choline acetyl transferase (ChAT), cholecystokinin (CCK), and glial fibrillary acidic protein (GFAP). These results suggest that transplantation of fetal neocortical tissue following IH injury in the neonatal period is associated with amelioration of motor deficits and that the grafted tissue demonstrated a neurochemical phenotype that resembled normal neocortex. This approach warrants continued investigation in light of potential therapeutic uses.

Animals↗
PubMed2000

A quantitative study of the pathological lesions in the neocortex and hippocampus of twelve patients with corticobasal degeneration.

The density of ballooned neurons (BN), tau-positive neurons with inclusion bodies (tau+ neurons), and tau-positive plaques (tau+ plaques) was determined in sections of the frontal, parietal, and temporal lobe in 12 patients with corticobasal degeneration (CBD). No significant differences in the mean density of BN and tau+ neurons were observed between neocortical regions. In the hippocampus, the densities of BN were significantly lower than in the neocortex, and densities of tau+ neurons were greater in sectors CA1 and CA2, compared with CA3 and CA4. Tau+ plaques were present in one or more brain regions in six patients. Significantly more BN were recorded in the lower (laminae V/VI) compared with the upper cortex (laminae I/II/III) but tau+ neurons were equally frequent in the upper and lower cortex. No significant correlations were observed between the densities of BN and tau+ neurons, but the densities of BN in the superior temporal gyrus and tau+ plaques in the frontal cortex were positively correlated with age. A principal components analysis (PCA) suggested that differences in the density of tau+ neurons in the frontal and motor cortex were the most important sources of variation between patients. In addition, one patient with a particularly high density of tau+ neurons in the hippocampus appeared to be atypical of the patient group studied. The data support the hypothesis that, although clinically heterogeneous, CBD is a pathologically distinct disorder.

Aged↗
PubMedDate not supplied

Bursts of high-frequency synchronized electrical activity in the dog neocortex during food-related operant conditioning.

Bursts of high-frequency (HF, 80-90 Hz, 70-80 microV) oscillations in the electrical activity (EA, 1-200 Hz) of the dog neocortex were studied during operant conditioning. These bursts of HF oscillations appeared in the EA of interstimulus intervals at the generalization stage on a background of dominant oscillations of lower frequency and amplitude (10-40 microV). Use of a new strategy for primary analysis of EA production (specifically, a coefficient of inhomogeneity) allowed amplitude-frequency inhomogeneity of the EA to be estimated, with isolation of bursts of HF oscillations. Use of an original nonharmonic analysis, consisting of expansion of EA waves into a system of half-waves which were used to construct distribution maps, revealed the regional properties of bursts of HF oscillations. The results of these investigations supplement previous data obtained using other methodological approaches (Fourier transformation and spectral density factor analysis). The properties of bursts of HF oscillations observed here provide evidence for the differential involvement of cortical areas (even close-lying areas separated by distances of 3-5 mm) in the spatial-temporal organization of potentials typical of this conditioning paradigm.

Animals↗
PubMedDate not supplied

Studies of the relationship between ultrastructural synaptic plasticity and ribosome number in dendritic terminals in the rat neocortex in a cellular conditioning model.

The relationship between structural changes in postsynaptic densities of axodendritic synapses and the sizes of postsynaptic ribosomal aggregations were studied. A positive correlation was found between the thickness of the postsynaptic density and the number of ribosomes. The role of dendritic mRNA and the possible mechanisms supporting rapid local protein synthesis during the modification of postsynaptic components is seen on combined administration of two neuromediators into the rat neocortex.

Animals↗
PubMed2003

Quantitative measurement of depolarization-induced anandamide release in human and rat neocortex.

It has been suggested that the endocannabinoid anandamide is released from central neurons upon depolarization of the cell membrane. In order to determine whether anandamide levels were increased after K(+) depolarization of fresh human and rat brain slices, we developed a rapid and sensitive method for the isolation and quantitation of anandamide. This included solvent extraction, solid phase separation, and reversed phase high performance liquid chromatography (HPLC) with fluorometric detection. Compared with basal levels, K(+) stimulation enhanced the neocortical anandamide concentration in both species (70.5 vs. 21.1 pmol/g tissue in humans, 14.3 vs. 3.2 pmol/g tissue in rats). Basal anandamide levels in the rat hippocampus (11.1 pmol/g) were significantly higher than in the neocortex. Anandamide was also detected in the human amygdala (67.8 pmol/g). In conclusion, our data provide evidence for the depolarization-induced synthesis of anandamide, supporting the hypothesis of a neuromodulatory action of this endocannabinoid. Furthermore, the presence of anandamide in the limbic system suggests participation in cognition, behavior or reward.

Amygdala↗
PubMed2002

Differential distribution of alpha and beta isoforms of p21-activated kinase in the monkey cerebral neocortex and hippocampus.

The present study aimed to elucidate the subcellular distribution of the Cdc42 and Rac activated alpha and beta isoforms of p21-activated kinase (PAK) in the monkey cerebral neocortex and hippocampus. These proteins have been shown to play morphological roles through effects on the actin cytoskeleton. alphaPAK immunoreaction product was concentrated in regions of axon terminals or dendrites, some distance (0.2-1 microm) away from the synapse. The labeled portion of dendrite often appeared with "ruffled" cell membranes or resembling non-synapse forming "buds." betaPAK immunoreaction product was concentrated in cell bodies and larger diameter dendrites. Immunogold labeled sections showed that most of the label for both alphaPAK and betaPAK was present in a perisynaptic or extrasynaptic location, and relatively little staining was present on the postsynaptic density. Because alphaPAK has been shown to be associated with new membrane structures involving the Rho family GTPase Rac1, which controls dendritic morphology, these observations suggest alphaPAK positive regions of axons and dendrites may mark new areas of neurite extension.

Animals↗
PubMed2006

Formation of the neocortex in mice developing in conditions of prenatal serotonin deficiency.

We report here detailed studies of structural changes occurring in the mouse neocortex formed and stratified in conditions of prenatal experimental blockade of serotonin synthesis. Studies were performed using F1(C57BL/CBA) hybrid mice. Endogenous serotonin levels were decreased by exposure of the mice to parachlorophenylalanine, which inhibits the key serotonin synthesis enzyme tryptophan hydroxylase. Offspring brains were studied at 1, 5 and 10 days (n = 10-15 for each time point) of postnatal development. Controls consisted of intact animals at the same periods of development. These experiments showed that prenatal blockade of serotonin synthesis leads to impaired formation of all neocortical layers, impaired growth, development, and differentiation of neurons, and alterations in neuron shape and size. As postnatal development proceeded, significant numbers of neurons died in the brain structures of these animals.

Animals↗
PubMed2006

Suppression of EEG gamma activity--an informative measure of spreading depression waves in the neocortex of the conscious rabbit.

Spreading depression can arise spontaneously in convulsions, migraine attacks, vascular lesions, and other pathological brain states. However, the methodological complexity of recording a direct current potential in the neocortex in humans and conscious animals significantly limits studies of the functional consequences of spreading depression. The present report describes a detailed analysis of the EEG dynamics at the moment of development of spreading depression waves and identifies specific signs allowing spreading depression to be recorded without recording changes in the direct current potential. At the moment of arrival of spreading depression, the interhemisphere equilibrium is highly disturbed because of large decreases in high-frequency activity. The time parameters of the dynamics of the gamma-1 and gamma-2 ranges were the most informative features of the development of spreading depression waves. Increases in power in the delta range developed with some delay on the background of a deep inhibition of high-frequency activity and are in essence a consequence of spreading depression. The encephalographic criteria of spreading depression waves identified here can significantly simplify the detection of this phenomenon both in experimental and clinical conditions in a number of pathological brain states.

Animals↗
PubMed2006

Calcium channel alpha2-delta type 1 subunit is the major binding protein for pregabalin in neocortex, hippocampus, amygdala, and spinal cord: an ex vivo autoradiographic study in alpha2-delta type 1 genetically modified mice.

Pregabalin is a synthetic amino acid compound effective in clinical trials for the treatment of post-herpetic neuralgia, diabetic peripheral neuropathy, generalized anxiety disorder and adjunctive therapy for partial seizures of epilepsy. However, the mechanisms by which pregabalin exerts its therapeutic effects are not yet completely understood. In vitro studies have shown that pregabalin binds with high affinity to the alpha(2)-delta (alpha(2)-delta) subunits (Type 1 and 2) of voltage-gated calcium channels. To assess whether alpha(2)-delta Type 1 is the major central nervous system (CNS) binding protein for pregabalin in vivo, a mutant mouse with an arginine-to-alanine mutation at amino acid 217 of the alpha(2)-delta Type 1 protein (R217A mutation) was generated. Previous site-directed mutagenesis studies revealed that the R217A mutation dramatically reduces alpha(2)-delta 1 binding to pregabalin in vitro. In this autoradiographic analysis of R217A mice, we show that the mutation to alpha(2)-delta Type 1 substantially reduces specific pregabalin binding in CNS regions that are known to preferentially express the alpha(2)-delta Type 1 protein, notably the neocortex, hippocampus, basolateral amygdala and spinal cord. In mutant mice, pregabalin binding was robust throughout regions where the alpha(2)-delta Type 2 subunit mRNA is abundant, such as cerebellum. These findings, in conjunction with prior in vitro binding data, provide evidence that the alpha(2)-delta Type 1 subunit of voltage-gated calcium channels is the major binding protein for pregabalin in CNS. Moreover, the distinct localization of alpha(2)-delta Type 1 and mutation-resistant binding (assumed to be alpha(2)-delta Type 2) in brain areas subserving different functions suggests that identification of subunit-specific ligands could further enhance pharmacologic specificity.

Amino Acid Substitution↗
PubMed2004

Hypothyroidism alters the development of radial glial cells in the term fetal and postnatal neocortex of the rat.

Alterations of thyroid function during human development are known to produce extensive damage to the central nervous system including severe mental retardation. Using immunohistochemistry to identify the intermediate filament nestin, we have studied the possible influence of fetal and neonatal hypothyroidism on neocortical neuronal migration by arresting the normal development of the radial glial scaffold. By embryonic day 21 (E21), hypothyroid animals had a significant decrease in the number of nestin immunoreactive processes in the presumptive visual cortex. By postnatal day 5 (P5), hypothyroid animals showed a significant increase in the number of glial processes in relation with controls, although only in the upper layers of the visual cortex. Moreover, by P10, there was a marked increase in the number of radial glial processes in hypothyroid animals in superficial and deep zones of the visual cortex with respect to control animals. Our data indicate an important delay in the formation of the radial glial scaffold during the embryonic stage in hypothyroid animals that was interestingly accompanied by the later presence of abundant nestin immunoreactive fibers at P10. This impairment in the evolution of radial glia during development might be affecting the normal neuronal migratory pattern in the neocortex of hypothyroid rats.

Animals↗