SEARCH · PubMed Health

Results for “DILS”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 397 records · Page 22Linked to original sources

PubMed2005

Drug-induced lupus erythematosus.

Drug-induced lupus is a syndrome which share symptoms and laboratory characteristics with idiopathic systemic lupus erythematosus (SLE). The terms drug-induced lupus (DIL) and drug-induced lupus erythematosus (DILE) are preferred, but other ones are also used-drug-related lupus, lupus-like syndrome and lupus erythematosus medicamentosus. The first case of DILE was reported in 1945 and associated with sulfadiazine. In 1953, it was reported that DILE was related to the use of hydralazine. More than 80 drugs have been associated with DILE. The average age of patients with DILE is nearly twice that of patients with idiopathic SLE. Approximately half the patients with drug-induced SLE are women, compared with 90% of patients with idiopathic SLE. Similarly to idiopathic lupus, DILE can be divided into systemic, sub-acute cutaneous and chronic cutaneous lupus. The syndrome is characterised by arthralgia, myalgia, pleurisy, rash and fever in association with antinuclear antibodies in the serum. The clinical and laboratory manifestations of drug-induced SLE are similar to those of idiopathic SLE, but central nervous system and renal involvement are rare in DILE. Recognition of DILE is important because it usually reverts within a few weeks after stopping the drug. This review discusses the general issues in DILE, such as pathogenic mechanisms, clinical forms and diagnostic criteria, and provides more detailed information for some of the most recent implicated drugs: minocycline, statins, anti-TNF-alpha agents.

Drug-Related Side Effects and Adverse Reactions↗

PubMedDate not supplied

Lipid phase separation correlates with activation in platelets during chilling.

When human platelets are chilled below 22 degrees C, they spontaneously activate, a phenomenon that severely limits their storage life. It has previously been proposed that there is a correlation between cold-induced platelet activation and passage of the membranes through a liquid-crystalline to gel phase transition. Because animal models are essential for developing methods for cold storage of platelets, it is necessary to investigate such a correlation in animal platelets. In this work, horse platelets were used as a model, and it was found that cold-induced morphological activation is related to the lipid phase transition. Using fluorescence microscopy with the lipophilic fluorescent dye 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (Dil-C18), and Fourier transform infrared spectroscopy (FTIR), it was found that lipid phase separation occurs during cooling and low temperature storage. Furthermore, removal of cholesterol from the plasma membrane also induced a phase separation, possibly between specific phospholipid classes. Steady-state fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH) and trimethylammonium-DPH (TMA-DPH) were compared in cells and multilamellar vesicles (MLV) composed of platelet lipids. Cholesterol depletion led to a decrease in the fluorescence anisotropy of the two probes, which can be explained by changes in the order of the phospholipid molecules. In addition, the lipid composition and fatty acid profile of the cellular phospholipids were determined. Based of the similarities between horse and human platelets, it is suggested that horse platelets may be used as a model for studying cold-stored platelets. The results are discussed in relation to the possible role of phase separation during cell signalling.

Animals↗

PubMedDate not supplied

In situ assessment of erythrocyte membrane properties during cold storage.

Membrane fluidity and overall protein secondary structure of human erythrocytes were studied in situ using Fourier transform infrared spectroscopy (FTIR). Erythrocyte membranes were found to have weakly cooperative phase transitions at 14 degrees C and at 34 degrees C, which were tentatively assigned to the melting of the inner membrane leaflet and the sphingolipid rich outer leaflet, respectively. Cholesterol depletion by methyl-beta-cyclodextrin (MbetaCD) resulted in a large increase in the cooperativity of these transitions, and led to the appearance of another phospholipid transition at 25 degrees C. Multiple, sharp membrane phase transitions were observed after 5 days cold storage (4 degrees C ), which indicated phase separation of the membrane lipids. Using fluorescence microscopy, it was determined that the lipid probe 1,1'-dioctadecyl-3,3,3',3-tetramethyl-indocarbocyanine perchlorate (dil-C18) remained homogeneously distributed in the erythrocyte membrane during cold storage, suggesting that lipid domains were below the resolution limit of the microscope. Using thin layer chromatography, changes in the membrane lipid composition were detected during cold storage. By contrast, assessment of the amide-II band with FTIR showed that the overall protein secondary structure of haemoglobin was stable during cold storage.

Adult↗

PubMedDate not supplied

The influenza haemagglutinin-induced fusion cascade: effects of target membrane permeability changes.

To define the stages in influenza haemagglutinin (HA)-mediated fusion the kinetics of fusion between cell pairs consisting of single influenza HA-expressing cells and single erythrocytes (RBC) which had been labelled with both a fluorescent lipid (Dil) in the membrane and a fluorescent solute (calcein) in the aqueous space have been monitored. It is shown that release of solute from the target cell occurs, following the formation of the hemi-fusion diaphragm. These results are discussed in terms of a model in which fusion peptide insertion into the target membrane induces lipid stalks, which results in the formation of a hemifusion diaphragm and a fusion pore. Bilayer expansion due to overproduction of these stalks can give rise to collateral damage of target membranes.

3T3 Cells↗

PubMed2003

Establishment and characterization of an angiosarcoma-derived cell line, AS-M.

A novel human endothelial cell line, AS-M, has been established from a cutaneous angiosarcoma on the scalp. The cells expressing platelet endothelial cell adhesion molecule-1 (CD31) were isolated using magnetic beads and subsequently cultured for a year. To date, the cells have undergone more than 100 population doublings (PDs). The AS-M cells manifested endothelial characteristics, such as active uptake of acetylated low-density lipoprotein labeled with 1,1'-dioctadecyl 3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil-Ac-LDL), capacity to bind the Ulex europeaus agglutin-I (UEA-I), and expression of von Willebrand factor (vWF) and CD31. The single cell-derived clone, AS-M.5, showed a constitutive expression of CD31, vWF, angiotensin-converting enzyme (ACE), endoglin (CD105), and the endothelial cell receptor tyrosine kinases KDR and Tie-1. Similarly to freshly isolated endothelial cells, the AS-M.5 responded to induction by bacterial lipopolysaccharide (LPS) by increased transcription of cell adhesion molecules and cytokines. The AS-M.5 cultures required endothelial growth supplements for optimal growth and long-term propagation in vitro. However, in contrast to normal endothelial cells, p53 gene products were detected in nuclei of AS-M.5 cells. Cytogenetic analyses consistently revealed a hypodiploid karyotype with complete loss of one homologue of several chromosomes and a homogeneous pattern of distinct karyotypic changes. Although the AS-M.5 presented characteristics suggestive of tumor cells, they did not develop into tumors when inoculated subcutaneously into nude mice. The cell line AS-M.5 could be a useful model system to study endothelial pathobiology in vitro.

Aged↗

PubMedDate not supplied

Effect of systemic insulin and angiotensin II receptor subtype-1 antagonist on endothelin-1 receptor subtype(s) regulation and binding in diabetic rat heart.

This study reports on the regulation and remodeling role of endothelin-1 (ET-1) and its receptor subtypes, ET(A)-Rs/ET(B)-Rs, at the coronary endothelium (CE) and cardiomyocyte (CM) sites. It is carried out in normal and normotensive rats with streptozotocin-induced diabetes mellitus receiving different treatment modalities. Normal rats were divided into two groups, namely a placebo (N) and a losartan-treated (NL), and diabetic rats into four groups receiving placebo (D), insulin-treated (DI), losartan-treated (DL), and insulin/losartan-treated (DIL) respectively. Binding kinetics of ET-1 to ET(A)-Rs/ET(B)-Rs on CE and CMs were assessed in the above groups to try to explain the effect of therapeutic doses of an angiotensin II receptor subtype-1 blocker on the dynamics of this ligand and its receptor in insulin supplemented diabetic animals. Each group was divided into two subgroups: CHAPS-untreated and CHAPS-treated rat hearts perfused with [125I]ET-1 to respectively estimate ET-1 binding affinity (tau = 1/k-n) to its receptor subtype(s) on CE and CMs using mathematical modeling describing a 1:1 reversible binding stoichiometry. Heart perfusion results revealed that insulin treatment significantly decreased tau on CE but not on CMs in diabetic rats. In diabetics treated with losartan, an increase in tau value on CE but not on CMs was noted. Cotreatment of diabetic rats with insulin and losartan normalized tau on CE but decreased it on CMs. Western blot, using snap-frozen heart tissues, revealed increase in ET(A)-R density in all diabetic groups. However, significant decrease in ET(B)-R density was observed in all groups compared to the normal, and was reconfirmed by immunohistochemical analysis. In conclusion, coadministration of insulin and losartan in nonhypertensive animals suffering from diabetes type 1 may offer new cardiac protection benefits by improving coronary blood flow and cardiomyocyte contractility through modulating ET-1 receptor subtypes density and affinity at CE and CM sites.

Angiotensin II Type 1 Receptor Blockers↗

PubMed1997

Residues K128-Q175 of human interleukin-6 are essential for its biological activity.

Internal deletion K128-Q175 of the human interleukin-6 (hIL-6) has been generated at the cDNA level. With pBV220 as expressing vector, the recombinant pBV*-DIL-6 encoding the deletion mutant (12 kD) of hIL-6 has been constructed. The resulted recombinant plasmids were then used to transform E. coli strain HB101, and the expression in the PLPR promoter system, which is temperature-regulatable, was achieved. After purification and renaturation, the biological activity of the expressed product, designated as DM120, was measured by MTT method in an IL-6-dependent cell line 7TD1. The results show that the amino acid residues of IL-6 128 to 175 are crucial for IL-6 activity. Receptor binding assay in vitro indicates that the entire region is not involved in forming the receptor binding surface.

Gene Deletion↗

PubMed2004

Passage-dependent changes in baboon endothelial cells--relevance to in vitro aging.

In vitro cell culture system is a useful model for aging-related changes in a wide spectrum of biomedical research. In this study, we explored the passage and donor age-dependent changes in baboon macrovascular endothelial cells that are relevant to both in vitro cell culture aging models and experiments using cell culture techniques. We collected baboon femoral arterial samples from nine baboons ranging in age from 6 months to 30 years (equivalent to humans approximately 18 months to 90 years of age). We then cultured baboon femoral artery endothelial cells (BFAECs) in standard DMEM medium with 20% fetal calf serum with 1:3 split for subculture. Endothelial functions were documented by morphology, Dil-LDL uptake and expression of eNOS, MCP-1, vWF, VCAM-1, ICAM-1, and E-Selectin with or without cytokine stimulation. Most of the cells became nonmitotic after 30 population doublings, or 10 passages, when they became flattened, enlarged, and senescent. While it took approximately 3 days to reach confluence from three-dilution seeding at early passages (<6), confluence was not achieved even after 7 days of culture for cells after the 9th or 10th passage. There was a linear decline in eNOS expression with passage. However, this decline was significantly less in endothelial cells from a young baboon (6 months) than those from an old baboon (30 years). While basal expression of adhesion molecules was not changed with passaging, responses to cytokine stimulation appeared to be increased in later passaged cells. Our study has provided evidence for passage-related changes in key endothelial functions. The donor age-related differences in this in vitro aging process suggests that in vitro endothelial culture can serve as a biomarker for in vivo aging. Nonhuman primates can provide a model for investigating such aging-related biological characteristics.

Aging↗

PubMedDate not supplied

Growth of thalamic afferents into mouse barrel cortex.

We studied thalamocortical afferent (TCA) growth into somatosensory cortex as the whisker barrels emerge in postnatal mice. Ingrowing fibers from the ventrobasal (VB) thalamus were selectively labeled by two means. Under direct vision, individual axons and populations of axons were labeled in vitro with HRP, or in fixed tissue with Dil (1,1'-dioctodecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate), in pieces of brain containing both the source nucleus in the thalamus and its cortical target. Many simple thalamocortical afferents are already within the upper cortical plate at birth [postnatal day one (PND1)]. Initially, TCAs from each point in the thalamus distribute in the cortex as two-dimensional "Gaussians," which overlap laterally to constitute a uniform projection pattern. The projection is topographic, because adjacent focal injections within VB label adjacent cortical loci. Subsequent development of barreloids (thalamic representations of the whiskers) partitions the TCA projection into a set of whisker-related Gaussians, centered on cortical targets whose collective topography reflects that of the source pattern. After barreloids form on about PND3, but before barrels appear in cytoarchitecture on about PND5, the overlapping TCAs segregate into dense terminal clusters in layer IV, around which barrels later mature. Time series of single fibers traced with camera lucida explain this transformation that is so noticeable at the population level. As early as PND1, individual TCAs emit multiple ascending collaterals on their horizontal run through white matter and oblique ascent into upper cortex. Subsequently, by PND4, and proceeding at least through PND7, there is accelerated terminal arborization of selected appropriate collateral branches and pruning back of other inappropriate ones. The selection mechanism appears to result from within-group reinforcement events that are stronger for branches toward the center of each whisker-related Gaussian distribution.

Animals↗

PubMedDate not supplied

A comparison of pattern formation by thalamocortical and serotonergic afferents in the rat barrel field cortex.

In the present study we compare the formation of vibrissa-related patterns by thalamocortical afferents from the ventrobasal (VB) nucleus to that by raphe-cortical, serotonergic afferents from the raphe nuclei. In opposite hemispheres of the same brain, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil) labeling of VB afferents and serotonin (5-HT) immunohistochemistry reveal that the pattern of vibrissa-specific patches is first exhibited by thalamocortical axons in barrel field cortex. Shortly thereafter, 5-HT axons form patches in the same locations as the dense concentrations of VB afferents. To assess a possible role of 5-HT afferents in the specification of barrel field cortex, neonatal rat pups were administered p-chloroamphetamine (PCA), a selective 5-HT neurotoxin. The formation of vibrissa-related patterns by thalamocortical and serotonergic afferents was compared in normal and PCA-treated rat pups at various developmental stages. PCA treatment led to a significant decrease in the number of serotonergic axons in barrel field cortex. Despite this decrease, VB afferents segregated in patches over individual barrels. However, a delay in the emergence of the thalamocortical pattern was noted in toxin-treated animals. We conclude that PCA treatment does not prevent formation of a vibrissa-specific pattern by thalamocortical afferents, and discuss the possibility that the 5-HT axons may play a trophic role in the maturation of VB afferents.

Animals↗

PubMedDate not supplied

Development of forward and feedback connections between areas V1 and V2 of human visual cortex.

We have determined the sequence in which forward connections between visual cortical areas V1 and V2, and feedback connections between V2 and V1 develop in humans. For this purpose Dil was injected into V1 and V2 of postmortem brains of different pre- and postnatal ages. The laminar distribution of labeled fibers and cell bodies in V1 and V2 indicates that forward and feedback connections emerge shortly before birth. The development of both pathways proceeds over several postnatal months such that the laminar termination pattern of forward connections appears relatively mature before feedback connections reach their mature form. At 37 weeks of gestation both forward and feedback connections originate exclusively from deep-layer neurons, which extend axons in deep layers only. By 9 d postnatal, forward connections from V1 to V2, in addition to layers 5 and 6, also arise from neurons in layer 4B of V1. At this stage for the first time forward fibers enter layer 4 at the topographically appropriate location of V2. At 9 d postnatal most feedback fibers from V2 still occupy deep layers of V1 but many, through interstitial growth, elaborate vertical sprouts at regular intervals along the length of horizontal axons. As feedback connections mature, distal segments of horizontal axons are pruned back to branch points and fibers assume L-shaped configurations. By 7 weeks of age forward fibers from V1 enter V2 through deep and superficial layers and provide input to layers 3 and 4. At this stage feedback fibers from V2 have entered layer 4B of V1. By 4 months of age forward connections have assumed all the laminar characteristics of mature connections; that is, they arise from layers 2/3, 4B, 5, and 6 of V1, and terminate in layers 3 and 4 of V2. In sharp contrast, at 4 months of age feedback connections to V1 are still immature, showing terminations in layers 4B, 5, and 6 but no input to layer 2/3. The protracted postnatal emergence of feedback connections is similar to that of local long-range connections within layer 2/3 of V1 (Burkhalter et al., 1993). Since both of these circuits are thought to provide information about the context in which objects are seen, it is interesting to speculate that the late onset of texture segmentation in infants (Atkinson and Braddick, 1992; Sireteanu and Rieth, 1992) may be related to the postnatal maturation of specific intracortical circuits.

Carbocyanines↗

PubMedDate not supplied

Transient axonal branching in the developing corpus callosum.

During development, there is a transient overproduction of axons in the corpus callosum; this overproduction of axons is due, in part, to a transient excess of neurons that send an axon through the corpus callosum. However, transient axonal branching could also contribute to the developmental overproduction of callosal axons. To investigate this possibility, we filled developing callosal axons in the Syrian hamster with the carbocyanine dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil). Light microscopic analysis showed that, indeed, developing callosal axons branch transiently in the hamster: branching was robust on postnatal day 0 (P0) and P3 (P0 = the first 24 hr after birth), less prominent on P6 and P8, and absent by P11. Immature callosal axons branched before or after crossing the midline and at all rostral-caudal and medial-lateral levels within the corpus callosum. The majority of callosal axon collaterals that were contained within individual 100-micron-thick sections were relatively short (mean = 15.1 microns) but some collaterals extended up to approximately 135 microns from the main axon trunk before passing out of the section in which they were observed. Nearly all of the collaterals emanated from the main axon trunk; higher-order collaterals were rare. Some callosal axon trunks had multiple collaterals. Branching callosal axons originated from multiple cortical areas, including area 17. Electron microscopic observations indicated that the processes designated as axon collaterals by light microscopic criteria would have been included in electron microscopic counts of developing callosal axons. Some callosal axon trunks and branches had ultrastructural features that suggested they were degenerating. In cats, developing callosal axons branch on embryonic day 57 (E57; the first 24 hr after conception = E0) and P0. Thus, it is likely that transient branching of immature callosal axons is a generalized feature of mammalian cortical development and that it contributes to the overproduction of callosal axons, albeit perhaps to varying degrees, in multiple species.

Aging↗

PubMedDate not supplied

An inbred epilepsy-prone substrain of BALB/c mice shows absence of the corpus callosum, an abnormal projection to the basal forebrain, and bilateral projections to the thalamus.

BALB/c mice lack a corpus callosum in about 11% of the population. Two inbred substrains of BALB/c mice, epilepsy-prone (EP) and epilepsy-resistant (ER), have been examined to determine whether these substrains differ in regard to corpus callosum morphology. Further, this study addressed the issue of whether misrouted cortical axons form an aberrant pathway instead of the corpus callosum. Initial studies that examined fresh brain tissue of adult animals revealed normal corpora callosa in all ER mice but deficient or absent corpora callosa in all EP mice. Subsequently, Dil crystals were placed in the motor cortices of aldehyde-fixed brains of 2-week-old animals to investigate cortical projections in both inbred substrains of mice. Fluorescent microscopy revealed that all of the ER animals had normal corpora callosa, whereas all EP animals exhibited either reduced corpora callosa (partially callosal) or an absence (acallosal) of this structure. Both acallosal and partially callosal EP mice displayed an extensive, aberrant projection to the basal forebrain as well as bilateral projections to midline and intralaminar thalamic nuclei. The fibers projecting to the basal forebrain arose from the cortex, coursed toward the midline before turning ventrally along the midline, and appeared to terminate in the medial septal nucleus and the nucleus of the diagonal band. ER animals lacked this aberrant cortical projection to the basal forebrain. Electron microscopic results obtained from EP mice indicated that labeled axons in this aberrant pathway formed axosomatic, axodendritic, and axospinous synapses with the neurons in the medial septal/diagonal band complex. The function of the aberrant projection to the basal forebrain remains unknown but it may provide an abnormal excitatory input to a region that provides cholinergic and GABAergic input to the cerebral cortex and hippocampus. The additional projections to midline and contralateral intralaminar thalamic nuclei in EP mice may function to intensify the synchronization of bilateral discharges.

Agenesis of Corpus Callosum↗

PubMedDate not supplied

A unique mosaic in the visual cortex of the reeler mutant mouse.

Numerous studies have revealed abnormal cytoarchitectonics in the reeler mouse brain. In the present study, acetylcholinesterase (AChE) histochemistry has revealed a distinctive mosaic within the occipital cortex of the reeler mouse. The mosaic does not appear until after the second postnatal week, perhaps in association with eye opening. AChE staining in the visual cortex of normal littermates does not exhibit a mosaic pattern, but rather, is present within bands or laminae. The AChE mosaic in reeler persists into adulthood. Immunocytochemical staining of the tenascin glycoprotein, an astrocyte-derived extracellular matrix molecule that is concentrated in boundaries around emerging functional patterns in the CNS, reveals a boundary-mosaic pattern in the first postnatal week. Dil axonal tracing in normal versus reeler mice indicates that the thalamocortical projections may also be associated with the AChE mosaic. The observation that a mosaic is unique to the occipital cortex of reeler mice suggests that it may evolve through abnormal cell and molecular interactions in the mutant cortex that normally lead to the development of functional visual representations.

Acetylcholinesterase↗

PubMedDate not supplied

Patterns of connectivity in the neocortex of the echidna (Tachyglossus aculeatus).

Patchy connections were traced in the visual and auditory cortex of the echidna (Tachyglossus aculeatus). Labeled neurons and clusters of axon collaterals were distributed in regular arrays after the application of a small crystal (approximately 100-300 microns diameter) of the carbocyanine dye Dil (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate) into the upper cortical layers. In general, the anterograde and retrograde labels were in register, but whereas the anterograde label was distributed throughout all six layers, the retrogradely filled neurons were absent from layer 1 and the highest density of labeled cells was in layers 5 and 6. The cells contained within the patches were all pyramidal or pyramid-like and contained long spines on their dendrites. Therefore, despite their unusual location within the lateral posterior cortex, the internal structure of the echidna visual and auditory cortices resembled that of eutherian mammals in containing a regular columnar array of connections that may represent the corticocortical projections.

Animals↗

PubMedDate not supplied

The origin and topography of long-range intrinsic projections in cat visual cortex: a developmental study.

We investigated the morphological features of long range intrinsically projecting neurons and their pattern of axonal arborization in cat area 17 at different stages of postnatal development. In one set of experiments intracortically projecting cells were retrogradely labeled in vivo with rhodamine latex beads and then visualized by in vitro filling with Lucifer yellow. In another approach, intracortical fibers including the cells of origin were labeled postmortem in fixed brains with the lipophilic carbocyanine dye Dil. The results of this study indicate that the long-range intrinsic circuitry of the primary visual cortex develops in three major steps. The first step consists of the development of unclustered long-range axons in the two outer compartments of the cerebral cortex, layer I and the subplate. These early connections could serve as a scaffold for the organization of the tangential architecture of the neocortex as they originate from cells that are the first to receive synaptic input from extrinsic afferents. The second step consists of the outgrowth of horizontal axon collaterals originating from cells located in layers II-VI. During the first 2-3 weeks these connections still differ from those in the adult because they span shorter distances, originate more often from neurons with morphological features of nonpyramidal cells, and lack the precise clustering of the mature connections. The third step consists of a selection process that leads to the elimination of axon terminals from locations between the clusters of tangentially projecting neurons. This selection starts at the end of the second postnatal week and, hence, overlaps in time with the still proceeding elongation of axons and continues beyond the end of the fourth postnatal week when axon length has reached its maximal extent. This refinement process enhances the specificity of long-range connections and is probably influenced by visual experience.

Animals↗

PubMedDate not supplied

Nonuniform alteration of dendritic development in the cerebral cortex following prenatal cocaine exposure.

Prenatal exposure to cocaine has the potential to modify normal brain development and result in behavioral dysfunction. We used a new animal model in which cocaine was administered intravenously during prenatal development in pregnant rabbits twice daily at low dosages. Analysis of brain development focused on two areas of the cerebral cortex, anterior cingulate and primary visual, in which dopamine afferents, a target of cocaine, are differentially distributed. All postnatal rabbits exposed to cocaine prenatally exhibited normal features of cortical organization, including thickness, lamination patterns, and cytoarchitectonic differentiation. General axonal and astroglial organization, assessed by neurofilament-H and glial fibrillary acidic protein immunostaining, also was unchanged in the cocaine-exposed animals. Analysis of dendritic organization was done using antibodies against microtubule-associated protein 2 (MAP2), which reveals mostly the larger apical shafts of cortical pyramidal cells. In the anterior cingulate cortex of adolescent rabbits exposed to cocaine in utero, there is a marked decrease in both dendritic bundling and typical long, straight MAP2-stained profiles. In normal animals, the long, bundled dendrites area readily traced in a single focal plane from layer III or V pyramidal cell somata to the pial surface in saline-treated animals. Instead, the drug-exposed animals contained many more short segments of MAP2-stained dendrites that could be viewed coursing in and out of the plane of focus in the sections. Apical dendrites in mature visual cortex appeared normal in the cocaine-exposed rabbits. Examination of MAP2 staining at various postnatal ages revealed that the dendritic changes expressed in the adolescent anterior cingulate cortex appeared less robust, but still evident at birth. By P10-14, dendritic modifications were similar to the adult. Counts of the number of MAP2-positive dendritic profiles crossing the layer II-III interface reached a nadir of 50% in the cocaine-exposed animals, indicative of a change in the organization of the apical dendrites compared to the control animals. Dendritic profiles of anterior cingulate neurons, filled by 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine percholate (Dil), confirmed that in the cocaine offspring, the dendrites coursed in an irregular, wavy manner from deep to superficial layers, suggestive of dendrites that were longer than normal, although cortical thickness was unchanged. The altered dendritic profiles also were seen in Golgi-impregnated neurons. The data indicate that prenatal exposure to cocaine can lead to specific alterations of neuronal growth that are long lasting. The lack of dendritic changes in visual cortex suggests that the drug does not modify development of cortical regions uniformly. This study also provides a new focus on the anterior cingulate cortex as a site in which aberrant structure-function relationships following prenatal cocaine exposure should be examined in both animal models and clinically.

Animals↗

PubMedDate not supplied

Cortical target depletion and ingrowth of geniculocortical axons: implications for cortical specification.

During the early development of the neocortex, thalamocortical axons arrive potentially in time to instruct migrating cortical neurons in several aspects of local differentiation, such as number of layer IV neurons and efferent connectivity. Migration of layer IV neurons into the cortical plate just precedes thalamocortical invasion, suggesting that these neurons could cue or tropically direct thalamic ingrowth. To explore the interactions of layer IV neurons and their thalamocortical input, we administered a mitotic inhibitor methylazoxymethanol acetate (MAM) intraperitoneally to time d pregnant hamsters on E14 when layer IV neurons are normally being generated in striate cortex. Reduced numbers of cortical neurons overall, the absence of small diameter granule neurons, and the absence of the zone of reduced density of callosally projecting neurons suggest that neither the depletion of layer IV cells in the ventricular zone nor thalamic afferents in the subplate or cortical plate respecify the later generated cohort of neurons (presumptive layer II/III neurons) to acquire morphological and connectional properties of layer IV. Dil injections into the dorsal lateral geniculate nucleus (LGd) of animals from embryonic (E15) and postnatal (P7) ages show that the final position of thalamic axons with respect to layer V is not affected by the absence of E14 neurons. In the normal visual cortex, geniculocortical axons have begun their arborization in their presumptive target layer in the upper cortex immediately below the undifferentiated cortical plate on P4, while in MAM animals, this process occurs 1 d later. The extent and density of arborization is much reduced in the thinner cortex of the MAM animals. We thus find no evidence for instruction of migrating neurons by thalamocortical axons to assume the layer IV phenotype; if instruction does occur, it must take place in a very restricted time window. Thalamic axons can also find their laminar position in the absence of cells of this phenotype.

Animals↗