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PubMed1994

Effects of neonatal mediodorsal thalamic lesions on structure and function of the rat prefrontal cortex.

The morphological and behavioral effects of neonatal electrothermal lesions of the mediodorsal thalamus on the development of the prefrontal cortex were studied. Lesions of the mediodorsal nucleus (MDT), inflicted on the day of birth, caused no significant changes in prefrontal architecture on day 35. On the other hand, a significant decrease in cortical width (4.7-7.7%) was observed at some places within the lateral and supragenual parts of the prefrontal cortex. However, these local decreases in cortical width were not reflected by a significant decrease of the total volume of the particular prefrontal subareas. In adulthood, rats with neonatal MDT lesions were exposed to an operant delayed alternation task, which is known to depend upon the integrity of the prefrontal cortex, in order to investigate the behavioral consequences of the lesions for prefrontal functioning. The lesions did not impair the rats abilities to learn the spatial delayed alternation task. Neonatally lesioned and control rats scored equally. Given the relatively mild effects of MDT lesioning, thalamic fibers do not seem to play a crucial role, at least not during the postnatal period of prefrontal cortical development. It is discussed whether or not this is a specific characteristic of agranular association cortex, in which the termination of thalamic and cortical afferents overlap in layer III.

Animals↗
PubMed1982

Prenatal appearance of a short nucleosomal DNA repeat length in neurons of the guinea pig cerebral cortex.

The organization of chromatin in neurons of the cerebral cortex of the guinea pig brain was analyzed by digesting isolated nuclei with micrococcal nuclease. During development, cortical neurons were observed to undergo an alteration in chromatin structure which results in an atypically short nucleosomal DNA repeat length of 164 bp. This change in chromatin organization occurs postnatally in certain mammals but in the guinea pig it takes place prior to birth between days 32 and 44 of fetal development. This suggests that the appearance of the short nucleosomal DNA repeat length in cortical neurons correlates to a particular stage of differentiation of cortical neurons rather than to the event of birth.

Animals↗
PubMed2001

Two modes of radial migration in early development of the cerebral cortex.

Layer formation in the developing cerebral cortex requires the movement of neurons from their site of origin to their final laminar position. We demonstrate, using time-lapse imaging of acute cortical slices, that two distinct forms of cell movement, locomotion and somal translocation, are responsible for the radial migration of cortical neurons. These modes are distinguished by their dynamic properties and morphological features. Locomotion and translocation are not cell-type specific; although at early ages some cells may move by translocation only, locomoting cells also translocate once their leading process reaches the marginal zone. The existence of two modes of radial migration may account for the differential effects of certain genetic mutations on cortical development.

Animals↗
PubMed2004

Cortical hyperostosis in an infant on prolonged prostaglandin infusion: case report and literature review.

The common side effects associated with the use of prostaglandins in newborn infants include apnoea, hyperthermia, diarrhoea, skin flushing and oedema. Periosteal reaction or cortical thickening of the bones, also known as cortical hyperostosis, is associated with a prolonged use of prostaglandins. This is a radiological diagnosis; therefore, its occurrence is most likely underestimated. We describe an infant who developed cortical hyperostosis simulating osteomyelitis with elevated alkaline phosphatase. The radiologic changes were initially attributed to congenital syphilis. This occurred after a prolonged infusion of prostaglandin E(1) for a cyanotic congenital heart disease.

Alprostadil↗
PubMed2001

Spontaneous synaptic activity of subplate neurons in neonatal rat somatosensory cortex.

Subplate neurons play an important role in early cortical development. To investigate whether these transient neurons receive synaptic inputs, we performed whole-cell recordings from visually identified and biocytin-labeled subplate cells in somatosensory cortical slices from postnatal day 0-3 rats. Subplate neurons had an average resting membrane potential of -55 mV and input resistance of approximately 1.1 G ohms. Suprathreshold current injection elicited in 67% of the cells repetitive action potentials at 4-13 Hz and the remaining 33% showed only one spike. Three classes of spontaneous postsynaptic currents (sPSCs) could be identified: (i) Fast sPSCs, with an average amplitude of 14 pA and a decay time of 6.3 ms, which showed a 95% decrease in their frequency during (+/-)-gamma-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA)/kainate receptor blockade. Cyclothiazide caused a 3.5-fold increase in the decay time, indicating that fast sPSCs were mediated by AMPA receptors. (ii) Slow sPSCs, with 18 pA amplitude and 51.2 ms decay time were blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist CPP. (iii) Chloride-driven sPSCs, with 34.4 pA amplitude and 123 ms decay time that were blocked by the gamma-amino-butyric acid A (GABA(A)) receptor antagonist gabazine. While tetrodotoxin citrate (TTX) blocked completely NMDA-mediated slow sPSCs, the frequency of AMPA- and GABA(A)-mediated sPSCs was reduced in TTX by 55 and 90%, respectively. These results indicate that subplate neurons receive functional synaptic inputs mediated by AMPA, NMDA and GABA(A) receptors.

Animals↗
PubMed1999

Heparan sulphate and HB-GAM (heparin-binding growth-associated molecule) in the development of the thalamocortical pathway of rat brain.

Extracellular matrix (ECM) molecules, such as laminin, tenascin, chondroitin sulphate proteoglycans and heparan sulphate proteoglycans have been suggested to have 'signpost' and directing roles in the formation of axonal projections in cortical development. We show here that the expression of the neurite outgrowth-promoting protein heparin-binding growth-associated molecule (HB-GAM) and N-syndecan, a transmembrane heparan sulphate proteoglycan previously isolated as a receptor for HB-GAM, is spatiotemporally associated with the developing thalamocortical pathway in the rat brain. Using in situ hybridization, thalamic neurons were shown to express mRNA for N-syndecan, and in vitro, thalamic neurons grew more neurites on HB-GAM than on laminin. The HB-GAM-induced neurite outgrowth in thalamic neurons was inhibited by heparitinase, heparin, soluble N-syndecan and by an excess of soluble HB-GAM in the culture medium. In a pathway assay, thalamic neurons selectively preferred attaching and growing neurites on matrices containing HB-GAM than on those containing fibronectin or laminin alone, suggesting that HB-GAM may modulate the effect of other ECM proteins. On an unfixed brain slice preparation, thalamic neurons repeatedly showed a typical neurite outgrowth and attachment pattern resembling the expression pattern of HB-GAM. On the brain slices, the neurite outgrowth was significantly inhibited by heparitinase, heparin and soluble HB-GAM, thus displaying features of neurite outgrowth on matrix-bound HB-GAM. Our results suggest that HB-GAM is important for the neurite outgrowth of thalamic neurons and it may function as an ECM-bound guidance cue for thalamic neurons that possess HB-GAM-binding heparan sulphates on their cell membrane.

Animals↗
PubMedDate not supplied

Familial Alzheimer's disease and cortical Lewy bodies: is there a genetic susceptibility factor?

The reason for the occurrence of Lewy body disease (LBD) in Alzheimer's disease (AD) patients is unknown. If brains from etiologically different AD groups differ in their tendency to develop cortical Lewy bodies, the concurrence of LBD in AD patients may be a manifestation of the AD process in specific AD subsets. To address this issue, we counted cortical Lewy bodies in AD patients with genetic abnormalities on chromosome 14 (n = 19), and chromosome 21 (n = 3), sporadic AD (n = 27), Down's syndrome (n = 1) and control (n = 26) patients. Cortical Lewy bodies were occasionally present in AD patients with long-duration disease in most of the above AD subgroups, but were not present in any of our age-matched control cases. We suggest that cortical Lewy body formation may be an intrinsic part of the late pathologic changes of AD regardless of etiology and that it is not specific to any of the AD subtypes studied.

Aged↗
PubMed1999

Morphogenetic roles of acetylcholine.

In the adult nervous system, neurotransmitters mediate cellular communication within neuronal circuits. In developing tissues and primitive organisms, neurotransmitters subserve growth regulatory and morphogenetic functions. Accumulated evidence suggests that acetylcholine, (ACh), released from growing axons, regulates growth, differentiation, and plasticity of developing central nervous system neurons. In addition to intrinsic cholinergic neurons, the cerebral cortex and hippocampus receive extensive innervation from cholinergic neurons in the basal forebrain, beginning prenatally and continuing throughout the period of active growth and synaptogenesis. Acute exposure to ethanol in early gestation (which prevents formation of basal forebrain cholinergic neurons) or neonatal lesioning of basal forebrain cholinergic neurons, significantly compromises cortical development and produces persistent impairment of cognitive functions. Neonatal visual deprivation alters developmental expression of muscarinic acetylcholine receptors (mAChR) in visual cortex, whereas local infusion of mAChR antagonists impairs plasticity of visual cortical neurons. These findings raise the possibility that exposure to environmental neurotoxins that affect cholinergic systems may seriously compromise brain development and have long-lasting morphologic, neurochemical, and functional consequences.

Acetylcholine↗
PubMedDate not supplied

An hypothesis on the early evolution of the development of the isocortex.

We propose an hypothesis on the evolutionary origin of the unique inside-out developmental gradient of the isocortex, in which deep layers originate before superficial layers. This contrasts with the development of the reptilian cortex, which originates in an outside-in gradient. In mice, a mutated protein, reelin, produces the reeler phenotype, whose cortex has an outside-in neurogenetic gradient like in reptiles. Reelin is normally located in the marginal layer of the developing cerebral cortex, and its normal function has been proposed to be a stop signal that prevents radially migrating cells from moving into the marginal zone. Additionally, mutations on the kinase Cdk5, or in its neuronal-specific activator p35, produce a deficit similar to reeler in that the neurogenetic gradient is outside-in. However, contrary to reeler, in which no cell-sparse layer I is observed, in these mice, a well-defined layer I exists, which suggests that migrating cells respond normally to reelin. Apparently, Cdk5/p35 participate in permitting cortical cells to move across pre-existing (earlier produced) cortical layers, in order to be able to contact reelin once they reach the marginal zone. We suggest that the evolutionary advent of the mammalian cortical inside-out gradient became partly possible through the activation of the Cdk5/p35 pathway, which permitted migrating cells to move across layers of older cells. At about the same time, reelin became an important element in cortical development as it prevented neuronal migration into the marginal zone (cortical layer I) and facilitated the migration of neurons past postmigratory elements.

Animals↗
PubMed1999

Multiple trophic actions of heparin-binding epidermal growth factor (HB-EGF) in the central nervous system.

The epidermal growth factor (EGF) family of ligands interacts with the epidermal growth factor receptor (EGF-R) to produce numerous direct and indirect actions on central nervous system cells. They induce the proliferation of astrocytes and multipotent progenitors ('stem' cells) and promote the survival and differentiation of postmitotic neurons. Heparin-binding epidermal growth factor (HB-EGF) interacts with both EGF-R and a related receptor, ErbB4, whereas transforming growth factor alpha (TGFalpha) interacts only with EGF-R. Because of the unique characteristics of HB-EGF and the potential utility of EGF family members in brain repair, we examine the effects of HB-EGF on rat and mouse CNS cells in vitro and compare them to those of TGFalpha. We find that, like TGFalpha, HB-EGF stimulates the proliferation of CNS astrocytes and multipotent progenitors. These proliferative effects require the expression of EGF-R, as no such effects are observed in cells derived from EGF-R-/- mice. Both HB-EGF and TGFalpha enhanced the survival of neurons derived from the neocortex and the striatum. Within these neuron-enriched cultures, nestin-positive cells but not neurons express EGF-R mRNA, indicating that the neurotrophic actions of EGF-R ligands are a result of indirect stimulation mediated by non-neuronal cells. The neurotrophic actions of HB-EGF and TGFalpha are accompanied by an elevation in immunoreactive dual phosphorylated mitogen-activated protein kinase (MAP kinase) in neurons, providing evidence that the MAP kinase cascade mediates these actions. In situ hybridization studies demonstrate that HB-EGF mRNA is present within the brainstem as early as E14 and subsequently is found in the developing cortical plate, hippocampus, cerebellar Purkinje cells and ventrobasal thalamus, among other brain areas. These findings indicate that HB-EGF may be an important trophic factor in the developing CNS and is a useful candidate molecule for brain repair strategies.

Animals↗
PubMed1999

Subplate neuron ablation alters neurotrophin expression and ocular dominance column formation.

Ocular dominance column formation in visual cortex depends on both the presence of subplate neurons and the endogenous expression of neurotrophins. Here we show that deletion of subplate neurons, which supply glutamatergic inputs to visual cortex, leads to a paradoxical increase in brain-derived neurotrophic factor mRNA in the same region of visual cortex in which ocular dominance columns are absent. Subplate neuron ablation also increases glutamic acid decarboxylase-67 levels, indicating an alteration in cortical inhibition. These observations imply a role for this special class of neurons in modulating activity-dependent competition by regulating levels of neurotrophins and excitability within a developing cortical circuit.

Base Sequence↗
PubMed2004

Structural and functional aberrations in the cerebral cortex of tenascin-C deficient mice.

The extracellular matrix glycoprotein tenascin-C (TNC) has been implicated in neural development and plasticity but many of its functions in vivo remain obscure. Here we addressed the question as to whether the constitutive absence of TNC in mice affects cortical physiology and structure. Defined major cell populations (neurons and inhibitory neuronal subpopulations, astrocytes, oligodendrocytes and microglia) were quantified in the somatosensory and motor cortices of adult TNC deficient (TNC-/-) and wild-type (TNC+/+) mice by immunofluorescence labelling and stereology. In both areas studied we found abnormally high neuronal density, astrogliosis, low density of parvalbumin-positive interneurons and reduced ratios of oligodendrocytes to neurons and of inhibitory to excitatory neurons in the TNC deficient as opposed to the non-deficient animals. Analysis of Golgi-impregnated layer V pyramidal neurons in TNC-/- animals showed aberrant dendrite tortuosity and redistribution of stubby spines within first- to third-order dendritic arbors. Significantly enhanced responses upon whisker stimulation were recorded epicranially over the barrel and the motor cortices of TNC-/- as compared to TNC+/+ animals, and this effect might be associated with the diminished inhibitory circuitry. These results indicate that TNC is essential for normal cortical development and function.

Animals↗
PubMed2006

Shh maintains Nkx2.1 in the MGE by a Gli3-independent mechanism.

Gamma-aminobutyric acidergic (GABAergic) interneurons perform crucial roles in cortical development and function. These roles are executed by diverse subgroups of interneurons, and dysfunction of particular subgroups may contribute to a variety of neuropsychiatric diseases. In rodents, most cortical interneurons originate in the pallidal telencephalon that also gives rise to the GABAergic neurons of the striatum and other ventral structures. In this paper, we examine the evidence for distinct origins of interneuron subgroups and then discuss the role of the homeobox gene thyroid transcription factor1 (Ttf-1 or Nkx2.1) in the specification of interneurons from the medial ganglionic eminence (MGE). Nkx2.1 is induced in the pallidal telencephalon by the action of sonic hedgehog (Shh) that antagonizes formation of the dorsalizing Gli3 repressor (Gli3R) protein. Recent evidence suggests that Shh is also required to maintain Nkx2.1 expression, and thus MGE interneuron specification, during embryonic neurogenesis. Here we provide evidence that, in contrast to the initial induction of Nkx2.1 during telencephalic patterning, the Nkx2.1 maintenance function of Shh does not require blocking the formation of the Gli3R. The plastic nature of Nkx2.1 expression during the age range of interneuron genesis suggests that factors regulating this gene can be critical determinants of the balance of excitation and inhibition in the postnatal cerebral cortex.

Animals↗
PubMed2006

Hes6 inhibits astrocyte differentiation and promotes neurogenesis through different mechanisms.

The mechanisms regulating the generation of cell diversity in the mammalian cerebral cortex are beginning to be elucidated. In that regard, Hairy/Enhancer of split (Hes) 1 and 5 are basic helix-loop-helix (bHLH) factors that inhibit the differentiation of pluripotent cortical progenitors into neurons. In contrast, a related Hes family member termed Hes6 promotes neurogenesis. It is shown here that knockdown of endogenous Hes6 causes supernumerary cortical progenitors to differentiate into cells that exhibit an astrocytic morphology and express the astrocyte marker protein GFAP. Conversely, exogenous Hes6 expression in cortical progenitors inhibits astrocyte differentiation. The negative effect of Hes6 on astrocyte differentiation is independent of its ability to promote neuronal differentiation. We also show that neither its proneuronal nor its anti-gliogenic functions appear to depend on Hes6 ability to bind to DNA via the basic arm of its bHLH domain. Both of these activities require Hes6 to be localized to nuclei, but only its anti-gliogenic function depends on two short peptides, LNHLL and WRPW, that are conserved in all Hes6 proteins. These findings suggest that Hes6 is an important regulator of the neurogenic phase of cortical development by promoting the neuronal fate while suppressing astrocyte differentiation. They suggest further that separate molecular mechanisms underlie the proneuronal and anti-gliogenic activities of Hes6 in cortical progenitor cells.

Animals↗
PubMed1999

Pyramidal anterior polar cataracts.

OBJECTIVE: To document clinical features and subsequent management of pyramidal anterior polar cataracts in children. DESIGN: Retrospective, noncomparative case series and clinicopathologic correlation. PARTICIPANTS: Fifteen patients who presented to the pediatric ophthalmology clinic. INTERVENTION: All patients underwent measurement of visual acuity, assessment of ocular motility, examination of the anterior and posterior segments, and cycloplegic refraction. Amblyopia treatment was instituted when appropriate. When visual impairment occurred from cataract progression or amblyopia or both, cataract removal with or without lens implantation was performed. After surgery, correction of refractive error and treatment of amblyopia were instituted. Several pyramidal opacities were retrieved during cataract extraction and examined by light and electron microscopy. MAIN OUTCOME MEASURES: Visual acuity at initial presentation, size of lens opacity before surgery, amblyopia status, most recent visual acuity after cataract extraction, and histologic examination of lens opacity. RESULTS: Nine children had bilateral and six had unilateral pyramidal cataracts (24 eyes). There was no discernible inheritance pattern. Patients were followed for 27 months on average. Twenty of 24 eyes developed cortical opacification that extended significantly beyond the base of the pyramidal lesion. Nineteen eyes required cataract surgery: 10 eyes underwent lensectomy with anterior vitrectomy and 9 had extracapsular cataract extraction, 8 of which had insertion of a posterior chamber intraocular lens. Amblyopia was present or developed in all six patients with unilateral cataract and in eight of nine patients with bilateral cataract. Visual acuity in many eyes remained poor despite amblyopia therapy. The pyramidal opacities consisted of hyperplastic lens epithelium, which exhibited a loss of polarity and was surrounded by a collagenous matrix. CONCLUSIONS: Pyramidal anterior polar cataracts are present at birth and may represent a variant of anterior polar lens opacities. They may be unilateral or, if bilateral, they may be either symmetric or asymmetric. They consist of hyperplastic lens epithelium in a collagenous matrix. Patients with pyramidal cataracts are likely to develop amblyopia. This can result from either unilateral occurrence or asymmetry of bilateral opacities and is often worsened by surrounding cortical opacification. Many patients require cataract surgery. All infants and young children with anterior polar opacities showing this configuration should be followed for cataract progression and amblyopia.

Adolescent↗
PubMed2001

Identification of a sensitive period of prenatal cocaine exposure that alters the development of the anterior cingulate cortex.

Administration of cocaine to pregnant rabbits produces robust and long-lasting anatomical, neurochemical and behavioral alterations in their offspring. For example, exposure to cocaine following implantation [embryonic day (E) 8] through gestation (E29) produces increased length and decreased bundling of layer III and V pyramidal neuron dendrites, increased parvalbumin expression in the dendrites of interneurons, and increased GABA levels in the anterior cingulate cortex (ACC) and other dopamine-rich cortical areas. We have investigated the presence of a sensitive period of in utero exposure during specific developmental epochs prior to and during the onset of cortical development that might be capable of producing such effects. Cocaine (3 mg/kg i.v., twice daily) or saline was administered during embryonic days E16-E25 (onset and peak of corticogenesis), E8-E15 (prior to cortical plate formation), E8-E25 or E8-E29 as in earlier studies. Examination of the ACC in offspring exposed from E8 to E25 and from E16 to E25 were found to induce alterations in the development of pyramidal neurons and interneurons that are nearly identical to those induced by the complete exposure (E8-E29) paradigm. No alterations were observed following the E8-E15 cocaine exposure. These data suggest that exposure to cocaine during E16-E25, the time of peak corticogenesis, appearance of cortical monoamines and onset of D(1) dopamine receptor expression, is necessary and sufficient to produce long-term effects on the organization of excitatory pyramidal neurons and inhibitory interneurons in the ACC.

Animals↗
PubMed1999

The transcription factor, Pax6, is required for cell proliferation and differentiation in the developing cerebral cortex.

The cerebral cortex develops from the dorsal telencephalon, at the anterior end of the neural tube. Neurons are generated by cell division at the inner surface of the telencephalic wall (in the ventricular zone) and migrate towards its outer surface, where they complete their differentiation. Recent studies have suggested that the transcription factor Pax6 is important for regulation of cell proliferation, migration and differentiation at various sites in the CNS. This gene is widely expressed from neural plate stage in the developing CNS, including the embryonic cerebral cortex, where it is required for radial glial cell development and neuronal migration. We report new findings indicating that, in the absence of Pax6, proliferative rates in the early embryonic cortex are increased and the differentiation of many cortical cells is defective. A major question concerns the degree to which cortical defects in the absence of Pax6 are a direct consequence of losing the gene function from defective cells themselves, rather than being secondary to abnormalities in other cells. Cortical defects in the absence of Pax6 become much more pronounced later in cortical development, and we propose that many result from a compounding of abnormalities in proliferation and differentiation that first appear at the onset of corticogenesis.

Animals↗
PubMed2002

Physiology and pathophysiology of nitric oxide in the nervous system, with special mention of the islands of Calleja and the circunventricular organs.

Nitric oxide (NO) has been recognized as a key regulatory factor in many physiological processes, including central nervous system function, development, and phatophysiology. NO is produced by a class of enzymes known as NO synthases (NOS) and in normal adult animals only the neuronal isoform (nNOS) is detectable. During cortical development, nNOS was found at E14 in neuroblasts of the marginal zone and its expression raised to a zenith by P5, decreasing afterwards until reaching a steady level by P10. At that time, nNOS was found mainly in pyramidal neurons. Interestingly, the inducible isoform of the enzyme (iNOS) was also active from P3 to P7, but it disappeared almost completely by P20. The neurodegeneration observed during normal aging and following hypoxic accidents seems to be the result of cumulative free radical damage, and excessive production of NO may be at the basis of the cascade. After ischemic events we observed an elevation in the number of neurons expressing nNOS coincident with an elevation in Ca2+-dependent NOS activity for up to 120 min. After this period, nNOS activity began to decrease but it was substituted by a rapid increase in Ca2+-independent activity coincident with the histological appearance of previously undetectable iNOS-immunoreactive neurons. These increases in NO production were accompanied by specific patterns of protein nitration, a process that seems to result in loss of protein function. In particular, we observed a correlation between exposure to ischemia-reperfusion and nitration of cytochrome c. This process was coincident with the exit of the cytochrome from the mitochondria to the surrounding cytoplasm, an early event in neuronal apoptosis. Interestingly, most of the morphological and molecular changes associated with ischemic damage were prevented by treatment with inhibitors of NO production, indicating a clear path in the search for efficacious drugs in the battle against cerebrovascular accidents.

Animals↗