Stages Of Brain Development Research Articles

Effects of prenatal gamma-irradiation on postnatal astrogliogenesis in the hippocampal formation of rat

Female Wistar rats were exposed to a single 1.0 Gy dose of gamma radiation on gestational days 13, 15, 17 or 19 (E13, E15, E17 and E19, respectively). Their 8- and 16-day old male offsprings were injected with 3 H -thymidine and sacrificed 4 h after the injection. Brain sections were immunostained for S100β protein and subjected to autoradiography. Thereafter, the dorsal part of the hippocampal formation was examined microscopically and numbers and locations of proliferating astrocytes were recorded. Following prenatal irradiation, the intensity of astrocyte proliferation was considerably reduced, especially in the region of dentate gyrus. The reduction showed regular trend of changes being much stronger in brains irradiated on E19 than in those irradiated on E13. The changes, therefore, were related to the stage of brain development at which the irradiation was performed. A possible role of neuronal regulatory influence on the postnatal development of glial cells was discussed.

Neuronal nitric oxide synthase is permanently decreased in the cerebellum of rats subjected to chronic neonatal blockade of N-methyl- d-aspartate receptors

Pharmacological blockade of the (NMDA) receptor at critical stages of brain development may have long-lasting effects on brain chemistry and on animal behavior. We report here experiments in which the competitive NMDA receptor antagonist CGP 39551 was administered to rat pups from postnatal day 7 (P7) to P18. The stage of treatment was selected to primarily target the cerebellum, whose granule cells undergo post-mitotic migration and establishment of synaptic connections during this period. We focused our study on the long-term consequences of CGP 39551 treatment on the neuronal isoform of nitric oxide synthase (nNOS) since nNOS is highly expressed in the cerebellum and it is functionally linked to the NMDA receptor. Treated rats exhibited a long-lasting (up to P70) decrease in the intensity of nNOS immunocytochemical staining in the cerebellar cortex accompanied by a decrement of calcium-dependent NOS catalytic activity. A comparable decrease of enzyme activity was measured in the cerebral cortex, but not in the hippocampus, of adult rats. Other neurochemical markers (glutamatergic, gabaergic, purinergic) and glutamine synthetase were unchanged, while a cholinergic marker was slightly increased in the cerebellum of CGP 39551 treated animals. Taken together these data show that blockade of NMDA receptor during the critical period of formation and stabilization of neuronal circuits preferentially affects long-term nNOS expression and catalytic activity in the cerebellum.

279 Neuronal apoptosis is asymmetric during sexual differentiation and lateralization of a nucleus related to courtship vocal behaviour in gerbil neonates

Selective elimination of a large proportion of cortical synapses constitutes the last major stage in brain development which is linked to sexual maturation. Various neurodevelopmental theories have proposed an association between schizophrenia and late brain maturational events. Based on epidemiological and psychopharmacological data, Saugstad hypothesised a relationship between timing of puberty, synaptic density and psychosis proneness. Early puberty should result in an earlier end to synaptic pruning, a larger number of surviving connections and an increased risk for affective psychosis. In contrast, in late maturers prolonged synapse elimination should lead to lower synaptic density which constitutes a diathesis for schizophrenia. We used EEG coherence as a neurophysiological measure of cortico-cortical connectivity. Late maturers were expected to show higher coherence, especially for short-distance connections where lower synaptic density should lead to decreased local differentiation.EEG was recorded from 12 bipolar derivations in 19 early and 19 late maturing subjects of both sexes under conditions of rest and photic stimulation at different flicker frequencies. Whereas there were no coherence differences between early and late maturers during rest, both groups differed during flicker stimulation. As hypothesised, late maturers were found to have higher short-distance coherence. Late maturers were also found to have higher intrahemispheric long-distance coherence. These findings were restricted to δ, α and β2 bands and were more pronounced in males. Our findings are interpreted in terms of a structural difference in neuronal connectivity between extreme early and late maturers.

Alcohol-Induced Inhibition of Cocaine Metabolism and the Formation of Cocaethylene in Neonatal Rats

Due to the significant species differences in the timing of different stages of brain development, to study the effects of drugs during the period equivalent to the third trimester in humans it is necessary to administer the drugs to neonatal rats. rather than in utero. In this study, we investigated the pharmacokinetic interactions between alcohol and cocaine. Such information is critical in understanding the roles of alcohol and cocaine in mediating neuroteratogenesis. Sprague-Dawley rat pups (10 days old) were given IP injections of alcohol (3.3 or 5.0 g/kg) and/or cocaine (40 mg/kg). At 20, 60, or 100 min (60 and 100 min for 3.3 g/kg alcohol only) after injections, 20 microl of tail blood was collected for blood alcohol concentration (BAC) determination. Immediately after tail blood collection, blood was collected and pooled for determinations of blood cocaine (BCC), benzoylecgonine (BBC), and cocaethylene concentration (BCEC). The slopes of the ascending BAC curves were unaffected in the presence of cocaine. BCC levels declined significantly as a function of time after the peak level at 20 min postinjection time. BCC levels were unchanged in pups receiving 3.3 g/kg alcohol, but the levels were significantly higher in 5.0 g/kg pups 20 min after injections. BBC concentrations were reduced to nearly 50% in the presence of alcohol (both doses) 20 min after injections. BCEC was detected at all time points when both alcohol and cocaine were injected. Taken together, these findings indicated that the enzymatic systems involved in converting cocaine to cocaethylene were functional at an early postnatal age, and the metabolism of cocaine was affected by the presence of alcohol in neonatal rats.

Association of Purα with RNAs Homologous to 7 SL Determines Its Binding Ability to the Myelin Basic Protein Promoter DNA Sequence

Cell type and developmental stage expression of the myelin basic protein (MBP) gene in mouse brain is regulated at the transcriptional level. Earlier studies from our laboratory have led to the identification of a DNA binding protein from mouse brain, named Puralpha, which interacts with the MB1 regulatory motif of the MBP and stimulates its transcription in glial cells. In this report, we demonstrate that a cellular RNA, with significant homology to 7 SL RNA is associated with Puralpha. Results from band shift competition studies indicate that Puralpha-associated RNA (PU-RNA), inhibits the interaction of immunopurified Puralpha with the MB1 DNA sequence. Results from Northern blot studies indicated that PU-RNA is expressed during various stages of brain development. Of interest, this RNA was found in association with Puralpha that was produced in the mouse brain at the early stage of brain development. Results from Northwestern analysis using a PU-RNA probe identified the regions within Puralpha that are important for Puralpha/PU-RNA association. Production of Puralpha at the early stage of brain development and its association with PU-RNA at this stage, when Puralpha exhibits poor binding ability to the MB1 DNA sequence, suggests that PU-RNA may function as a co-factor that negatively regulates Puralpha interaction with the MBP promoter sequence.

Modeling the Developmental Neurotoxicity of Chlorpyrifosin Vitro:Macromolecule Synthesis in PC12 Cells

Exposure to apparently subtoxic doses of chlorpyrifos during late stages of brain development affects cell acquisition through a mixture of cholinergic and noncholinergic mechanisms. In the current study, we modeled these effectsin vitrousing rat pheochromocytoma (PC12), a cell line that, upon nerve-growth factor (NGF)-induced differentiation, develops the appearance and function of cholinergic target neurons, including the expression of cholinergic receptors. In the undifferentiated state (no NGF), chlorpyrifos evoked an immediate (1 h), robust, concentration-dependent inhibition of DNA synthesis as evaluated by [3H]thymidine incorporation, with a threshold of 0.5–1.5 μg/ml. Continuous exposure for up to 24 h maintained the same degree of inhibition. The effects were selective for DNA synthesis, as much smaller inhibitions were found for synthesis of RNA or protein. In contrast, direct cholinergic stimulation of the cells by 100 μM nicotine had much smaller effects on DNA synthesis. Moreover, the effects of chlorpyrifos on DNA synthesis could not be blocked by nicotinic or muscarinic antagonists, confirming that the effects were not mediated primarily through cholinergic hyperstimulation consequent to cholinesterase inhibition or to direct receptor-mediated effects. When PC12 cells underwent NGF-induced differentiation, the rate of cell replication fell dramatically and neurite extension was evident both from morphological examination and from biochemical markers (increased protein:DNA ratio). After introduction of NGF, chlorpyrifos maintained its ability to inhibit DNA synthesis acutely. However, the ability to inhibit RNA and protein synthesis initially intensified and then disappeared, indicating a shift in macromolecular targets as differentiation proceeded. We also tested the effects of long-term exposure to chlorpyrifos during the process of NGF-induced differentiation. Continuous chlorpyrifos exposure resulted in severe reductions in macromolecule synthesis and a deficit in the total number of cells, effects similar to those seen with chlorpyrifos treatmentin vivo.At the highest concentrations, neurite extension was also inhibited. Our results suggest that chlorpyrifos can interact directly with developing neural cells to inhibit replication and neuritic outgrowth.

Ketamine blocks a conditioned taste aversion (CTA) in neonatal rats 1

MICKLEY, G. A., M. A. SCHALDACH, K. J. SNYDER, S. A. BALOGH, T. LEN, K. NEIMANIS, P. M. GOULIS, J. HUG, K. SAUCHAK, D. R. REMMERS-ROEBER, C. WALKER AND B. K. YAMAMOTO. Ketamine Blocks a Conditioned Taste Aversion (CTA) in Neonatal Rats. PHYSIOL BEHAV 64(3) 381–390, 1998.—These experiments explored the effects of glutamate, N-methyl- d-aspartate (NMDA) receptor blockade on the formation, retention, and expression of conditioned taste aversion (CTA) in young rats. Previous data from our laboratory suggested that ketamine administration potentiates a CTA in E18 rat fetuses. The current studies investigated this phenomenon in neonates. High-pressure liquid chromatography (HPLC) methods were used to determine the amount of ketamine that must be injected intraperitoneally (i.p.) to achieve brain ketamine levels in neonates comparable to those found in the fetuses from our previous experiments. Then, on their day of birth, Sprague–Dawley rat pups received injections of either 0.1, 10, or 70 mg/kg of ketamine HCl, i.p. or a Sal control injection. One-half hour later, pups were injected orally with either Saccharin (Sac; 10 μL of 0.3%) or water followed by an injection of either lithium chloride (LiCl; 81 mg/kg) or Sal (i.p.). The CTA was evaluated in two different tests. Two weeks after conditioning, the dam was anesthetized and the frequency with which pups attached to Sac-painted nipples versus nipples painted with water was measured (i.e., the nipple taste test, NTT). Controls for state-dependent learning were run in which 10 mg/kg of ketamine or saline (Sal) was administered before both taste aversion conditioning and the NTT. After weaning, the CTA was also evaluated by measuring the amount of Sac (0.3%) or water consumed during a two-bottle test. Neonates that received Sal control injections before the Sac + LiCl pairing acquired CTAs and avoided Sac-painted nipples. However, the pups injected with ketamine on the conditioning day only (P0) did not avoid Sac-painted nipples (as compared to controls). Pups that had ketamine both at the time of CTA training and testing, or just before the NTT, also failed to avoid Sac-painted nipples. Ketamine’s acute effects apparently influenced the outcome of the NTT of state-dependent control subjects. Rat pups that received the highest doses of ketamine (10 or 70 mg/kg) and tasted Sac on P0 later failed to show a neophobia for Sac-painted nipples. Whereas, rat pups that received the high dose of ketamine and water on P0, later exhibited a neophobic response. These data suggest that ketamine did not impair the animal’s ability to taste Sac. These data reflecting a ketamine-induced blockade of neonatal CTAs may be contrasted with our previous findings in which ketamine potentiated fetal CTAs. However, they are in consonance with data from adult rats suggesting that ketamine can cause an amnesia for CTAs. NMDA receptor blockade may shape memory formation in a manner that is dependent on the stage of brain development.

Early Cannabinoid Exposure as a Source of Vulnerability to Opiate Addiction: A Model in Laboratory Rodents

Recent findings have identified an endogenous brain system mediating the actions of cannabis sativa preparations. This system includes the brain cannabinoid receptor (CB-1) and its endogenous ligands anandamide and 2-arachidonoyl-glycerol. The endogenous cannabinoid system is not only present in the adult brain, but is also active at early stages of brain development. Studies developed at our laboratory have revealed that maternal exposure to psychoactive cannabinoid results in neuro-developmental alterations. A model is proposed in which early Δ9-tetrahydrocannabinol (THC) exposure during critical developmental periods results in permanent alterations in brain function by either the stimulation of CB-1 receptors present during the development, or by the alterations in maternal glucocorticoid secretion. Those alterations will be revealed in adulthood after challenges either with drugs (i.e. opiates) or with environmental stressors (i.e. novelty). They will include a modified pattern of neuro-chemical, endocrine, and behavioral responses that might lead ultimately to inadaptation and vulnerability to opiate abuse.

The 5 α-reductase in the central nervous system: expression and modes of control

The present paper will summarize two important aspects of the interactions between steroids and the brain, which have recently been studied in the authors' laboratory. In particular the paper will consider data on: (1) the significance of the two isoforms of the 5 α-R during brain ontogenesis and development, and (2) the cross-talk between glial and neuronal elements, particularly in relation to the metabolism of sex hormones. (1) The data obtained have shown that the 5 α-R type 1 enzyme is constitutively expressed in the rat CNS at all stages of brain development. Moreover, the expression of the 5 α-R type 1 is similar in males and in females, and does not appear to be controlled by androgens. The gene expression of the 5 α-R type 2 is totally different. This isoform appears to be expressed in the rat brain almost exclusively in the late fetal/early post-natal life and is controlled by testosterone. (2) The present data show that two cell lines derived respectively from a rat glioma (C6 cell line) and from a human astrocytoma (1321N1 cell line) are able to convert testosterone and progesterone into their corresponding 5 α-reduced metabolites dihydrotestosterone and dihydroprogesterone. The possibility that secretory products of normal and tumoral brain cells might be able to influence steroid metabolism occurring in the two glial cell lines previously mentioned has been considered.

Neuroanatomical and neurophysiological mechanisms involved in central nervous system dysfunctions induced by prenatal alcohol exposure.

One of the most severe consequences of maternal ethanol consumption is the damage to the developing central nervous system, which is manifested by long-term cognitive and behavioral deficits in the offspring. Prenatal exposure to ethanol affects many crucial neurochemical and cellular components of the developing brain. Ethanol interferes with all of the stages of brain development, and the severity of the damage depends on the amount of ethanol intake and level of exposure. Experimental observations also indicate that the toxic effects of ethanol are not uniform: some brain regions are more affected than others and, even within a given region, some cell populations are more vulnerable than others. The neocortex, the hippocampus, and the cerebellum are the regions in which the neurotoxic effects of ethanol have been associated with the behavioral deficits. At the cellular level, ethanol disrupts basic developmental processes, including interference with division and proliferation, cell growth, and differentiation and the migration of maturing cells. Alterations in astroglia development and in neuronal-glial interactions may also influence the development of the nervous system. An impairment of several neurotransmitter systems and/or their receptors, as well as changes in the endocrine environment during brain development, are also important factors involved in the behavioral dysfunctions observed after prenatal ethanol exposure. Finally, some molecular mechanisms of ethanol-induced behavioral dysfunctions will be discussed.

Normal developing rat brain expresses a platelet-derived growth factor B chain (c-sis) mRNA truncated at the 5' end.

The 5' untranslated sequence (5' UTS) of platelet-derived growth factor B (PDGF-B/c-sis) mRNA is highly preserved through evolution, and inhibits translation of downstream coding sequences. In this study, using Northern analysis we identified two PDGF-B/c-sis mRNAs (3.5 kb and 2.6 kb) expressed in normal developing rat brain. In contrast to the constitutive expression of 3.5 kb mRNA, the expression of 2.6 kb mRNA increased markedly in accordance with those stages of brain development at which we had previously demonstrated an increased immunoreactivity for PDGF-B/c-SIS in neurons (Sasahara et al., 1992). By PCR cloning and the RNase protection assay, we determined the complete sequence of rat PDGF-B/c-sis, and found that the 2.6 kb transcript was a form of the 3.5 kb message truncated at the 5' end, and that the predominant 2.6 kb mRNA commenced 15 nt upstream of the signal peptide. Accordingly, it is suggested that the truncation of 5' UTS contributes to the expression of PDGF-B/c-SIS protein in the CNS. Lack of translational inhibitory 5' UTS of PDGF-B/c-sis transcript and resultant efficient protein translation have been reported in only a few transformed cells and cultured umbilical vein endothelial cells. We have extended this knowledge to the developing rat brain, and suggest that a similar mechanism could operate widely in non-transformed tissue in vivo.

Distribution of the endothelial constitutive nitric oxide synthase in the developing rat brain: an immunohistochemical study

The present study deals with the distribution of endothelial constitutive nitric oxide synthase (ecNOS) in the developing rat brain using optimized protocols for preparation and fixation and the tyramide-signal-amplification technique. The immunostaining patterns of a monoclonal antibody against ecNOS are compared with results obtained with a rat pan-endothelial marker, the monoclonal RECA-1 antibody. It is shown that ecNOS is present in the endothelial lining of all types of blood vessels and the choroid plexuses of the rat brain from the beginning of vasculogenesis at embryonic day 11 until adulthood (75 weeks). The same is true for RECA-1 immunoreactivity, that was demonstrated in the developmental brain vasculature for the first time. Both antigens expressed identical immunostaining patterns. At all investigated stages of brain development neither ecNOS negative blood vessels nor ecNOS positive non-endothelial cells, e.g., neurons, were found. The data indicate that ecNOS is involved in the embryonic angiogenesis and the regulation of hemodynamic functions of brain vasculature throughout the individual life.

Is early adulthood a critical developmental stage for psychosis proneness? A survey of delusional ideation in normal subjects

It has been hypothesized that late adolescence and early adulthood might be a brain developmental stage favoring the clinical expression of psychotic symptoms in psychiatric or neurological diseases. The aim of the present survey was to examine the relationship between age and delusional ideation in a sample of subjects with no psychiatric disorder. The survey was carried out with the Aquitaine Sentinel Network of general practitioners. Consecutive practice attenders were invited to complete the PDI-21 (Peters Delusional Inventory 21 items), a self-report questionnaire designed to measure delusional ideation in the normal population. The study concerned 444 patients who had no lifetime history of psychiatric disorder and who completed the PDI-21. A principal component analysis of the PDI-21 items was performed in order to identify delusional dimensions. An age-related decrease in the likelihood to report delusional ideas was found, younger subjects scoring higher on most dimensions of delusional ideation, such as ‘persecution’, ‘thought disturbance’, ‘grandiosity’ and ‘paranormal beliefs’. ‘Religiosity’ was the only dimension positively associated with age. The results suggest that there may be a physiological neurodevelopmental stage favouring the expression of psychosis proneness in normal subjects, and support the hypothesis that the association between age and positive psychotic symptoms in functional and organic psychoses may be linked to the interaction between normal brain maturational processes and cerebral abnormalities involved in the aetiology of functional and organic psychoses.

Effect of stages of brain development on N-methyl-D-aspartate receptor gene transcription in perinatal rat

Effect of stages of brain development on N-methyl-D-aspartate receptor gene transcription in perinatal rat

Specific Binding of Acidic Phospholipids to Microtubule-associated Protein MAP1B Regulates Its Interaction with Tubulin

Microtubule-associated protein MAP1B, a major neuronal cytoskeletal protein, is expressed highly during the early stage of brain development and is thought to play an important role in brain development. Although it has been shown that MAP1B localizes both in cytosol and particulate fractions, the underlying molecular mechanism in the membrane localization has yet to be elucidated. In the present study, we show that MAP1B purified from young rat brain can bind to acidic phospholipids, such as phosphatidylserine, but not to a neutral phospholipid, phosphatidylcholine. Furthermore, the binding of MAP1B to taxol-stabilized microtubules was inhibited by the addition of phosphatidylserine or phosphatidylinositol. The addition of phosphatidylcholine showed no effect on the binding of MAP1B to the microtubules. A 120-kDa microtubule-binding fragment of MAP1B was also released from microtubules by the addition of acidic phospholipids. Synthetic peptides derived from the C-terminal half of the tubulin-binding domain, but not that corresponding to the N-terminal half, bound to acidic phospholipids specifically. These results suggest that MAP1B binds to biological membranes through its tubulin-binding site, and the binding may play a regulatory role in MAP1B-microtubule interaction.

Distribution and substrate properties of agrin, a heparan sulfate proteoglycan of developing axonal pathways

The distribution and substrate properties of agrin, an extracellular matrix heparan sulfate proteoglycan (HSPG), was investigated in the developing chick nervous system by immunocytochemistry, Western blotting, and in neurite outgrowth assays. By comparing the distribution of agrin with that of laminin-1, merosin (laminin-2), neurofilament, and neural cell adhesion molecule (NCAM), it was found that throughout development, agrin is a constituent of all basal laminae. From embryonic day (E) 4 onwards, agrin is also abundant in axonal pathways of the central nervous system, such as the optic nerve, the tectobulbar pathway, the white matter of the spinal cord, and the marginal and the molecular layers of the forebrain and the cerebellum. The abundance of agrin in brain decreases from E13 onwards. In the peripheral nervous system, agrin is present throughout development as a constituent of the Schwann cell basal laminae. Western blots confirmed the immunocytochemical data, showing maximum expression of agrin occurs during the early to medium stages of brain development. Western blots also showed that in mouse and human brain, agrin exists as an HSPG. Purified agrin did not support neurite outgrowth, rather it inhibited retinal neurite extension on mixed agrin/merosin substrates. Despite the fact that agrin, when used as a substrate inhibited neurite outgrowth, its temporal and spatial overlap with growing axons suggests that agrin has a supportive role in the development of axonal pathways, possibly as a binding component for growth factors and cell adhesion proteins.

Expression of the cell adhesion molecule axonin-1 in neuromeres of the chicken diencephalon

Axonin-1/TAG-1, a member of the immunoglobulin (Ig) superfamily of adhesion molecules, has been shown to be selectively expressed by a subset of neurons and fiber tracts in the developing nervous system of vertebrates. Axonin-1/TAG-1 is thought to play a role in the outgrowth, guidance, and fasciculation of neurites. In the present study, we map the expression of axonin-1 in the diencephalon of the chicken brain at early and intermediate stages of development [2-8 days of incubation; embryonic day (E)2-E8] by immunohistochemical methods. Results show that axonin-1 is first expressed at about E2.5 by postmitotic neurons scattered throughout most of the diencephalon. During the neuromeric stage of brain development (about E3-E5), axonin-1+ nerve cell bodies are predominantly found in two neuromeric subdivisions: 1) in the alar plate of the precommissural pretectum and dorsal thalamus and 2) in the posterior preoptic region of the hypothalamus. The axonin-1+ fiber bundles emerging from these areas grow across segmental boundaries. For example, axonin-1+ neurites originating in the dorsal thalamus cross the zona limitans intrathalamica at a right angle to project to the striatum. Later, the axonin-1+ neuromere areas give rise to particular axonin-1+ gray and white matter structures. Most of these structures correspond to the structures described to express TAG-1 in rodents. In conclusion, axonin-1 can be used as a marker to study aspects of the transition from the early neuromeric structure to the mature anatomy of the chicken brain.

Oxygen Free Radical Generation During in-Utero Hypoxia in the Preterm and Term Fetal Guinea Pig Brain. † 966

Previous studies have shown that hypoxia increases the generation of oxygen free radicals in the brain of the term guinea pig fetus. The present study tests the hypothesis that free radical production during hypoxia changes with each stage of brain development. Pregnant guinea pigs at 40 days (preterm, n=12) and 60 days (term n=14) gestation were assigned to normoxic or hypoxic groups and exposed to 21% or 7% oxygen, respectively, for 60 minutes. Fetal cerebral cortical tissue was homogenized in N2 bubbled ice-cold 100 mMα -phenyl-N-tert-butylnitrone (PBN) to trap oxygen free radicals. Trapped PBN spin adducts were extracted in toluene and free radical generation was measured by electron spin resonance spectroscopy (ESR) performed at-20°C. Peak height of the spin adduct signal was used as an index of the intensity of free radical formation and expressed as units/g dry tissue. Fetal brain hypoxia was documented biochemically by decreased levels of ATP and phosphocreatine. In the preterm group, cortical tissue from hypoxic fetuses showed an increase in spin adducts (normoxic:41.4±3.5 units/g tissue vs. hypoxic:55.1±6.4 units/g tissue, 33% increase, p<0.01). In the term group, cortical tissue from hypoxic fetuses also showed a significant increase in spin adducts (normoxic: 33.2±7.3 units/g tissue vs. hypoxic: 57.9±9.2 units/g tissue, 71% increase, p<0.01). Baseline free radical generation during normoxia was 23% higher in preterm than term. The higher baseline in the normoxic preterm brain may reflect decreased levels of antioxidant enzymes at this stage of gestation. However, the greater magnitude of change in free radicals following hypoxia in the term fetus suggests that susceptibility to hypoxia-induced free radical injury increases with brain maturation. We speculate that the lower level of free radical generation during hypoxia in the immature brain may be due to the lower concentrations of membrane highly unsaturated fatty acids available as a source of free radical production, and/or to the underdevelopment of free radical generating mechanisms.

Expression of androgen-activating enzymes in cultured cells of developing rat brain.

Dihydrotestosterone and estradiol, two active metabolites formed locally in the brain from testosterone, modulate several functions of the developing rat CNS; these compounds derive from the 5 alpha-reduction or the aromatization of the A-ring of the hormone. Also, progesterone and corticosteroids may be 5 alpha-reduced and subsequently 3 alpha-hydroxylated, becoming modulators of specific neuronal functions. Although the aromatase is a single enzyme, two types of 5 alpha-reductase have been cloned, showing peculiar biochemical properties and probably different functions. Therefore, the isoform(s) of the enzyme 5 alpha-reductase(s) present in early stage of brain development have been characterized in primary neuronal and glial cell cultures obtained from the fetal or neonatal rat brain, respectively. Aromatase expression was also studied. The results have shown that in all the brain cells examined type 1 5 alpha-reductase mRNA is expressed. No specific transcript of type 2 5 alpha-reductase is detectable in any of the cell types examined. Finally, the aromatase gene is expressed only in cultured fetal neurons and especially in those derived from the hypothalamic area of the rat embryos. It is interesting that no aromatase mRNA is detectable in mixed glia or in type 1 astrocytes and oligodendrocytes cultured separately.

Effects of acute prenatal ethanol exposure on Bergmann glia cells early postnatal development

Effects of acute ethanol exposure during the prenatal phase of Bergmann glia cell (Bgc) generation were evaluated in three postnatal days. Ethanol exposed rats showed Bgc with reduced soma size, decreased number and width of their fibers, and increased fiber length, when compared with control animals. These differences, however, were significant at postnatal day 12. Our results demonstrate that acute, prenatal exposure to ethanol during critical stages of brain development disrupts Bgc early postnatal development.