Les publications

IF du Neurocentre

799 publications

* equal contribution
Les IF indiqués ont été collectés par le Web of Sciences en Juin 2020

Mice deficient for FgfR2-IIIb were generated by placing translational stop codons and an IRES-LacZ cassette into exon IIIb of FgfR2. Expression of the alternatively spliced receptor isoform, FgfR2-IIIc, was not affected in mice deficient for the IIIb isoform. FgfR2-IIIb(-/-) (lac)(Z) mice survive to term but show dysgenesis of the kidneys, salivary glands, adrenal glands, thymus, pancreas, skin, otic vesicles, glandular stomach, and hair follicles, and agenesis of the lungs, anterior pituitary, thyroid, teeth, and limbs. Detailed analysis of limb development revealed an essential role for FgfR2-IIIb in maintaining the AER. Its absence did not prevent expression of Fgf8, Fgf10, Bmp4, and Msx1, but did prevent induction of Shh and Fgf4, indicating that they are downstream targets of FgfR2-IIIb activation. In the absence of FgfR2-IIIb, extensive apoptosis of the limb bud ectoderm and mesenchyme occurs between E10 and E10.5, providing evidence that Fgfs act primarily as survival factors. We propose that FgfR2-IIIb is not required for limb bud initiation, but is essential for its maintenance and growth.

The dental school arose from the premise that a dental school would round out the university and add prestige to the burgeoning Health Professions Division with its five schools and eight health programs. The school was founded in light of the following circumstances. Patient Pool Evaluation of community facilities and services revealed that there was an increasing patient pool, without disturbing the present mix. There was evidence of a need for dental care for large numbers of unserved or underserved people. Financial Considerations Proforma and cash flow budget projections showed financial stability of this project. The university was recognized to have the ability to absorb initial capital costs. HPD had a history of the success in functioning with tuition-dependent budgets. University Factors The university has had success in establishing and operating five health professions schools. A complete and experienced infrastructure has existed for sixteen years in the University and in the Health Professions Division. The university would provide unconditional administrative support.

02/2001 | Eur J Neurosci
Influence of glucocorticoids on dopaminergic transmission in the rat dorsolateral striatum.
Barrot M, Abrous DN, Marinelli M, Rouge-Pont F, Le Moal M, Piazza PV

Glucocorticoid hormones exert strong influences on central neurotransmitter systems. In the present work, we examined the functional consequences of corticosterone suppression on the dopaminergic transmission in the dorsolateral striatum by studying the expression of Fos-like proteins and extracellular dopamine levels. Glucocorticoid hormones were suppressed by adrenalectomy, and the specificity of the effects assessed by restoring physiological plasmatic corticosterone concentrations. We show that, in the dorsolateral striatum, glucocorticoids modify postsynaptic dopaminergic transmission. Suppression of glucocorticoids decreased the induction of Fos proteins in response to a direct agonist of dopamine D(1) receptors (SKF 82958, 1.5 mg/kg, i.p.), but not the release of dopamine induced by morphine (2 mg/kg, s.c.) or the density of the limiting enzyme of dopamine synthesis, tyrosine hydroxylase. In contrast to the dopaminergic response to morphine, the response to cocaine (15 mg/kg, i.p.) was modified by the suppression of corticosterone. In this case, adrenalectomy increased cocaine-induced changes in extracellular dopamine but did not modify the expression of Fos-like proteins. This absence of changes in cocaine-induced Fos-like proteins might result from a compensatory mechanism between the increase in the dopaminergic response and the decrease in the functional activity of dopamine D(1) receptors. The increased dopaminergic response to cocaine also contrasts with the decreased response previously observed in the shell of the nucleus accumbens [Barrot et al. (2000) Eur. J. Neurosci., 12, 973-979]. The present data highlight the profound heterogeneous influence of glucocorticoids within dopaminergic projections.

02/2001 | Eur J Neurosci
Differential role of the nitric oxide pathway on delta(9)-THC-induced central nervous system effects in the mouse.
Azad SC, Marsicano G, Eberlein I, Putzke J, Zieglgansberger W, Spanagel R, Lutz B

This study investigated whether the nitric oxide pathway was involved in the central effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive constituent of cannabis sativa. Body temperature, nociception and locomotion were measured in neuronal nitric oxide synthase (nNOS) knock-out (KO) mice and wild-type (WT) controls after intraperitoneal application of Delta(9)-THC. These Delta(9)-THC-induced effects are known to be mediated through the brain-type cannabinoid receptor 1 (CB1). Therefore, in situ hybridization (ISH) experiments were performed in the adult murine brain to determine possible changes in CB1 mRNA levels in nNOS-KO, compared with WT mice, and to reveal brain areas where CB1 and nNOS were coexpressed in the same neurons. We found that an intraperitoneal injection of 10 mg/kg Delta(9)-THC led to the same increase in the hot plate latencies in both genotypes, suggesting that Delta(9)-THC-mediated antinociception does not involve nNOS. In contrast, a significant Delta(9)-THC-induced decrease of body temperature and locomotor activity was only observed in WT, but not in nNOS-KO mice. ISH revealed significantly lower levels of CB1 mRNA in the ventromedial hypothalamus (VMH) and the caudate putamen (Cpu) of the nNOS-KO animals, compared with WT mice. Both areas are known to be among the regions involved in cannabinoid-induced thermoregulation and decrease of locomotion. A numerical evaluation of nNOS/CB1 coexpression showed that approximately half of the nNOS-positive cells in the dorsolateral Cpu also express low levels of CB1. ISH of adjacent serial sections with CB1 and nNOS, revealed expression of both transcripts in VMH, suggesting that numerous nNOS-positive cells of VMH coexpress CB1. Our findings indicate that the nitric oxide pathway is involved in some, but not all of the central effects of Delta(9)-THC.

01/2001 | Neurotox Res
Long term neurodevelopmental and behavioral effects of perinatal life events in rats.
Koehl M, Lemaire V, Vallee M, Abrous N, Piazza PV, Mayo W, Maccari S, Le Moal M

Modern neurosciences are now able to open new avenues concerning an experimental approach to clinical neurosciences and psychiatry. Detection and prediction of potential vulnerabilities such as behavioral disturbances and neurodegenerative diseases, are urgent tasks leading to prevention that must be encouraged in parallel to the enormous efforts displayed for treatments. Besides possible genetic origins of diseases, environmental factors are now coming under scrutiny, and especially deleterious and challenging life events and stress occurring during prenatal and postnatal critical periods may orient brain functions towards deleterious developments. The hypothesis that will be examined is that early events might be at the origin of pathological transformations and symptoms after long periods of apparent normal abilities and behavioral homeostasis. We used models of prenatal stress and postnatal manipulations such as cross-fostering. It will be demonstrated that such events induce long-term changes, cognitive and emotional modifications appearing first, when offspring are adults, followed by cognitive defects later in life. Increased sensitivity of the hypothalamic pituitary-adrenal axis (HPA), the endocrine system controlling the secretion of stress hormones (corticoids), appears to be a major element of pathogenesis. HPA axis dysfunction appears very early after birth (3 days) and lasts for months. Cumulative exposure to high levels of hormones seems to be detrimental for some brain regions, especially the hippocampus and major neurotransmitter systems such as dopamine neurons. We evidenced that neuronal modifications in hippocampal region are correlated with behavioral and cognitive defects, relating environment, stress in early life, hormonal changes, long-term neuropathological processes and impaired cognition in aging. Moreover appears in offspring, when adults, a proneness to engage in drug dependence. These data emphasize the need to consider early environmental life events as etiological factors for delayed neuropsychiatric disturbances, neurodegenerative defects included. Moreover, they strengthen the interest for a longitudinal approach to promote experimental psychopathology.

12/12/2000 | Hum Mol Genet
Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader-Willi syndrome.
Muscatelli F, Abrous DN, Massacrier A, Boccaccio I, Le Moal M, Cau P, Cremer H

Prader-Willi syndrome (PWS) is a complex neurogenetic disorder with considerable clinical variability that is thought in large part to be the result of a hypothalamic defect. PWS results from the absence of paternal expression of imprinted genes localized in the 15q11-q13 region; however, none of the characterized genes has so far been shown to be involved in the etiology of PWS. Here, we provide a detailed investigation of a mouse model deficient for NECDIN: Linked to the mutation, a neonatal lethality of variable penetrance is observed. Viable NECDIN: mutants show a reduction in both oxytocin-producing and luteinizing hormone-releasing hormone (LHRH)-producing neurons in hypothalamus. This represents the first evidence of a hypothalamic deficiency in a mouse model of PWS. NECDIN:-deficient mice also display increased skin scraping activity in the open field test and improved spatial learning and memory in the Morris water maze. The latter features are reminiscent of the skin picking and improved spatial memory that are characteristics of the PWS phenotype. These striking parallels in hypothalamic structure, emotional and cognitive-related behaviors strongly suggest that NECDIN is responsible for at least a subset of the multiple clinical manifestations of PWS.

12/2000 | Neuron
PDZ domain suppression of an ER retention signal in NMDA receptor NR1 splice variants.
Standley S, Roche KW, McCallum J, Sans N, Wenthold RJ

The NMDA receptor NR1 subunit has four splice variants that differ in their C-terminal, cytoplasmic domain. We investigated the contribution of the C-terminal cassettes, C0, C1, C2, and C2', to trafficking of NR1 in heterologous cells and neurons. We identified an ER retention signal (RRR) in the C1 cassette of NR1, which is similar to the RXR motif in ATP-sensitive K(+) channels (Zerangue et al., 1999). We found that surface expression of NR1-3, which contains C1, is due to a site on the C2' cassette, which includes the terminal 4 amino acid PDZ-interacting domain. This site suppresses ER retention of the C1 cassette and leads to surface expression. These findings suggest a role for PDZ proteins in facilitating the transition of receptors from an intracellular pool to the surface of the neuron.

11/2000 | Recenti Prog Med
[Steroid therapy and adrenal function].
Cota D, Ceroni L, Pasquali R

Glucocorticoids are frequently used for both diagnostic and therapeutic purposes. Their action mimics endogenous glucocorticoid actions by altering the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Therefore, they can be responsible for iatrogenic diseases, particularly if used at high doses and for a long time. The aim of this brief review is to show the main pharmacological characteristics and the endocrine effects of glucocorticoids. The HPA axis insufficiency, related to acute glucocorticoid withdrawal, is also discussed.

06/10/2000 | J Biol Chem
Theromin, a novel leech thrombin inhibitor.
Salzet M , Chopin V , Baert J , Matias I , Malecha J

We purified the most potent thrombin inhibitor described to date from the rhynchobdellid leech Theromyzon tessulatum. Designated theromin, it was purified to apparent homogeneity by gel permeation and anion exchange chromatography followed by two reverse-phase steps of high performance liquid chromatography. The primary sequence of theromin (a homodimer of 67 amino acid residues including 16 cysteine residues) was determined by a combination of reduction and s-beta-pyridylethylation, Edman degradation, trypsin enzymatic digestion, and matrix-assisted laser desorption mass spectrometry measurement. Theromin exhibits no sequence homology with any other thrombin inhibitors. Furthermore, theromin significantly diminishes, in a dose-dependent manner, the level of human granulocyte and monocyte activation induced by lipopolysaccharides. In summary, this potent thrombin inhibitor promises to have high biomedical significance.

10/2000 | Med Sci (Paris)
Régénération postlésionnelle des cellules sensorielles vestibulaires : bilan et espoirs
Bartolami S, Montcouquiol M, Travo C, Sans A

30/09/2000 | Brain Res Dev Brain Res
Postnatal developmental changes in AMPA and NMDA receptors in the rat vestibular nuclei.
Sans NA, Montcouquiol ME, Raymond J

Changes in the expression of the AMPA receptor subunits GluR1-4 and of the NMDA receptor subunits NR1, NR2A-D were investigated in the developing rat medial and lateral vestibular nuclei. Analyses were performed using nonradioactive in situ hybridization and immunoblotting with subunit-specific antibodies. During the postnatal development, glutamatergic receptor subunits were differentially expressed in the vestibular nuclei. The level of expression of GluR1, GluR4 and NR1 subunits was higher in the developing brain as compared to the adult. We observed a gradual increase in GluR2/3, NR2A, NR2B and NR2C levels of expression in the medial and lateral vestibular nuclei during the first 3 weeks of postnatal development. In situ hybridization results were consistent with immunoblot analyses. The differential expression of AMPA and NMDA receptor subunits in immature vestibular neurons is consistent with changes in glutamate receptor properties. This may be related to the postsynaptic regulation of receptor subunits associated with the synaptic plasticity of the vestibular neuron connections during specific sequences of postnatal development.

26/09/2000 | Proc Natl Acad Sci U S A
Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus.
Lemaire V, Koehl M, Le Moal M, Abrous DN

Early experiences such as prenatal stress significantly influence the development of the brain and the organization of behavior. In particular, prenatal stress impairs memory processes but the mechanism for this effect is not known. Hippocampal granule neurons are generated throughout life and are involved in hippocampal-dependent learning. Here, we report that prenatal stress in rats induced lifespan reduction of neurogenesis in the dentate gyrus and produced impairment in hippocampal-related spatial tasks. Prenatal stress blocked the increase of learning-induced neurogenesis. These data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for psychopathological vulnerabilities in aging.

09/2000 | Exp Neurol
Influence of environment on the efficacy of intrastriatal dopaminergic grafts.
Dobrossy MD, Le Moal M, Montaron MF, Abrous N

Functional recovery is influenced by experience. The aim of the present work was to examine the effects of 'enriched' environment (EE) versus an 'impoverished' environment on the anatomical and functional integration of intrastriatal dopaminergic grafts. These influences were studied using a paradigm where grafting was performed before the dopamine-depleting lesion. Dopaminergic grafts were implanted into the left neostriatum of adult male rats. In the enriched group, grafted rats were housed collectively and were trained on different behavioral tests following grafting. In contrast, impoverished grafted rats were housed individually and not further manipulated. Ten weeks after grafting, the mesotelencephalic dopaminergic pathway was destroyed unilaterally to the grafted side and different behaviors were followed for 7 months. Grafting prior to lesioning had no prophylactic effects on the performance as the graft did not prevent the onset of the lesion-induced impairments. However, under EE conditions, a graft effect was manifested in the reduction of drug-induced rotation and on the indices of bias as tested by a spatial alternation test. No positive graft effects were observed in the skilled paw reaching test. Grafted rats raised under impoverished conditions performed in a fashion indistinguishable from the control lesioned animals on most measures of behavior. A beneficial effect of EE conditions was observed on survival of TH-positive neurons within the grafts. The results suggest that survival of grafted neurons, and the reduction of the magnitude of particular behavioral impairments, can be optimized by increasing the complexity of the subject's environment.

07/2000 | Therapie
[An animal model of human declarative (relational) memory and of its dysfunction].
Jaffard R, Etchamendy N, Desmedt A, Krazem A, Cortes-Torrea C, Marighetto A

The present work was aimed at determining, both at the psychological and at the neurobiological levels, aspects of rodent memory that fall into line with human declarative memory which is known to be selectively impaired in amnesic subjects and during the course of ageing. The ability to compare and to contrast items in memory, and to support inferential use of memories in novel situations (flexibility), were considered to be the two key psychological features of human declarative memory that were altered by both hippocampal lesions and hippocampal dysfunction. Adult and aged mice were trained on learning tasks using two-stage paradigms, the aim of which was to assess memory performance through these two psychological aspects in the same subjects. Results suggest that ageing specifically impairs the ability to both compare and contrast items in memory (declarative/relational memory based on complex associations), without altering memory based on simple S-R associations (procedural memory). Hippocampal lesions in adult mice produced the same dissociation between relational memory (impaired) and procedural memory (spared). Pharmacological experiments showed that, depending on the drug used, the relational memory deficit of aged mice may be selectively reversed (i.e. without changes in procedural memory) and that the behavioural efficacy of certain treatments was shown to parallel their potency in re-establishing normal (i.e. adult) levels of hippocampal plasticity-related mechanisms. Together with previous findings, these results suggest that the storage and use of relational representations would critically depend on the plasticity of hippocampal synapses, which via their connections with cortical areas, would support the storage of associations between perceptual, behavioral and cognitive events.

07/2000 | j gravit physiol
Developmental study of rat vestibular neuronal circuits during a spaceflight of 17 days.
Raymond J, Dememes D, Blanc E, Sans N, Venteo S, Dechesne CJ

The aim of this study was to investigate the potential plasticity of the vestibular system, in structural and biochemical terms, at the level of the gravity receptors (the sensory hair cells), the primary neurons relaying the sensory signals (the vestibular ganglion neurons) and their projections into the vestibular nuclei. We studied the biochemical differentiation of the sensory cells and of the vestibular ganglion by investigating which calcium-binding proteins were present. We studied the development of peripheral synaptic connections of the efferent system by investigating the distribution of CGRP (calcitonin-gene related-peptide) and we also studied the cerebellar synaptic connections in the vestibular nuclei, as identified by the presence of calbindin. Putative changes were studied after a 17-day episode of microgravity (Neurolab STS-90), in developing rats between postnatal days 8 and 25. The extent to which these changes could be caused by alterations in gravity was determined by examining sensory and nervous structures not involved in gravity detection, the cochlea and the cochlear nuclei.

01/06/2000 | J Neurosci
Vertical shifts in self-administration dose-response functions predict a drug-vulnerable phenotype predisposed to addiction.
Piazza PV, Deroche-Gamonent V, Rouge-Pont F, Deroche-Gamonet V, Le Moal M

The role of individual differences in the etiology of addiction is a very controversial issue. Neuroendocrine phenotypes that are able to predispose an individual to the development of drug intake have been identified previously. However, such information has been gathered by comparing individuals who differ in their sensitivity to low doses of the drug. Consequently, it remains unclear whether a phenotype predicting a higher sensitivity to low drug doses would be relevant in environmental conditions, such as the ones encountered by humans in which high drug doses are available. In this report, we studied dose-response, dose-intake, and ratio-intake functions for intravenous cocaine self-administration in the laboratory rat. We show that individual differences in drug self-administration originate from vertical shift in the dose-response function. Thus, no matter the dose, drug intake is very high in some 'vulnerable' subjects and very low in other 'resistant' ones. Vulnerable subjects, the upward shifted ones, would then have a higher chance to develop drug abuse also when high drug doses are available. In conclusion, these results provide a solid foundation for the existence of a drug-vulnerable phenotype relevant for the etiology of addiction.

06/2000 | Minerva Endocrinol
[Pseudo-Cushing syndrome. Physiopathologic aspects and differential diagnosis].
Ceroni L, Cota D, Pasquali R

Pseudo-Cushing Syndromes (PCS) are a heterogeneous group of disorders, including alcoholism and depression, that share many of the clinical and biochemical features of Cushing's Syndrome (CS). It has been suggested that hypercortisolism of PCS may be the result of increased hypothalamic corticotropin-releasing hormone secretion in the context of a hypothalamic-pituitary-adrenal axis that is otherwise normally constituted. The substantial overlap in clinical features and daily urinary free cortisol levels between several patients with CS and those with PCS can make the differential diagnosis difficult. The most accurate tests in the distinction of CS from alcohol-induced PCS are dexamethasone-CRH and a midnight serum cortisol measurement. In depressed patients, the insulin tolerance test may be useful, although some overlap may exist. This brief review summarises the principal pathophysiological events of PCS and provides a useful strategy for differential diagnosis.

06/2000 | transgenic res
An in vivo model of hyperacute rejection: characterization and evaluation of the effect of transgenic human complement inhibitors.
Mora M, Lazzer M, Marsicano G, Mulder LC, Carraresi L, Pieri A, Benanchi A, Grifoni D, Nuti S, Bruzzone P, Comporti M, Cortesini R, Rossini M

Hyperacute rejection (HAR) occurring after transplantation within phylogenetically distant species is a severe reaction triggered by preexisting xenoreactive antibodies and complement activation, leading to the destruction of the donor organ. Expression of human complement inhibitors in transgenic pig organs prolongs the survival of xenograft in experimental models. Moreover, the extent of protection from hyperacute rejection is dependent on the level and site of expression of the transgenic molecules and, probably, on the combination of different molecules. In this regard a small animal model to test the efficacy of expression vectors and different human molecules could be very advantageous. A murine model developed in our laboratory was characterized by measurement of several parameters characteristic of HAR in the livers of control and transgenic mice expressing transgenic human DAF (CD55) or MCP (CD46) at the end of 2 h of perfusion with human plasma and after I day. The parameters studied were heamatological values of hepatic functions (GOT and GPT), induction of pro-inflammatory molecules and histopathological evaluation. Cytokines (IL-1alpha, IL-1beta, IL-6) induction and exposure of P-selectin on the endothelial cell surface, was only observed in control animals after 2 h of perfusion, as an early event. GOT and GPT values increase dramatically after 2 h perfusion and 1 day after the treatment according to the histopathological observation of liver damage. On the contrary, the livers of hDAF or hMCP transgenic mice, under the same treatment were significantly protected although the extent of this protection is dependent on the level of expression of transgenic human molecules.

Fibroblast growth factors (FGFs) transmit their signals through four transmembrane receptors that are designated FGFR1-4. Alternative splicing in the extracellular region of FGFR1-3 generates receptor variants with different ligand binding affinities. Thus two types of transmembrane receptors (IIIb and IIIc isoforms) have been identified for FGFR2 and FGFR3, and the existence of analogous variants has been postulated for FGFR1 based on its genomic structure. However, only a single full-length transmembrane FGFR1 variant (FGFR1-IIIc) has been identified so far. Here we describe the cloning of a full-length cDNA encoding FGFR1-IIIb from a mouse skin wound cDNA library. This receptor isoform was expressed at the highest levels in a subset of sebaceous glands of the skin and in neurons of the hippocampus and the cerebellum. FGFR1-IIIb was expressed in L6 rat skeletal muscle myoblasts and used in cross-linking and receptor binding studies. FGF-1 was found to bind the receptor with high affinity, whereas FGF-2, -10, and -7 bound with significantly lower affinities. Despite their apparently similar but low affinities, FGF-10 but not FGF-7 induced the activation of p44/42 mitogen-activated protein kinase in FGFR1-IIIb-expressing L6 myoblasts and stimulated mitogenesis in these cells, demonstrating that this new receptor variant is a functional transmembrane receptor for FGF-10.

15/05/2000 | Neuroreport
Detection and localization of BDNF in vestibular nuclei during the postnatal development of the rat.
Montcouquiol ME, Sans NA, Travo C, Sans A, Valat J

The changes in expression and the subcellular localization of brain-derived neurotrophic factor (BDNF) protein in the rat vestibular nuclear complex (VNC), have been investigated at different postnatal stages. Immunoblotting and ELISA analyses showed a down-regulation of BDNF protein expression in VNC with age. In addition, observations by confocal microscopy revealed that BDNF is mainly located in neuronal somata at postnatal day 8 (P8) and restricted to processes by P15. These results support the idea that BDNF could have different roles in the VNC according to the stage of development The protein could act as a neurotrophic factor in embryonic and early postnatal stages whereas in later developmental stages of the VNC it could be involved in neuronal maturation and regulation of neuronal circuitry.

05/2000 | Learn Mem
Further evidence for a dissociation between different forms of mnemonic
Marighetto A, Touzani K, Etchamendy N, Torrea CC, De Nanteuil G, Guez D, Jaffard R, Morain P

It has been demonstrated previously on the radial maze that the emergence of an

04/2000 | Int J Dev Neurosci
PSA-NCAM: an important regulator of hippocampal plasticity.
Cremer H, Chazal G, Lledo PM, Rougon G, Montaron MF, Mayo W, Le Moal M, Abrous DN

The Neural Cell Adhesion Molecule (NCAM) serves as a temporally and spatially regulated modulator of a variety of cell-cell interactions. This review summarizes recent results of studies aimed at understanding its regulation of expression and biological function, thereby focussing on its polysialylated isoforms (PSA-NCAM). The detailed analysis of the expression of PSA and NCAM in the hippocampal mossy fiber system and the morphological consequences of PSA-NCAM deficiency in mice support the notion that the levels of expression of NCAM are important not only for the regulation and maintenance of structural changes, such as migration, axonal growth and fasciculation, but also for activity-induced plasticity. There is evidence that PSA-NCAM can specifically contribute to a presynaptic form of plasticity, namely long-term potentiation at hippocampal mossy fiber synapses. This is consistent with previous observations that NCAM-deficient mice show deficits in spatial learning and exploratory behavior. Furthermore, our data points to an important role of the hypothalamic-pituitary-adrenal axis, which is the principle adaptive response of the organism to environmental challenges, in the control of PSA-NCAM expression in the hippocampal formation. In particular, we evidence an inhibitory influence of corticosterone on PSA-NCAM expression.

27/03/2000 | J Comp Neurol
Serotonergic systems in the spinal cord of the amphibian urodele Pleurodeles waltl.
Branchereau P, Rodriguez JJ, Delvolve I, Abrous DN, Le Moal M, Cabelguen JM

The role of the monoamine serotonin (5-HT) in modulating the neural networks underlying axial locomotor movements was studied in an adult amphibian urodele, Pleurodeles waltl. 5-HT was applied to an in vitro brainstem-spinal cord preparation of P. waltl, which displayed fictive axial locomotor patterns following bath application of N-methyl-D-aspartate (5 microM) with D-serine (10 microM). Our results showed that 5-HT (1-25 microM) produces a reversible increase in the cycle duration and the duration of rhythmic bursting activity recorded extracellularly from ventral roots innervating the axial musculature. When applied alone, 5-HT does not trigger axial locomotor activity. The distribution pattern of 5-HT immunoreactive (5-HT-ir) cells along the spinal cord was investigated both in intact and in chronic spinal animals. The number of 5-HT-ir cell bodies is higher at brachial levels and decreases through crural levels. Sparse oval or fusiform 5-HT-ir somata are present within the gray matter, just ventrolateral to the central canal. Longitudinal fibers were detected throughout the entire white matter, except in the medial part of the dorsal funiculi. Two columns of intensely labeled and profusely branching thick and thin fibers associated with numerous varicosities run continuously along the ventrolateral surface of the spinal cord. Three weeks following full spinal cord transection at the level of the second spinal root, all longitudinal processes had disappeared, indicating their supraspinal origin, whereas the ventrolateral plexes remained, suggesting that they originated from intraspinal 5-HT-ir cell bodies. Our data showing that spinal 5-HT is organized according to a rostrocaudal gradient suggest that the 5-HT systems of P. waltl are not related to the presence of limb motor pools but more likely are related to axial central pattern generators (CPGs) networks down the length of the spinal cord. The possible involvement of these two sources (descending vs. intraspinal) of 5-HT innervation in the modulation of the axial CPGs is discussed.

Fibroblast growth factors are a family of intercellular signaling molecules with multiple and varied roles in animal development. Most are exported from cells by means of a classical amino-terminal signal sequence that is cleaved from the mature protein during its passage through the secretory pathway. Fibroblast growth factor-9 (Fgf-9) does not contain a recognizable signal sequence, although it is efficiently secreted. In this study, we show that Fgf-9 enters the endoplasmic reticulum and traverses the Golgi complex in a similar manner to other constitutively secreted proteins. Deletion and point mutation analysis has revealed an atypical non-cleaved signal sequence within the amino-terminal region of Fgf-9. Moreover, the first 28 amino acids of Fgf-9 can function as an efficient non-cleaved signal peptide when appended to the amino terminus of green fluorescent protein.

03/2000 | Eur J Neurosci
The dopaminergic hyper-responsiveness of the shell of the nucleus accumbens is hormone-dependent.
Barrot M, Marinelli M, Abrous DN, Rouge-Pont F, Le Moal M, Piazza PV

The dopaminergic projection to the shell of the nucleus accumbens is the most reactive to stress, reward and drugs of abuse and this subregion of the nucleus accumbens is also considered a target of therapeutic effects of atypical antipsychotic drugs (APD). In this report we show, by means of in vivo microdialysis and Fos immunohistochemistry, that the hyper-responsiveness which characterizes the dopaminergic transmission to the shell is dependent on glucocorticoid hormones. In Sprague-Dawley rats, after suppression of endogenous glucocorticoids by adrenalectomy, extracellular dopamine levels selectively decreased in the shell, whilst they remained unchanged in the core. This effect was observed in basal conditions, after a mild stress (vehicle injection), as well as after subcutaneous administration of morphine (2 mg/kg, s.c. ) or intraperitoneal injection of cocaine (15 mg/kg, i.p.). The decrease in dopamine observed in the shell had a postsynaptic impact, as shown by less induction of Fos-like proteins selectively in the shell in response to cocaine. However, the induction of Fos-like proteins by the full D1 agonist SKF82958 (1.5 mg/kg, i.p.) remained unchanged after adrenalectomy, suggesting that the changes in Fos expression after cocaine injection were likely to depend on changes in extracellular dopamine levels rather than on changes in postsynaptic sensitivity to dopamine. The effects of adrenalectomy were glucocorticoid-specific given that they were prevented by corticosterone treatment. This anatomical specificity in the control of neuronal activity by a hormonal input highlights the role of steroid hormones in shaping the functional activity of the brain.

01/02/2000 | J Neurosci
A developmental change in NMDA receptor-associated proteins at hippocampal synapses.
Sans N, Petralia RS, Wang YX, Blahos J 2nd, Hell JW, Wenthold RJ

The membrane-associated guanylate kinases [Chapsyn-110/postsynaptic density-93 (PSD-93), synapse-associated protein-90 (SAP-90)/PSD-95, and SAP-102] are believed to cluster and anchor NMDA receptors at the synapse and to play a role in signal transduction. We have investigated the developmental changes in expression of these proteins in rat hippocampus using biochemical analyses and quantitative immunogold electron microscopy. At postnatal day 2 (P2), SAP-102 was highly expressed, whereas PSD-93 and PSD-95 were low. SAP-102 expression increased during the first week, stayed stable through P35, and showed a reduced expression at 6 months. From P2 through 6 months, PSD-93 and PSD-95 increased. For PSD-95, the percent of labeled synapses increased almost threefold with age, whereas the number of gold particles per labeled synapse did not change significantly, suggesting that the increase in PSD-95 is attributable primarily to an increase in the number of synapses containing PSD-95. In contrast, for SAP-102, both percent labeled synapses and the number of gold particles per labeled synapse decreased during this time. From Western blots of hippocampus and immunogold analysis of CA1 synapses, the high expression of NR2B at P2 coincides with the high level of SAP-102 at synapses, whereas the later expression of NR2A coincides with that of PSD-93 and PSD-95. To determine whether the changes in PSD-93/95 and SAP-102 reflect preferred associations with NR2A and NR2B, respectively, we measured co-immunoprecipitation in the adult hippocampus. These studies suggest that there is a preference for complexes of NR2A/PSD-93/95 and NR2B/SAP-102. These results indicate that individual receptor-associated proteins may have specific functions that are critical to synapse development.

02/2000 | Development
An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal-epithelial signalling during mouse organogenesis.
De Moerlooze L, Spencer-Dene B, Revest JM, Hajihosseini M, Rosewell I, Dickson C

The fibroblast growth factor receptor 2 gene is differentially spliced to encode two transmembrane tyrosine kinase receptor proteins that have different ligand-binding specificities and exclusive tissue distributions. We have used Cre-mediated excision to generate mice lacking the IIIb form of fibroblast growth factor receptor 2 whilst retaining expression of the IIIc form. Fibroblast growth factor receptor 2(IIIb) null mice are viable until birth, but have severe defects of the limbs, lung and anterior pituitary gland. The development of these structures appears to initiate, but then fails with the tissues undergoing extensive apoptosis. There are also developmental abnormalities of the salivary glands, inner ear, teeth and skin, as well as minor defects in skull formation. Our findings point to a key role for fibroblast growth factor receptor 2(IIIb) in mesenchymal-epithelial signalling during early organogenesis.

We have examined the behavioural consequences of a partial unilateral dopaminergic denervation of the rat striatum. This partial lesion was obtained by an intrastriatal 6-hydroxy-dopamine injection (6-OHDA, 20 or 10 microgram divided between two injection sites) and was compared with a unilateral complete lesion resulting from an injection of 6-OHDA (2 x 6 microgram) into the medial forebrain bundle. Quantification of striatal dopamine (DA) and its metabolites, and the immunohistochemical evaluation of the nigrostriatal DA system confirmed the complete and partial lesions. Animals with complete striatal denervation displayed both apomorphine- and amphetamine-induced rotations whereas the partial denervation elicited amphetamine-induced rotations only. However, the rates of amphetamine-induced rotation were not correlated with the size of the lesion. In contrast, the paw-reaching impairments were significantly correlated with the striatal dopaminergic depletion. When evaluated in the staircase test, animals with partial denervation were impaired exclusively for the paw contralateral to the side of the lesion. This motor deficit (50-75%) included all components of the skilled paw use (i.e. attempt, motor coordination and success) and was observed at least 12 weeks after the lesion. However, these animals were able to perform normal stepping adjustments with the impaired paw, indicating that the partial lesion induced a coordination deficit of the paw rather than a deficit of movement initiation. After a complete lesion, stepping adjustments of the contralateral paw were dramatically impaired (by 80%), an akinesia which almost certainly accounted for the great deficit in skilled paw use. The paw-reaching impairments resulting from the partial striatal denervation are proposed as a model of the early symptoms of Parkinson's disease and may be useful for the development of restorative therapies.

Cannabinoids can modulate motor behaviour, learning and memory, cognition and pain perception. These effects correlate with the expression of the cannabinoid receptor 1 (CB1) and with the presence of endogenous cannabinoids in the brain. In trying to obtain further insights into the mechanisms underlying the modulatory effects of cannabinoids, CB1-positive neurons were determined in the murine forebrain at a single cell resolution. We performed a double in situ hybridization study to detect mRNA of CB1 in combination with mRNA of glutamic acid decarboxylase 65k, neuropeptide cholecystokinin (CCK), parvalbumin, calretinin and calbindin D28k, respectively. Our results revealed that CB1-expressing cells can be divided into distinct neuronal subpopulations. There is a clear distinction between neurons containing CB1 mRNA either at high levels or low levels. The majority of high CB1-expressing cells are GABAergic (gamma-aminobutyric acid) neurons belonging mainly to the cholecystokinin-positive and parvalbumin-negative type of interneurons (basket cells) and, to a lower extent, to the calbindin D28k-positive mid-proximal dendritic inhibitory interneurons. Only a fraction of low CB1-expressing cells is GABAergic. In the hippocampus, amygdala and entorhinal cortex area, CB1 mRNA is present at low but significant levels in many non-GABAergic cells that can be considered as projecting principal neurons. Thus, a complex mechanism appears to underlie the modulatory effects of cannabinoids. They might act on principal glutamatergic circuits as well as modulate local GABAergic inhibitory circuits. CB1 is very highly coexpressed with CCK. It is known that cannabinoids and CCK often have opposite effects on behaviour and physiology. Therefore, we suggest that a putative cross-talk between cannabinoids and CCK might exist and will be relevant to better understanding of physiology and pharmacology of the cannabinoid system.

1. The effects of adenosine on synaptic transmission in magnocellular neurosecretory cells were investigated using whole-cell patch-clamp recordings in acute rat hypothalamic slices that included the supraoptic nucleus. 2. Adenosine reversibly reduced the amplitude of evoked inhibitory (IPSCs) and excitatory (EPSCs) postsynaptic currents in a dose-dependent manner (IC50 approximately 10 microM for both types of current). 3. Depression of IPSCs and EPSCs by adenosine was reversed by the application of the A1 adenosine receptor antagonist 8-cyclopentyl-1, 3-dimethylxanthine (CPT; 10 microM). 4. When pairs of stimuli were given at short intervals, adenosine inhibitory action was always less effective on the second of the two responses than on the first, resulting in an increased paired-pulse facilitation and suggesting a presynaptic site of action. This observation was confirmed by analysis of spontaneous miniature synaptic currents whose frequency, but not amplitude or kinetics, was reversibly reduced by 100 microM adenosine. 5. CPT had no effect on synaptic responses evoked at a low frequency of stimulation (0.05-0.5 Hz), indicating the absence of tonic activation of A1 receptors under these recording conditions. However, CPT inhibited a time-dependent depression of both IPSCs and EPSCs induced during a 1 Hz train of stimuli. 6. Taken together, these results suggest that adenosine can be released within the supraoptic nucleus at a concentration sufficient to inhibit the release of GABA and glutamate via the activation of presynaptic A1 receptors. By its inhibitory feedback action on the major afferent inputs to oxytocin and vasopressin neurones, adenosine could optimally adjust electrical and secretory activities of hypothalamic magnocellular neurones.

11/1999 | Eur J Neurosci
Behavioural trait of reactivity to novelty is related to hippocampal neurogenesis.
Lemaire V, Aurousseau C, Le Moal M, Abrous DN

The hippocampal formation is one of the brain areas where neurogenesis persists during adulthood, with new neurons being continuously added to the population of dentate granule cells. However, the functional implications of this neurogenesis are unknown. On the other hand, the hippocampal formation is particularly concerned with the detection of novelty, and there are indications that dentate granule cells play a significant role in this function. Recently, the existence of inter-individual differences in behavioural reactivity to novelty has been evidenced, related to differences in the reactivity of the hypothalamic-pituitary-adrenal axis (HPA). Rats that are highly reactive to novelty (HR) exhibit a prolonged corticosterone secretion in response to novelty and to stress when compared with low reactive rats (LR). Taking advantage of the existence of these inter-individual differences, we investigated whether neurogenesis in the dentate gyrus is correlated with the behavioural trait of reactivity to novelty. Rats were first selected according to their locomotor reactivity to a novel environment. Two weeks later, cell proliferation, evaluated by the incorporation of 5-bromo-2'-deoxyuridine (BrdU) in progenitors, was studied by immunohistochemistry. We found that cell proliferation in the dentate gyrus was negatively correlated with locomotor reactivity to novelty. Indeed, cell proliferation in LR rats was twice that observed in HR rats. In contrast, survival of nascent neurons was not influenced by the behavioural trait of reactivity to novelty. Using an unbiased stereology, we show that LR rats had more cells within the granule cell layer of the dentate gyrus than did HR rats. These results demonstrate the existence of inter-individual differences in neurogenesis and total granule cell number within the dentate gyrus. These differences in hippocampal plasticity can be predicted by the behavioural trait of reactivity to novelty.

We studied changes in thalamo-prefrontal cortical transmission in behaving mice following both low-frequency stimulation of the mediodorsal thalamus (MD) and during extinction of a conditioned fear response. Electrical stimulation of the MD induces a field potential in the medial prefrontal cortex (mPFC) characterized by two initial negative-positive complexes (N1-P1 and N2-P2) followed by two positive-negative complexes (P2-N3 and P3-N4). The N1-P1 and N2-P2 complexes were identified as resulting from orthodromic and antidromic prefrontal activation, respectively. Because the two complexes were not often easily dissociated, plasticity in the prefrontal synaptic transmission was considered to result from changes in N1-P2 amplitude. Low-frequency thalamic stimulation (1, 200 pulses at 2 Hz) produced either long-term (at least 32 min) depression or potentiation of the N1-P2 amplitude. Mice submitted to fear conditioning (tone-shock association), displayed on the first day of extinction (tone-alone presentations) a strong freezing behavior, which decreased progressively, but was still high the following day. Extinction of conditioned fear was accompanied the first day by a depression of prefrontal transmission, which was converted into potentiation the following day. Potentiation of prefrontal transmission lasted at least 24 h following the second day of the fear extinction procedure. In conclusion, low-frequency thalamic stimulation can produce, in behaving mice, either depression or potentiation of prefrontal synaptic transmission. Decrease in prefrontal synaptic transmission observed during the first day of extinction may reflect processing of the high degree of predictiveness of danger (unconditioned stimulus: US) by the aversive conditioned stimulus (CS). However, the subsequent potentiation of transmission in the mPFC may be related to processing of cognitive information such as the CS will no longer be followed by the US, even if emotional response (freezing) to the CS is still high.

01/10/1999 | Science
Precisely localized LTD in the neocortex revealed by infrared-guided laser stimulation.
Dodt H, Eder M, Frick A, Zieglgansberger W

In a direct approach to elucidate the origin of long-term depression (LTD), glutamate was applied onto dendrites of neurons in rat neocortical slices. An infrared-guided laser stimulation was used to release glutamate from caged glutamate in the focal spot of an ultraviolet laser. A burst of light flashes caused an LTD-like depression of glutamate receptor responses, which was highly confined to the region of 'tetanic' stimulation (<10 micrometers). A similar depression of glutamate receptor responses was observed during LTD of synaptic transmission. A spatially highly specific postsynaptic mechanism can account for the LTD induced by glutamate release.

09/1999 | Eur J Neurosci
Knowing which and knowing what: a potential mouse model for age-related human
Marighetto A, Etchamendy N, Touzani K, Torrea CC, Yee BK, Rawlins JN, Jaffard R

The present study was built on the original report of Eichenbaum et al.

Activation of dopaminergic (DA) transmission by psychostimulants increases c-fos expression. d-Amphetamine-induced c-fos activation is reduced in the neostriatum deprived of DA afferents. Dopaminergic grafts implanted into the denervated neostriatum induce a c-fos hyperexpression when challenged with d-amphetamine, which is correlated with the exaggerated compensation of d-amphetamine-induced rotation. The aim of the present study was to test the generality of this phenomenon and the effects of DA grafts on the expression of three immediate early gene-coded proteins (c-Fos, Jun-B, Krox-24) following a challenge with either d-amphetamine or cocaine. c-fos basal expression was low in the neostriatum and was increased by the administration of psychostimulants. These effects were blocked by the DA lesion and restored by the DA grafts. A c-fos hyperexpression was observed within the grafted neostriatum, which was correlated with the compensation of d-amphetamine- or cocaine-induced rotation. Basal levels of Jun-B- and Krox-24-LI nuclei were high within the neostriatum. Administration of d-amphetamine or cocaine did not influence the expression of these IEG-coded proteins. Jun-B expression was not affected by the surgical procedure. In contrast, lesion of DA afferents of neostriatum decreased Krox-24 basal expression, an effect reversed by the grafts. Thus, the expression of c-fos but not Jun-B or Krox-24 appeared to be a good marker for the rotational behavior exhibited by DA-grafted rats challenged with drugs that increased DA transmission. This generalized c-fos overshoot indicates an abnormal activation of postsynaptic neurons by dopamine and points to its value as an indicator of the deleterious effects of DA grafts.

A progressive increase in the frequency and intensity of drug use is one of the major behavioural phenomena characterizing the development of addiction. The nature of the drug-induced adaptations involved in this escalating drug intake remains unknown. Some theories propose that this escalation is due to a progressive decrease (tolerance) in the reinforcing or incentive effects of the drug. Alternative views posit that with chronic use the reinforcing or incentive effects of drugs increase, by a sensitization or a learning mechanism. In this report, we address the question of whether escalating cocaine intake is paralleled by an increase or a decrease in the reinforcing and incentive effects of the drug. Using the experimental model of intravenous drug self-administration with a within-session dose-response paradigm, we first studied the course of cocaine intake over 14 sessions in rats. After acquisition of cocaine self-administration, cocaine intake progressively increased at each dose tested. Then rats, previously allowed to self-administer cocaine during either six or 29 sessions, were compared in three different tests of the incentive and reinforcing effects of cocaine: cocaine-induced reinstatement of self-administration, cocaine-induced runway and cocaine-induced place conditioning. As compared with rats briefly exposed to cocaine self-administration (six sessions), rats with the longer experience (29 sessions) exhibited a higher intake of cocaine paralleled by a higher responsiveness in the cocaine-induced reinstatement and runway tests. Both groups of rats were similarly sensitive to the rewarding effects of the drug as evaluated by the threshold dose of cocaine inducing place conditioning. Our results demonstrate that escalating cocaine intake is paralleled by an increase in the motivational properties of the drug in the absence of apparent signs of tolerance to the reinforcing or incentive effects of cocaine.

07/1999 | Ann Neurol
Levodopa induces a cytoplasmic localization of D1 dopamine receptors in striatal neurons in Parkinson's disease.
Muriel MP, Bernard V, Levey AI, Laribi O, Abrous DN, Agid Y, Bloch B, Hirsch EC

Parkinson's disease is characterized by a massive loss of nigral dopamine neurons that results in a reduction of dopamine concentrations in the striatum. The most commonly used treatment for this disease is levodopa therapy to restore striatal dopamine. This treatment is mediated by dopamine receptors, but the effect of treatment and the disease on receptor distribution is unknown. In this study, the distribution of D1 dopamine receptors was analyzed at the cellular and subcellular level in the striatum of 5 patients with Parkinson's disease (all treated with levodopa) and 4 control subjects. In the control brains, D1 dopamine receptors were mostly detected on the plasma membrane of medium-sized spiny neurons. The quantitative analysis performed at the ultrastructural level in patients with Parkinson's disease revealed an increase in immunostaining in the cytoplasm of medium-sized neurons. This effect was likely the result of the treatment rather than the dopaminergic denervation, as such changes were not observed in the striatum of rats with a unilateral 6-hydroxydopamine nigrostriatal lesion, but were present in normal or lesioned rats treated with a D1 dopamine agonist. Altered localization of D1 dopamine receptors may participate in the occurrence of side effects of levodopa therapy such as dyskinesia and fluctuations in motor performances.

Several electrochemical techniques allow the measurement of dopamine release in freely moving animals and brain slices. In this report, we applied one of these techniques, coulometry, coupled to high-performance liquid chromatography (HPLC), to the study of dopamine release in primary cultures of embryonic mesencephalic dopaminergic neurons. Between day 9 and 33 of culture, concentrations of dopamine, above the detection threshold, were found in the incubation buffer (Krebs ringer buffer, KRB). Concentrations of dopamine in the incubation buffer reflected neuronal release as they were: (i) positively correlated with the number of tyrosine hydroxylase-positive dopamine neurons in the culture; (ii) tetrodotoxin (TTX) sensitive and Ca2+ dependent; (iii) increased by a depolarizing stimulus, e.g. K+ (20 mM), or by the indirect dopamine agonists amphetamine and cocaine; (iv) decreased by a hyperpolarizing stimulus, e.g. the dopamine D2-like receptor agonist quinpirole. Dopamine release in this model was also sensitive to the manipulation of glucocorticoids, potent modulators of dopamine release in vivo. Long-term treatment of the cell cultures with RU 39305, a selective antagonist of glucocorticoid receptors (GR), but not with spironolactone, a selective antagonist of mineralocorticoid receptors (MR), dose-dependently decreased K+-stimulated dopamine release. In conclusion, these results demonstrate an in vitro model that allows the studying of the release of endogenous dopamine in cell cultures and the effects of glucocorticoid hormones on the release dynamics.

Lentiviruses have in their transmembrane glycoprotein (TM) a highly immunogenic structure referred to as the principal immunodominant domain (PID). The PID forms a loop of 5 to 7 amino acids between two conserved cysteines. Previous studies showed that envelope (Env) glycoprotein functions of feline immunodeficiency virus (FIV) could be retained after extensive mutation of the PID loop sequence, in spite of its high conservation. In order to compare Env function in different lentiviruses, either random mutations were introduced in the PID loop sequence of human immunodeficiency virus type 1 (HIV-1) or the entire HIV-1 PID loop was replaced by the corresponding PID loop of FIV or simian immunodeficiency virus (SIV). In the macrophage-tropic HIV-1 ADA Env, mutations impaired the processing of the gp160 Env precursor, thereby abolishing viral infectivity. However, 6 of the 108 random Env mutants that were screened retained the capacity to induce cell membrane fusion. The SIV and FIV sequences and five random mutations were then introduced in the context of T-cell-line-adapted HIV-1 LAI which, although phenotypically distant from HIV-1 ADA, has an identical PID loop sequence. In contrast to the situation for HIV-1 ADA mutants, the cleavage of the Env precursor was unaffected in most HIV-1 LAI mutants. Such mutations, however, resulted in increased shedding of the gp120 surface glycoprotein (SU) from the gp41 TM. The HIV-1 LAI Env mutants showed high fusogenic efficiency. Three Env mutants retained the capacity to mediate virus entry in target cells, although less efficiently than the wild-type Env, and allowed the reconstitution of infectious molecular clones. These results indicated that in HIV-1, like FIV, the conserved PID sequence can be changed without impairing Env function. However, functional constraints on the PID of HIV-1 vary depending on the structural context of Env, presumably in relation to the role of the PID in the interaction of the SU and TM subunits and the stability of the Env complex.

We have previously demonstrated that mild traumatic brain injury (TBI) of the right parietal cortex results in a relatively selective deficit in conditioned fear responding. However, this behavioural deficit is very consistent and unrelated to the extent of the cortical necrotic lesion. We were therefore interested in determining if other brain regions might show a consistent response to mild TBI, and therefore, more reliably relate to the behavioural change. Increased expression of inducible transcription factors (ITFs) has been used to study which brain regions respond to a variety of events. In the present study, we examined the expression patterns of immunoreactivity (IR) for four ITFs (c-Fos, c-Jun, JunB, and Krox-24) at 3 h after mild fluid percussion TBI. Changes in ITF expression were only observed ipsilateral to the side of TBI. The clearest changes were observed in brain regions known to be involved in conditioned fear responding, such as the amygdala complex and hippocampal formation and several cortical regions. In contrast, no changes in IR for any of the ITFs were observed in the striatum, nucleus accumbens, nucleus basalis magnocellularis, septum or periacqueductal grey. Unlike the extent of visible damage to the cortex at the site of impact, the overexpression of ITFs showed a notable consistency between animals subjected to TBI. This consistency in regions known to be involved in conditioned fear responding (i.e., amygdala complex and hippocampal formation) lead us to suggest that it is these changes, rather than the more variable cortical necrotic lesion, that is responsible for the behavioural deficits we observe following mild TBI. Importantly, our results demonstrate that like the hippocampus, the amygdala is a sub-cortical structure particularly sensitive to the effects of mild brain trauma and underline the fact that cerebral regions distant from the location of the fluid impact can be affected.

05/1999 | J Virol
Shared usage of the chemokine receptor CXCR4 by primary and laboratory-adapted strains of feline immunodeficiency virus.
Richardson J, Pancino G, Merat R, Leste-Lasserre T, Moraillon A, Schneider-Mergener J, Alizon M, Sonigo P, Heveker N

Strains of the feline immunodeficiency virus (FIV) presently under investigation exhibit distinct patterns of in vitro tropism. In particular, the adaptation of FIV for propagation in Crandell feline kidney (CrFK) cells results in the selection of strains capable of forming syncytia with cell lines of diverse species origin. The infection of CrFK cells by CrFK-adapted strains appears to require the chemokine receptor CXCR4 and is inhibited by its natural ligand, stromal cell-derived factor 1alpha (SDF-1alpha). Here we found that inhibitors of CXCR4-mediated infection by human immunodeficiency virus type I (HIV-1), such as the bicyclam AMD3100 and short peptides derived from the amino-terminal region of SDF-1alpha, also blocked infection of CrFK by FIV. Nevertheless, we observed differences in the ranking order of the peptides as inhibitors of FIV and HIV-1 and showed that such differences are related to the species origin of CXCR4 and not that of the viral envelope. These results suggest that, although the envelope glycoproteins of FIV and HIV-1 are substantially divergent, FIV and HIV-1 interact with CXCR4 in a highly similar manner. We have also addressed the role of CXCR4 in the life cycle of primary isolates of FIV. Various CXCR4 ligands inhibited infection of feline peripheral blood mononuclear cells (PBMC) by primary FIV isolates in a concentration-dependent manner. These ligands also blocked the viral transduction of feline PBMC by pseudotyped viral particles when infection was mediated by the envelope glycoprotein of a primary FIV isolate but not by the G protein of vesicular stomatitis virus, indicating that they act at an envelope-mediated step and presumably at viral entry. These findings strongly suggest that primary and CrFK-adapted strains of FIV, despite disparate in vitro tropisms, share usage of CXCR4.

04/1999 | Eur J Neurosci
Adrenalectomy increases neurogenesis but not PSA-NCAM expression in aged dentate gyrus.
Montaron MF, Petry KG, Rodriguez JJ, Marinelli M, Aurousseau C, Rougon G, Le Moal M, Abrous DN

Ageing is accompanied by a decline in neurogenesis and in polysialylated isoforms of neural cell adhesion molecule (PSA-NCAM) expression within the hippocampus and by elevated basal levels of circulating corticosterone. In a companion study, we demonstrated that suppression of corticosterone by adrenalectomy increased neurogenesis and PSA-NCAM expression in the dentate gyrus of adult rats. Here we show that adrenalectomy increased neurogenesis in this structure in old rats, as measured by the incorporation of 5-bromo-2'-deoxyuridine in neuronal progenitors. This effect was prevented by corticosterone replacement. In contrast, PSA-NCAM expression remained unchanged in comparison with controls. Thus, in the aged brain, stem cells are still present and able to enter the cell cycle. This may point to ways of protecting or treating age-related cognitive impairments.

04/1999 | Eur J Neurosci
Functional heterogeneity in dopamine release and in the expression of Fos-like proteins within the rat striatal complex.
Barrot M, Marinelli M, Abrous DN, Rouge-Pont F, Le Moal M, Piazza PV

The dorsolateral striatum, and the core and shell of the nucleus accumbens are three major anatomical regions of the striatal complex. The shell is considered as a part of the extended amygdala, and is involved in the control of motivation and reward. The core and the striatum are considered central to sensory motor integration. In this study we compared the responses of these three regions to mild stress and drugs of abuse by measuring extracellular dopamine (DA) concentrations and Fos-like immunoreactivity (Fos-LI). The results are summarrized as follows. (i) In unchallenged conditions, extracellular DA concentrations were highest in the dorsolateral striatum and lowest in the core, whereas Fos-LI was highest in the shell and lowest in the dorsolateral striatum. (ii) After challenges that increase DA by depolarizing DAergic neurons (injection stress or 2 mg/kg morphine), the shell presented the largest increase in DA levels and Fos-LI. (iii) After the administration of a DA-uptake blocker (15 mg/kg cocaine), the percentage increase in DA was still largest in the shell. However, the absolute increase in DA and Fos-LI in the shell and the dorsolateral striatum were similar. (iv) After a full D1 agonist (SKF82958), Fos-LI was highest in the shell and lowest in the dorsolateral striatum. In conclusion, the nucleus accumbens shell seems to be the area of the striatal complex most functionally reactive to stress and drugs of abuse. However, the dorsolateral striatum and the core appear functionally distinct, as for most of the parameters studied these two regions differed.

F3, a mouse glycosyl-phosphatidylinositol anchored molecule of the immunoglobulin superfamily, is known to influence axonal growth and fasciculation via multiple interactions of its modular immunoglobulin-like domains. We prepared an Fc chimeric molecule (F3IgFc) to identify molecules interacting with these domains and characterize the functional impact of the interactions. We affinity-isolated tenascin-C and isoforms of the proteoglycan-type protein tyrosine phosphatases zeta/beta (PTPzeta/RPTPbeta) from extracts of developing mouse brain. We showed that both PTPzeta/RPTPbeta and tenascin-C can bind directly to F3, possibly in an exclusive manner, with the highest affinity for the F3-PTPzeta/RPTPbeta interaction. We observed a strong binding of F3IgFc-coated fluorospheres to astrocytes in neural primary cultures and to C6 astrocytoma cells, and demonstrated, in antibody perturbation experiments, that F3-Ig binding on astrocytes depends on its interaction with PTPzeta/RPTPbeta. We also found by confocal analysis that tenascin-C and PTPzeta/RPTPbeta were colocalized on astrocytes which suggests a complex interplay of interactions between PTPzeta/RPTPbeta, tenascin-C and F3. We showed that the interaction between PTPzeta/RPTPbeta and F3-Ig-like domains can trigger bidirectional signalling. C6 glia-expressed PTPzeta/RPTPbeta stimulated neurite outgrowth by cortical and cerebellar neurons, whereas preclustered F3IgFc specifically modified the distribution of phosphotyrosine labelling in these glial cells. Both effects could be prevented and/or mimicked by anti-F3 and anti-6B4PG antibodies. These results identify F3 and PTPzeta/RPTPbeta as potential mediators of a reciprocal exchange of information between glia and neurons.

1999 | J Soc Biol
[Corticosteroid hormones and the brain].
Le Moal M, Vallee M, Maccari S, Mayo W, Montaron MF, Piazza PV, Abrous N

The anatomical and functional links between the hormone stress axis and the cortico-limbic brain regions which integrate emotion and motivation are well documented. It is important, considering the consequences of stress on the brain, to take into account the regulatory buffer capacities of the personality-cognitive processes. Another point of interest is evaluation of the long term effects of repeated life events on chronic environmental pressures which induce brain negative feedback defects and, subsequently, insidious cellular changes in regions such as the hippocampus that lead to memory or adaptive impairments. An example is provided by perinatal stress that induces, later in life, both hormonal and cognitive deleterious changes.

1999 | Adv Exp Med Biol
Bidirectional signaling between neurons and glial cells via the F3 neuronal adhesion molecule.
Revest JM, Faivre-Sarrailh C, Schachner M, Rougon G

F3, a glycosyl-phosphatidylinositol anchored molecule of the immunoglobulin superfamily, is known to influence axonal growth and fasciculation via multiple interactions of its modular immunoglobulin-like domains. We prepared a Fc chimeric molecule (F3IgFc) to identify a) the phenotype of cells bearing F3Ig receptors, b) the glial-expressed molecules interacting with these domains and, c) to characterize in in vitro models the functional impact of the interactions. We observed a strong binding of F3IgFc coated fluorospheres to astrocytes in neural primary cultures and to C6 astrocytoma cells. In agreement, in extracts of developing mouse brain F3IgFc is able to bind tenascin-R, tenascin-C, and isoforms of the proteoglycan-type protein tyrosine phosphatases z/beta. All these molecules are synthetized by glial cells as an indication that F3 participates in neuron-glia interactions. We showed that C6 glia-expressed PTPz/RPTP beta stimulated neurite outgrowth by cortical and cerebellar neurons whereas preclustered F3IgFc specifically modified the distribution and intensity of phosphotyrosine labeling in these glial cells. We also showed that inhibition of tenascin-R interaction with F3 prevented defasciculation of cerebellar explants which normally display a defasciculated outgrowth of neurites on a growth permissive substrate. These results identify F3, RTPz/RPTP beta, and tenascin-R as potential mediators of a reciprocal exchange of information between glia and neurons.