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1.
Molecules ; 25(7)2020 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-32218362

RESUMEN

Interfacial properties such as interfacial profiles, surface activity, wetting transitions, and interfacial tensions along the three-phase line are described for a Type IIIa binary mixture. The methodological approach combines the square gradient theory coupled to the statistical associating fluid theory for Mie potentials of variable range, and coarse-grained molecular dynamics simulations using the same underlying potential. The water + n-hexane mixture at three-phase equilibrium is chosen as a benchmark test case. The results show that the use of the same molecular representation for both the theory and the simulations provides a complementary picture of the aforementioned mixture, with an excellent agreement between the molecular models and the available experimental data. Interfacial tension calculations are extended to temperatures where experimental data are not available. From these extrapolations, it is possible to infer a first order wetting transition at 347.2 K, where hexane starts to completely wet the water/vapor interface. Similarly, the upper critical end point is estimated at 486.3 K. Both results show a very good agreement to the available experimental information. The concentration profiles confirm the wetting behavior of n-hexane along with a strong positive surface activity that increases with temperature, contrasting the weak positive surface activity of water that decreases with temperature.


Asunto(s)
Termodinámica , Modelos Químicos , Simulación de Dinámica Molecular , Tensión Superficial
2.
J Hepatol ; 54(3): 481-8, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21163545

RESUMEN

BACKGROUND & AIMS: Early neuroendocrine pathways contribute to liver regeneration after partial hepatectomy (PH). We investigated one of these pathways involving acute cholestasis, immediate portal hyperpressure, and arginine vasopressin (AVP) secretion. METHODS: Surgical procedure (PH, Portal vein stenosis (PVS), bile duct ligation (BDL), spinal cord lesion (SCL)) and treatments (capsaicin, bile acids (BA), oleanolic acid (OA)) were performed on rats and/or wild type or TGR5 (GPBAR1) knock-out mice. In these models, the activation of AVP-secreting supraoptic nuclei (SON) was analyzed, as well as plasma BA, AVP, and portal vein pressure (PVP). Plasma BA, AVP, and PVP were also determined in human living donors for liver transplantation. RESULTS: Acute cholestasis (mimicked by BDL or BA injection) as well as portal hyperpressure (mimicked by PVS) independently activated SON and AVP secretion. BA accumulated in the brain after PH or BDL, and TGR5 was expressed in SON. SON activation was mimicked by the TGR5 agonist OA and inhibited in TGR5 KO mice after BDL. An afferent nerve pathway also contributed to post-PH AVP secretion, as capsaicin treatment or SCL resulted in a weaker SON activation after PH. CONCLUSIONS: After PH in rodents, acute cholestasis and portal hypertension, via the nervous and endocrine routes, stimulate the secretion of AVP that may protect the liver against shear stress and bile acids overload. Data in living donors suggest that this pathway may also operate in humans.


Asunto(s)
Hepatectomía , Regeneración Hepática/fisiología , Sistemas Neurosecretores/fisiología , Adulto , Animales , Arginina Vasopresina/fisiología , Ácidos y Sales Biliares/fisiología , Presión Sanguínea/fisiología , Colestasis/fisiopatología , Femenino , Humanos , Hipertensión Portal/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Sistema Porta/fisiología , Ratas , Ratas Wistar , Receptores Acoplados a Proteínas G/deficiencia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiología , Transducción de Señal , Núcleo Supraóptico/fisiología
3.
J Soc Biol ; 203(1): 39-47, 2009.
Artículo en Francés | MEDLINE | ID: mdl-19358810

RESUMEN

In adult mammals, the CNS vasculature remains essentially quiescent, excepted for specific pathologies. In the seventies, it was reported that proliferation of astrocytes and endothelial cells occurs within the hypothalamic magnocellular nuclei when strong metabolic activation of the vasopressinergic and oxytocinergic neurons was induced by prolonged hyperosmotic stimulation. Using more appropriate techniques, we first demonstrated that in these nuclei, the proliferative response to osmotic stimulus is essentially associated with local angiogenesis. We then showed that hypothalamic magnocellular neurons express vascular endothelial growth factor (VEGF), a potent angiogenic factor, that plays a major rôle in the angiogenesis induced by osmotic stimuli. We then demonstrated a correlation between increased VEGF secretion and local hypoxia. In AVP-deficient Brattleboro rats, the dramatic activation of magnocellular hypothalamic neurons failed to induce hypoxia, VEGF expression or angiogenesis suggesting a major role of hypothalamic AVP. Lastly we showed that 1) hypoxia and angiogenesis were not observed in non-osmotically stimulated Wistar rats in which circulating AVP was increased by the prolonged infusion of exogenous AVP, 2) contractile arterioles afferent to the magnocellular nuclei were strongly constricted by the perivascular application of AVP via V1a receptors (V1a-R) stimulation, and 3) following the intracerebral administration of selective V1a-R antagonist to osmotically stimulated rats, hypothalamic hypoxia and angiogenesis were inhibited. Together, these data strongly suggest that the angiogenesis induced by osmotic stimulation relates to tissue hypoxia resulting from the constriction of local arterioles, via the stimulation of perivascular V1a-R by AVP locally released from dendrites.


Asunto(s)
Arginina Vasopresina/fisiología , Hipotálamo/fisiología , Neovascularización Fisiológica/fisiología , Animales , Arginina Vasopresina/deficiencia , Arginina Vasopresina/genética , Arteriolas/metabolismo , Astrocitos/citología , Hipoxia de la Célula , Arterias Cerebrales/metabolismo , Dendritas/metabolismo , Endotelio Vascular/citología , Hipotálamo/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Ratas Brattleboro , Ratas Wistar , Receptores de Vasopresinas/efectos de los fármacos , Receptores de Vasopresinas/fisiología , Solución Salina Hipertónica/administración & dosificación , Solución Salina Hipertónica/farmacología , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Factor A de Crecimiento Endotelial Vascular/genética , Vasoconstricción/fisiología
4.
Endocrinology ; 150(1): 239-50, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18787031

RESUMEN

The hypothalamic hormone vasopressin (AVP) has known mitogenic effects on various cell types. This study was designed to determine whether sustained elevated levels of circulating AVP could influence cell proliferation within adult tissues known to express different AVP receptors, including the pituitary, adrenal gland, liver, and kidney. Plasmatic AVP was chronically increased by submitting animals to prolonged hyperosmotic stimulation or implanting them with a AVP-containing osmotic minipump. After several days of either treatment, increased cell proliferation was detected only within the kidney. This kidney cell proliferation was not affected by the administration of selective V1a or V1b receptor antagonists but was either inhibited or mimicked by the administration of a selective V2 receptor antagonist or agonist, respectively. Kidney proliferative cells mostly concerned a subpopulation of differentiated tubular cells known to express the V2 receptors and were associated with the phosphorylation of ERK. These data indicate that in the adult rat, sustained elevated levels of circulating AVP stimulates the proliferation of a subpopulation of kidney tubular cells expressing the V2 receptor, providing the first illustration of a mitogenic effect of AVP via the activation of the V2 receptor subtype.


Asunto(s)
Arginina Vasopresina/sangre , Túbulos Renales/fisiología , Receptores de Vasopresinas/fisiología , Animales , Arginina Vasopresina/farmacología , División Celular/efectos de los fármacos , Desamino Arginina Vasopresina/farmacología , Túbulos Renales/citología , Túbulos Renales/efectos de los fármacos , Masculino , Concentración Osmolar , Ratas , Ratas Sprague-Dawley , Cloruro de Sodio/farmacología
5.
Endocrinology ; 149(9): 4279-88, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18483147

RESUMEN

We have previously shown that hyperosmotic stimulation of adult Wistar rats induces local angiogenesis within hypothalamic magnocellular nuclei, in relation to the secretion of vascular endothelial growth factor (VEGF) by the magnocellular neurons. The present study aimed at understanding how osmotic stimulus relates to increased VEGF secretion. We first demonstrate a correlation between increased VEGF secretion and local hypoxia. Osmotic stimulation is known to stimulate the metabolic activity of hypothalamic magnocellular neurons producing arginine vasopressin (AVP) and to increase the secretion of AVP, both by axon terminals into the circulation and by dendrites into the extracellular space. In AVP-deficient Brattleboro rats, the dramatic activation of magnocellular hypothalamic neurons failed to induce hypoxia, VEGF expression, or angiogenesis, suggesting a major role of hypothalamic AVP. A possible involvement of dendritic AVP release is supported by the findings that 1) hypoxia and angiogenesis were not observed in non osmotically stimulated Wistar rats in which circulating AVP was increased by the prolonged infusion of exogenous AVP, 2) contractile arterioles afferent to the magnocellular nuclei were strongly constricted by the perivascular application of AVP via V1a receptors (V1a-R) stimulation, and 3) after the intracerebral or ip administrations of selective V1a-R antagonists to osmotically stimulated rats, hypothalamic hypoxia and angiogenesis were or were not inhibited, respectively. Together, these data strongly suggest that the angiogenesis induced by osmotic stimulation relates to tissue hypoxia resulting from the constriction of local arterioles, via the stimulation of perivascular V1a-R by AVP locally released from dendrites.


Asunto(s)
Arginina Vasopresina/fisiología , Dendritas/metabolismo , Hipotálamo/irrigación sanguínea , Hipoxia Encefálica/fisiopatología , Neovascularización Fisiológica/fisiología , Vasoconstricción/fisiología , Equilibrio Hidroelectrolítico/fisiología , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas , Arginina Vasopresina/antagonistas & inhibidores , Arginina Vasopresina/metabolismo , Arginina Vasopresina/farmacología , Dendritas/efectos de los fármacos , Hipotálamo/metabolismo , Hipoxia Encefálica/metabolismo , Inyecciones Intraventriculares , Masculino , Modelos Biológicos , Neovascularización Fisiológica/efectos de los fármacos , Ósmosis , Ratas , Ratas Brattleboro , Ratas Long-Evans , Ratas Wistar , Núcleo Supraóptico/efectos de los fármacos , Núcleo Supraóptico/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Vasoconstricción/efectos de los fármacos , Equilibrio Hidroelectrolítico/efectos de los fármacos
6.
Cell Calcium ; 43(1): 95-104, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17555812

RESUMEN

Calcium-mobilizing hormones and neurotransmitters are known to affect cell morphology and function including cell differentiation or division. In this study, we examined vasopressin (AVP)-induced morphological changes in a polarized system of rat hepatocytes. Light and electron microscope observations showed that AVP induced microvilli formation and a remodeling of the isolated hepatocyte F-actin submembrane cytoskeleton, these two events being correlated. We showed that these effects were rapid, reversible, observed at nanomolar AVP concentration and mediated by the V(1a) receptor. On polarized multicellular systems of hepatocytes, we observed a rapid reduction of the bile canaliculi lumen at the apical pole and micovilli formation at the basolateral domain with an enlarged F-actin cytoskeleton. Neither activation of protein kinase C nor A via phorbol ester or dibutyryl cAMP induced such rapid morphological changes, at variance with ionomycin, suggesting that AVP-induced intracellular calcium rise plays a crucial role in those effects. By using spectrofluorimetry and cytochemistry, we showed that calcium release from intracellular stores was involved in bile canaliculus contraction, while calcium entry from the extracellular space controlled microvilli formation. Taken together, AVP and calcium-mobilizing agonists differentially regulate physiological hepatocyte plasma membrane events at the basal and the apical domains via topographically specialized calcium-dependent mechanisms.


Asunto(s)
Arginina Vasopresina/farmacología , Calcio/metabolismo , Hepatocitos/ultraestructura , Citoesqueleto de Actina/ultraestructura , Actinas/análisis , Animales , Canalículos Biliares/efectos de los fármacos , Canalículos Biliares/ultraestructura , Polaridad Celular , Células Cultivadas , Femenino , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Microvellosidades/efectos de los fármacos , Microvellosidades/ultraestructura , Ratas , Ratas Wistar
7.
Aging Cell ; 6(2): 197-207, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17328688

RESUMEN

Growth hormone (GH) secretion decreases spontaneously during lifespan, and the resulting GH deficiency participates in aging-related morbidity. This deficiency appears to involve a defect in the activity of hypothalamic GH-releasing hormone (GHRH) neurons. Here, we investigated this hypothesis, as well as the underlying mechanisms, in identified GHRH neurons from adult ( approximately 13 weeks old) and aged ( approximately 100 weeks old) transgenic GHRH-green fluorescent protein mice, using morphological, biochemical and electrophysiological methods. Surprisingly, the spontaneous action potential frequency was similar in adult and aged GHRH neurons studied in brain slices. This was explained by a lack of change in the intrinsic excitability, and simultaneous increases in both stimulatory glutamatergic- and inhibitory GABAergic-synaptic currents of aged GHRH neurons. Aging did not decrease GHRH and enhanced green fluorescent protein contents, GHRH neuronal number or GHRH-fibre distribution, but we found a striking enlargement of GHRH-positive axons, suggesting neuropeptide accumulation. Unlike in adults, autophagic vacuoles were evident in aged GHRH-axonal profiles using electron microscopy. Thus, GHRH neurons are involved in aging of the GH axis. Aging had a subtle effect at the nerve terminal level in GHRH neurons, contrasting with the view that neuronal aging is accompanied by more widespread damage.


Asunto(s)
Senescencia Celular/fisiología , Hormona Liberadora de Hormona del Crecimiento/metabolismo , Neuronas/fisiología , Terminales Presinápticos/ultraestructura , Potenciales de Acción , Vías Aferentes/fisiología , Animales , Potenciales Postsinápticos Excitadores , Proteínas Fluorescentes Verdes/análisis , Proteínas Fluorescentes Verdes/genética , Hormona del Crecimiento/fisiología , Hormona Liberadora de Hormona del Crecimiento/genética , Masculino , Ratones , Ratones Transgénicos , Neuronas/metabolismo , Técnicas de Placa-Clamp , Terminales Presinápticos/metabolismo
8.
J Neurosci ; 27(7): 1631-41, 2007 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-17301171

RESUMEN

The organization of the peptidergic neurons of the hypothalamic arcuate nucleus is not fully understood. These include growth hormone-releasing hormone (GHRH) neurons involved in growth and metabolism. We studied identified GHRH neurons of GHRH-green fluorescent protein transgenic mice using patch-clamp methods and focused on gender differences, which govern the physiological patterns of GHRH release. Both the spontaneous firing rates and the intrinsic properties of GHRH neurons were similar in males and females, although higher glutamatergic currents were noticed in females. Surprisingly, marked gender differences in GHRH neuronal activity were observed in response to the muscarinic agonist carbachol (CCh). In females, CCh enhanced action potential firing in all GHRH neurons. In males, CCh enhanced action potential firing in two-thirds of GHRH neurons, whereas it decreased firing in the remainders. M1 agonist McN-A343 (10 microM) mimicked, and M1 antagonist pirenzepine (3 microM) blocked the effects of CCh. In both genders, CCh did not change the intrinsic properties of GHRH neurons, although it strongly increased the frequency of glutamatergic currents, in the presence or absence of tetrodotoxin. In males only, CCh enhanced the frequency of GABAergic currents, and this modulation was antagonized by tetrodotoxin. Thus, the muscarinic regulation involved differential control of afferent inputs at short and long distances in male and female mice. The dual-level control could be a mechanism whereby the selective modulation of the GHRH system (short-distance control) is adjusted to the integrated regulation of arcuate nucleus activity (long-distance control).


Asunto(s)
Vías Aferentes/fisiología , Hormona Liberadora de Hormona del Crecimiento/metabolismo , Neuronas/fisiología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Análisis de Varianza , Animales , Núcleo Arqueado del Hipotálamo/citología , Carbacol/farmacología , Agonistas Colinérgicos/farmacología , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Estimulación Eléctrica , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Potenciales Postsinápticos Excitadores/efectos de la radiación , Femenino , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Hormona Liberadora de Hormona del Crecimiento/genética , Inmunohistoquímica/métodos , Técnicas In Vitro , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Potenciales de la Membrana/efectos de la radiación , Ratones , Ratones Transgénicos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Técnicas de Placa-Clamp/métodos , Factores Sexuales , Proteína 2 de Transporte Vesicular de Glutamato/metabolismo , Ácido gamma-Aminobutírico/metabolismo
9.
Proc Natl Acad Sci U S A ; 102(46): 16880-5, 2005 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-16272219

RESUMEN

Pituitary growth hormone (GH)-secreting cells regulate growth and metabolism in animals and humans. To secrete highly ordered GH pulses (up to 1,000-fold rise in hormone levels in vivo), the pituitary GH cell population needs to mount coordinated responses to GH secretagogues, yet GH cells display an apparently heterogeneous scattered distribution in 2D histological studies. To address this paradox, we analyzed in 3D both positioning and signaling of GH cells using reconstructive, two-photon excitation microscopy to image the entire pituitary in GH-EGFP transgenic mice. Our results unveiled a homologous continuum of GH cells connected by adherens junctions that wired the whole gland and exhibited the three primary features of biological networks: robustness of architecture across lifespan, modularity correlated with pituitary GH contents and body growth, and connectivity with spatially stereotyped motifs of cell synchronization coordinating cell activity. These findings change our view of GH cells, from a collection of dispersed cells to a geometrically connected homotypic network of cells whose local morphology and connectivity can vary, to alter the timing of cellular responses to promote more coordinated pulsatile secretion. This large-scale 3D view of cell functioning provides a powerful approach to identify and understand other networks of endocrine cells that are thought to be scattered in situ. Many dispersed endocrine systems exhibit pulsatile outputs. We suggest that cell positioning and associated cell-cell connection mechanisms will be critical parameters that determine how well such systems can deliver a coordinated secretory pulse of hormone to their target tissues.


Asunto(s)
Hormona del Crecimiento/metabolismo , Adenohipófisis/metabolismo , Animales , Ratones , Ratones Transgénicos , Adenohipófisis/citología
11.
J Cell Biol ; 169(3): 503-14, 2005 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-15883200

RESUMEN

In contrast to its well-established actions as an organizer of synaptic differentiation at the neuromuscular junction, the proteoglycan agrin is still in search of a function in the nervous system. Here, we report an entirely unanticipated role for agrin in the dual modulation of electrical and chemical intercellular communication that occurs during the critical period of synapse formation. When applied at the developing splanchnic nerve-chromaffin cell cholinergic synapse in rat adrenal acute slices, agrin rapidly modified cell-to-cell communication mechanisms. Specifically, it led to decreased gap junction-mediated electrical coupling that preceded an increase in nicotinic synaptic transmission. This developmental switch from predominantly electrical to chemical communication was fully operational within one hour and depended on the activation of Src family-related tyrosine kinases. Hence, agrin may play a pivotal role in synaptogenesis in promoting a rapid switch between electrical coupling and synaptic neurotransmission.


Asunto(s)
Médula Suprarrenal/crecimiento & desarrollo , Agrina/metabolismo , Diferenciación Celular/fisiología , Uniones Comunicantes/metabolismo , Sinapsis/metabolismo , Transmisión Sináptica/fisiología , Acetilcolina/metabolismo , Médula Suprarrenal/citología , Médula Suprarrenal/metabolismo , Envejecimiento/metabolismo , Animales , Animales Recién Nacidos , Fibras Colinérgicas/metabolismo , Fibras Colinérgicas/ultraestructura , Células Cromafines/metabolismo , Células Cromafines/ultraestructura , Femenino , Uniones Comunicantes/ultraestructura , Técnicas de Cultivo de Órganos , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , Nervios Esplácnicos/metabolismo , Nervios Esplácnicos/ultraestructura , Sinapsis/ultraestructura , Factores de Tiempo , Regulación hacia Arriba/fisiología , Familia-src Quinasas/metabolismo
12.
J Neurosci ; 25(9): 2267-76, 2005 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-15745952

RESUMEN

In the CNS, insulin-like growth factor-1 (IGF-1) is mainly known for its trophic effect both during development and in adulthood. Here, we show than in adult rat supraoptic nucleus (SON), IGF-1 receptor immunoreactivity is present in neurons, whereas IGF-1 immunoreactivity is found principally in astrocytes and more moderately in neurons. In vivo application of IGF-1 within the SON acutely inhibits the activity of both vasopressin and oxytocin neurons, the two populations of SON neuroendocrine cells. Recordings of acutely isolated SON neurons showed that this inhibition occurs through two rapid and reversible mechanisms, both involving the neuronal IGF-1 receptor but different intracellular messengers. IGF-1 inhibits Gd3+-sensitive and osmosensitive mechanoreceptor cation current via phosphatidylinositol-3 (PI3) kinase activation. IGF-1 also potentiates taurine-activated glycine receptor (GlyR) Cl- currents by increasing the agonist sensitivity through a extremely rapid (within a second) PI3 kinase-independent mechanism. Both mechanoreceptor channels and GlyR, which form the excitatory and inhibitory components of SON neuron osmosensitivity, are active at rest, and their respective inhibition and potentiation will both be inhibitory, leading to strong decrease in neuronal activity. It will be of interest to determine whether IGF-1 is released by neurons, thus participating in an inhibitory autocontrol, or astrocytes, then joining the growing family of glia-to-neuron transmitters that modulate neuronal and synaptic activity. Through the opposite and complementary acute regulation of mechanoreceptors and GlyR, IGF-1 appears as a new important neuromodulator in the adult CNS, participating in the complex integration of neural messages that regulates the level of neuronal excitability.


Asunto(s)
Factor I del Crecimiento Similar a la Insulina/farmacología , Mecanorreceptores/fisiología , Inhibición Neural/efectos de los fármacos , Neuronas/efectos de los fármacos , Receptores de Glicina/fisiología , Núcleo Supraóptico/citología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Androstadienos/farmacología , Animales , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Interacciones Farmacológicas , Estimulación Eléctrica/métodos , Inhibidores Enzimáticos/farmacología , Proteína Ácida Fibrilar de la Glía/metabolismo , Glicinérgicos/farmacología , Inmunohistoquímica/métodos , Técnicas In Vitro , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Neuronas/metabolismo , Oxitocina/metabolismo , Técnicas de Placa-Clamp/métodos , Ratas , Receptor IGF Tipo 1/metabolismo , Estricnina/farmacología , Taurina/metabolismo , Taurina/farmacología , Tritio/metabolismo , Vasopresinas/metabolismo , Wortmanina
13.
BMC Neurosci ; 6: 20, 2005 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-15790414

RESUMEN

BACKGROUND: In mammals, the CNS vasculature is established during the postnatal period via active angiogenesis, providing different brain regions with capillary networks of various densities that locally supply adapted metabolic support to neurons. Thereafter this vasculature remains essentially quiescent excepted for specific pathologies. In the adult rat hypothalamus, a particularly dense network of capillary vessels is associated with the supraoptic (SON) and paraventricular (PVN) nuclei containing the magnocellular neurons secreting vasopressin and oxytocin, two neurohormones involved in the control of the body fluid homoeostasis. In the seventies, it was reported that proliferation of astrocytes and endothelial cells occurs within these hypothalamic nuclei when strong metabolic activation of the vasopressinergic and oxytocinergic neurons was induced by prolonged hyperosmotic stimulation. The aim of the present study was to determine whether such proliferative response to osmotic stimulus is related to local angiogenesis and to elucidate the cellular and molecular mechanisms involved. RESULTS: Our results provide evidence that cell proliferation occurring within the SON of osmotically stimulated adult rats corresponds to local angiogenesis. We show that 1) a large majority of the SON proliferative cells is associated with capillary vessels, 2) this proliferative response correlates with a progressive increase in density of the capillary network within the nucleus, and 3) SON capillary vessels exhibit an increased expression of nestin and vimentin, two markers of newly formed vessels. Contrasting with most adult CNS neurons, hypothalamic magnocellular neurons were found to express vascular endothelial growth factor (VEGF), a potent angiogenic factor whose production was increased by osmotic stimulus. When VEGF was inhibited by dexamethasone treatment or by the local application of a blocking antibody, the angiogenic response was strongly inhibited within the hypothalamic magnocellular nuclei of hyperosmotically stimulated rats. CONCLUSION: This study shows that the functional stimulation of hypothalamic magnocellular neurons of adult rats induces reversible angiogenesis via the local secretion of neuronal VEGF. Since many diseases are driven by unregulated angiogenesis, the hypothalamic magnocellular nuclei should provide an interesting model to study the cellular and molecular mechanisms involved in the regulation of angiogenesis processes within the adult CNS.


Asunto(s)
Hipotálamo Anterior/fisiología , Neovascularización Fisiológica/fisiología , Factor A de Crecimiento Endotelial Vascular/fisiología , Animales , Proliferación Celular/efectos de los fármacos , Hipotálamo Anterior/citología , Hipotálamo Anterior/efectos de los fármacos , Masculino , Neovascularización Fisiológica/efectos de los fármacos , Concentración Osmolar , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/fisiología , Ratas , Ratas Wistar , Cloruro de Sodio/farmacología , Factor A de Crecimiento Endotelial Vascular/biosíntesis
14.
Eur J Neurosci ; 21(2): 493-500, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15673448

RESUMEN

Altered synaptic transmission and plasticity in brain areas involved in reward and learning are thought to underlie the long-lasting effects of addictive drugs. In support of this idea, opiates reduce neurogenesis [A.J. Eisch et al. (2000) Proceedings of the National Academy of Sciences USA, 97, 7579-7584] and enhance long-term potentiation in adult rodent hippocampus [J.M. Harrison et al. (2002) Journal of Neurophysiology, 87, 2464-2470], a key structure of learning and memory processes. Here we studied how repeated morphine treatment and withdrawal affect cell proliferation and neuronal phenotypes in the dentate gyrus-CA3 region of the adult rat hippocampus. Our data showed a strong reduction of cellular proliferation in morphine-dependent animals (54% of control) that was followed by a rebound increase after 1 week withdrawal and a return to normal after 2 weeks withdrawal. Morphine dependence was also associated with a drastic reduction in the expression levels of the polysialylated form of neural cell adhesion molecule (68% of control), an adhesion molecule expressed by newly generated neurons and involved in cell migration and structural plasticity. Polysialylated neural cell adhesion molecule levels quickly returned to normal following withdrawal. In morphine-dependent rats, we found a significant increase of glutamate decarboxylase-67 mRNA transcription (170% of control) in dentate gyrus granular cells which was followed by a marked rebound decrease after 1 week withdrawal and a return to normal after 4 weeks withdrawal. Together, the results show, for the first time, that, in addition to reducing cell proliferation and neurogenesis, chronic exposure to morphine dramatically alters neuronal phenotypes in the dentate gyrus-CA3 region of the adult rat hippocampus.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Glutamato Descarboxilasa/metabolismo , Hipocampo/efectos de los fármacos , Isoenzimas/metabolismo , Morfina/administración & dosificación , Narcóticos/administración & dosificación , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Ácidos Siálicos/metabolismo , Animales , Bromodesoxiuridina/metabolismo , Recuento de Células/métodos , Esquema de Medicación , Regulación de la Expresión Génica/efectos de los fármacos , Glutamato Descarboxilasa/genética , Hipocampo/citología , Hibridación in Situ/métodos , Isoenzimas/genética , Masculino , Molécula L1 de Adhesión de Célula Nerviosa/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Ácidos Siálicos/genética , Síndrome de Abstinencia a Sustancias/metabolismo , Factores de Tiempo
15.
Eur J Neurosci ; 20(1): 66-78, 2004 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15245480

RESUMEN

We have previously shown that oxytocin neurons located in the four hypothalamic magnocellular nuclei display synchronous bursts of action potentials before each milk ejection. The mechanisms involved in such a synchronization have, however, not yet been elucidated. In this study, we test the hypothesis of an extranuclear synchronization arising from a common extrahypothalamic input innervating bilateral magnocellular nuclei. First, two different retrograde tracers were injected into the right and left supraoptic nuclei of rats that were fixed 5-7 days later. Each tracer labelled numerous neurons in various brain regions ipsilateral or contralateral to the injection site, but colocalization of the two tracers within the same cell body could only be detected bilaterally in neurons in the ventromedial regions of the medulla oblongata. The axonal projections of these medullary neurons were then visualized by the unilateral microinjection of an anterograde tracer (BDA) within the ventromedial medulla oblongata. BDA-labelled axons afferent to the hypothalamus were found to branch towards both supraoptic nuclei through medial portions of the optic chiasma. Finally, in anaesthetized lactating rats, surgical lesions were placed medially through the optic chiasma and the electrical activity of oxytocin neurons in bilateral supraoptic nuclei was pair-recorded during suckling. The incidence of synchronous bursts in oxytocin neurons located within bilateral supraoptic nuclei were dramatically altered only when the medial portions of the optic chiasma were totally lesioned. Taken together, these data suggest that medullary neurons afferent to bilateral supraoptic nuclei are involved in the recruitment and synchronization of bursting in oxytocin neurons during suckling.


Asunto(s)
Biotina/análogos & derivados , Neuronas/metabolismo , Oxitocina/metabolismo , Núcleo Supraóptico/citología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Amidinas/farmacocinética , Animales , Animales Lactantes , Biotina/farmacocinética , Dextranos/farmacocinética , Electrofisiología/métodos , Femenino , Fluoresceína-5-Isotiocianato/farmacocinética , Colorantes Fluorescentes/farmacocinética , Lateralidad Funcional , Inmunohistoquímica/métodos , Inyecciones Intraventriculares/métodos , Microesferas , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Wistar , Tirosina 3-Monooxigenasa/metabolismo
16.
Endocrinology ; 145(10): 4737-47, 2004 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-15231696

RESUMEN

The median eminence (ME) is considered as the final common pathway connecting the nervous and endocrine systems. In this neurohemal structure, dynamic interactions among nerve terminals, tanycytes, and astrocytes determine through plastic processes the neurohormones access to the portal blood. Because brain-derived neurotrophic factor (BDNF) is involved in plastic changes, we investigated its presence and that of its receptors (TrkB) in the different cellular types described in the ME. Using in situ hybridization and immunohistochemical techniques, we demonstrated that BDNF immunoreactivity was essentially located in the astrocytes and to a lesser extent in tanycytes. By contrast, BDNF was not detected in nerve terminals reaching the external layer of the ME. TrkB antibodies recognizing the extracellular receptor domain labeled all of these different cell types, suggesting an autocrine or paracrine action of BDNF at this level. More selective antibodies showed that TrkB.FL immunostaining was found in tanycytes and nerve endings, whereas TrkB.T1 immunostaining was localized in all cellular types. Immobilization stress increased BDNF mRNA and BDNF immunoreactivity patterns and induced biphasic BDNF release from the ME, as analyzed by push-pull perfusion. In addition, we observed that 60-min stress intensified BDNF immunoreactivity in the internal layer and also its colocalization with glial fibrillary acidic protein. Stress also accentuated BDNF immunostaining in the perivascular space in elements that were not labeled with antibodies recognizing fibroblast or endothelial cells. These data disclosed a novel location of BDNF and its receptors in the ME, which are presumably involved in dynamic processes such as hormone release.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Eminencia Media/metabolismo , Neuronas/metabolismo , Receptor trkB/metabolismo , Estrés Fisiológico/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Corticosterona/sangre , Inmovilización , Inmunohistoquímica , Masculino , Eminencia Media/irrigación sanguínea , Eminencia Media/citología , Eminencia Media/ultraestructura , Pericitos/metabolismo , Isoformas de Proteínas/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Estrés Fisiológico/etiología , Factores de Tiempo
17.
J Biol Chem ; 279(19): 20257-66, 2004 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-14988405

RESUMEN

The 5-hydroxytryptamine type 2A (5-HT(2A)) receptor and the 5-HT(2C) receptor are closely related members of the G-protein-coupled receptors activated by serotonin that share very similar pharmacological profiles and cellular signaling pathways. These receptors express a canonical class I PDZ ligand (SXV) at their C-terminal extremity. Here, we have identified proteins that interact with the PDZ ligand of the 5-HT(2A) and 5-HT(2C) receptors by a proteomic approach associating affinity chromatography using immobilized synthetic peptides encompassing the PDZ ligand and mass spectrometry. We report that both receptor C termini interact with specific sets of PDZ proteins in vitro. The 5-HT(2C) receptor but not the 5-HT(2A) receptor binds to the Veli-3.CASK.Mint1 ternary complex and to SAP102. In addition, the 5-HT(2C) receptor binds more strongly to PSD-95 and MPP-3 than the 5-HT(2A) receptor. In contrast, a robust interaction between the 5-HT(2A) receptor and the channel-interacting PDZ protein CIPP was found, whereas CIPP did not significantly associate with the 5-HT(2C) receptor. We also show that residues located at the -1 position and upstream the PDZ ligand in the C terminus of the 5-HT(2A) and 5-HT(2C) receptors are major determinants in their interaction with specific PDZ proteins. Immunofluorescence and electron microscopy studies strongly suggested that these specific interactions also take place in living cells and that the 5-HT(2) receptor-PDZ protein complexes occur in intracellular compartments. The interaction of the 5-HT(2A) and the 5-HT(2C) receptor with specific sets of PDZ proteins may contribute to their different signal transduction properties.


Asunto(s)
Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Animales , Western Blotting , Encéfalo/metabolismo , Células COS , Cromatografía , Cromatografía de Afinidad , Homólogo 4 de la Proteína Discs Large , Electroforesis en Gel Bidimensional , Guanilato-Quinasas , Immunoblotting , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intracelular , Ligandos , Espectrometría de Masas , Proteínas de la Membrana , Ratones , Microscopía Confocal , Microscopía Electrónica , Microscopía Fluorescente , Proteínas del Tejido Nervioso/metabolismo , Péptidos/química , Plásmidos/metabolismo , Pruebas de Precipitina , Unión Proteica , Estructura Terciaria de Proteína , Proteoma , Receptor de Serotonina 5-HT2A/química , Receptor de Serotonina 5-HT2C/química , Transducción de Señal , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
18.
Ann N Y Acad Sci ; 1003: 212-25, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-14684448

RESUMEN

Addictive drugs are thought to alter normal brain function and cause the remodeling of synaptic functions in areas important to memory and reward. Excitatory transmission to the nucleus accumbens (NAc) is involved in the actions of most drugs of abuse, including cannabis. We have explored the functions of the endocannabinoid system at the prefrontal cortex-NAc synapses. Immunocytochemistry showed cannabinoid receptor (CB1) expression on axonal terminals making contacts with NAc neurons. In NAc slices, synthetic cannabinoids inhibit spontaneous and evoked glutamate-mediated transmission through presynaptic activation of presynaptic K+ channels and GABA-mediated transmission most likely via a direct presynaptic action on the vesicular release machinery. How does synaptic activity lead to the production of endogenous cannabinoids (eCBs) in the NAc? More generally, do eCBs participate in long-term synaptic plasticity in the brain? We found that tetanic stimulation (mimicking naturally occurring frequencies) of prelimbic glutamatergic afferents induced a presynaptic LTD dependent on eCB and CB1 receptors (eCB-LTD). Induction of eCB-LTD required postsynaptic activation of mGlu5 receptors and a rise in postsynaptic Ca2+ from ryanodine-sensitive intracellular Ca2+ stores. This retrograde signaling cascade involved postsynaptic eCB release and activation of presynaptic CB1 receptors. In the NAc, eCB-LTD might be part of a negative feedback loop, reducing glutamatergic synaptic strength during sustained cortical activity. The fact that this new form of LTD was occluded by an exogenous cannabinoid suggested that cannabis derivatives, such as marijuana, may alter normal eCB-mediated synaptic plasticity. These data suggest a major role of the eCB system in long-term synaptic plasticity and give insights into how cannabis derivatives, such as marijuana, alter normal eCB functions in the brain reward system.


Asunto(s)
Cannabinoides/farmacología , Núcleo Accumbens/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Electrofisiología , Glutamatos/fisiología , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Núcleo Accumbens/citología , Técnicas de Placa-Clamp , Receptor Cannabinoide CB1/efectos de los fármacos , Sinapsis/efectos de los fármacos , Tetrodotoxina/farmacología
19.
FASEB J ; 17(13): 1901-3, 2003 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-14519667

RESUMEN

Liver regeneration after partial hepatectomy is a plastic process during which the mechanisms that coordinate liver mass restoration compensate one another through a complex regulatory network of cytokines, growth factors, and hormones. Vasopressin, an agonist that triggers highly organized Ca2+ signals in the liver, may be one of these factors, although little in vivo evidence is available in support of this hypothesis. We provide evidence that hypothalamic vasopressin secretion is stimulated early after partial hepatectomy. Although hepatocytes were fully responsive to vasopressin during the first hours of regeneration, they became desensitized and exhibited slow oscillating Ca2+ responses to vasopressin on the following days. On the first day, hepatocyte V1a receptor density decreased and its lobular gradient increased in hepatectomized rats. By antagonizing the V1a receptor in vivo, we demonstrated that vasopressin contributes to NF-kappaB and cyclin (D1 and A) activation, to hepatocyte progression in the cell cycle, and to liver mass restoration. Finally, vasopressin exerted a choleretic effect shortly after hepatectomy, both in the isolated perfused liver and in the intact rat. In conclusion, we provide compelling in vivo evidence that vasopressin contributes significantly to growth initiation and bile flow stimulation in the early stages of liver regeneration.


Asunto(s)
Arginina Vasopresina/sangre , Bilis/metabolismo , Señalización del Calcio , Hepatocitos/metabolismo , Hipotálamo Anterior/metabolismo , Regeneración Hepática , Animales , Arginina Vasopresina/fisiología , Hepatectomía , Modelos Biológicos , Ratas , Receptores de Vasopresinas/metabolismo
20.
J Comp Neurol ; 457(4): 404-19, 2003 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-12561079

RESUMEN

S100B, the EF-hand Ca(++)-binding protein with gliotrophic and neurotrophic properties implicated in the pathogenesis of Alzheimer's disease, is coined as a glial marker, despite its documented presence in rodent brain neurons. We have generated a transgenic mouse whose EGFP reporter, controlled by the -1,669/+3,106 sequence of the murine S100B gene, allows the direct microscopic observation of most S100B-expressing cells in the central nervous system (CNS). From embryonic day 13 onward, EGFP expression was targeted to selected neuroepithelial, glial, and neuronal cells, indicating that cell-specific expression of S100B is regulated at the transcriptional level during development. In adult mice, the highest level of EGFP expression was found in ependymocytes; astrocytes; and spinal, medullar, pontine, and deep cerebellar S100B neurons. Our results, thus, agree with earlier reports suggesting that S100B is not a CNS glial-specific marker. In addition, we detected EGFP and S100B in forebrain neurons previously thought not to express S100B in the mouse, including neurons of primary motor and somatosensory neocortical areas, the ventral pallidum and prerubral field. Another interesting finding was the selected EGFP targeting to neonatal S100B oligodendrocytes and adult NG2 progenitors as opposed to mature S100B oligodendrocytes. This finding suggests that, except for oligodendrocytes at the last stage of myelin maturation, the -1,669/+3,106 sequence of the S100B gene is a useful reagent for driving expression of transgenes in most S100B-expressing cells of mouse brain.


Asunto(s)
Sistema Nervioso Central/metabolismo , Proteínas Luminiscentes/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Neuroglía/metabolismo , Neuronas/metabolismo , Proteínas S100/metabolismo , Animales , Western Blotting , Técnica del Anticuerpo Fluorescente , Proteínas Fluorescentes Verdes , Proteínas Luminiscentes/genética , Ratones , Ratones Transgénicos , Subunidad beta de la Proteína de Unión al Calcio S100
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