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1.
J Comput Neurosci ; 52(2): 133-144, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38581476

RESUMEN

Spatial navigation through novel spaces and to known goal locations recruits multiple integrated structures in the mammalian brain. Within this extended network, the hippocampus enables formation and retrieval of cognitive spatial maps and contributes to decision making at choice points. Exploration and navigation to known goal locations produce synchronous activity of hippocampal neurons resulting in rhythmic oscillation events in local networks. Power of specific oscillatory frequencies and numbers of these events recorded in local field potentials correlate with distinct cognitive aspects of spatial navigation. Typically, oscillatory power in brain circuits is analyzed with Fourier transforms or short-time Fourier methods, which involve assumptions about the signal that are likely not true and fail to succinctly capture potentially informative features. To avoid such assumptions, we applied a method that combines manifold discovery techniques with dynamical systems theory, namely diffusion maps and Takens' time-delay embedding theory, that avoids limitations seen in traditional methods. This method, called diffusion mapped delay coordinates (DMDC), when applied to hippocampal signals recorded from juvenile rats freely navigating a Y-maze, replicates some outcomes seen with standard approaches and identifies age differences in dynamic states that traditional analyses are unable to detect. Thus, DMDC may serve as a suitable complement to more traditional analyses of LFPs recorded from behaving subjects that may enhance information yield.


Asunto(s)
Hipocampo , Animales , Hipocampo/fisiología , Masculino , Ratas , Ratas Long-Evans , Neuronas/fisiología , Navegación Espacial/fisiología , Aprendizaje por Laberinto/fisiología , Modelos Neurológicos , Potenciales de Acción/fisiología
2.
Nat Neurosci ; 7(9): 947-53, 2004 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-15300253

RESUMEN

Glucocorticoids, the adrenal steroids released during stress, compromise the ability of neurons to survive neurological injury. In contrast, estrogen protects neurons against such injuries. We designed three genetic interventions to manipulate the actions of glucocorticoids, which reduced their deleterious effects in both in vitro and in vivo rat models. The most effective of these interventions created a chimeric receptor combining the ligand-binding domain of the glucocorticoid receptor and the DNA-binding domain of the estrogen receptor. Expression of this chimeric receptor reduced hippocampal lesion size after neurological damage by 63% and reversed the outcome of the stress response by rendering glucocorticoids protective rather than destructive. Our findings elucidate three principal steps in the neuronal stress-response pathway, all of which are amenable to therapeutic intervention.


Asunto(s)
Glucocorticoides/antagonistas & inhibidores , Neuronas/fisiología , Receptores de Glucocorticoides/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Estrés Fisiológico/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/genética , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , Animales , Western Blotting/métodos , Recuento de Células/métodos , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Técnicas de Cultivo , Receptor alfa de Estrógeno , Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Humanos , Proteínas Inmediatas-Precoces , Inmunohistoquímica/métodos , Indoles , Ácido Kaínico/toxicidad , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Modelos Moleculares , Neuronas/efectos de los fármacos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína/fisiología , ARN Mensajero/metabolismo , Ratas , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Receptores de Glucocorticoides/genética , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Estrés Fisiológico/genética , Transgenes , Translocación Genética/fisiología
3.
Hippocampus ; 14(6): 701-9, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15318329

RESUMEN

Calcium is a key signaling ion for induction of synaptic plasticity processes that are believed to influence cognition. Mechanisms regulating activity-induced increases in neuronal calcium and related synaptic modifications are not fully understood. Moreover, involvement of specific synapses in discrete aspects of spatial learning remains to be elucidated. We used herpes simplex amplicons to overexpress calbindin D(28k) (CaBP) selectively in dentate gyrus (DG) granule cells. We then examined the effects on hippocampal network activity by recording evoked synaptic responses in vivo and in vitro and analyzing hippocampal-dependent behavior. Relative to Lac-Z- and sham-infected controls, CaBP overexpression increased mossy fiber (MF-CA3) excitatory postsynaptic potentials and reduced paired-pulse facilitation (PPF), suggesting an increase in presynaptic strength. Additionally, CaBP overexpression reduced long-term potentiation (LTP), caused a frequency-dependent inhibition of post-tetanic potentiation (PTP), and impaired spatial navigation. Thus, increasing CaBP levels selectively in the DG disrupts MF-CA3 presynaptic function and impairs spatial cognition. The results demonstrate the power of gene delivery in the study of the neural substrates of learning and memory and suggest that mossy fiber synaptic plasticity is critical for long-term spatial memory.


Asunto(s)
Giro Dentado/metabolismo , Trastornos de la Memoria/metabolismo , Fibras Musgosas del Hipocampo/metabolismo , Terminales Presinápticos/metabolismo , Proteína G de Unión al Calcio S100/metabolismo , Transmisión Sináptica/genética , Animales , Calbindinas , Calcio/metabolismo , Señalización del Calcio/genética , Giro Dentado/citología , Giro Dentado/fisiopatología , Modelos Animales de Enfermedad , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores/genética , Vectores Genéticos/genética , Potenciación a Largo Plazo/genética , Masculino , Trastornos de la Memoria/genética , Trastornos de la Memoria/fisiopatología , Fibras Musgosas del Hipocampo/fisiopatología , Ratas , Ratas Sprague-Dawley , Proteína G de Unión al Calcio S100/biosíntesis , Proteína G de Unión al Calcio S100/genética , Transfección , Regulación hacia Arriba/genética
4.
Trends Neurosci ; 24(12): 695-700, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11718873

RESUMEN

Increasing knowledge of neuron death mediators has led to gene therapy techniques for neuroprotection. Overexpression of numerous genes enhances survival after necrotic or neurodegenerative damage. Nonetheless, although encouraging, little is accomplished if a neuron is spared from death, but not from dysfunction. This article reviews neuroprotection experiments that include some measure of function, and synthesizes basic principles relating to its maintenance. Variations in gene delivery systems, including virus-type and latency between damage onset and vector delivery, probably impact the therapeutic outcome. Additionally, functional sparing might depend on factors related to insult severity, neuron type involved or the step in the death cascade that is targeted.


Asunto(s)
Terapia Genética/métodos , Enfermedades Neurodegenerativas/fisiopatología , Enfermedades Neurodegenerativas/terapia , Neuronas/fisiología , Animales , Humanos
5.
Ann N Y Acad Sci ; 939: 340-57, 2001 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-11462790

RESUMEN

Significant advances have been made over the past few years concerning the cellular and molecular events underlying neuron death. Recently, it is becoming increasingly clear that some of genes induced during cerebral ischemia may actually serve to rescue the cell from death. However, the injured cell may not be capable of expressing protein at high enough levels to be protective. One of the most exciting arenas of such interventions is the use of viral vectors to deliver potentially neuroprotective genes at high levels. Neurotropic herpes simplex viral (HSV) strains are an obvious choice for gene therapy to the brain, and we have used bipromoter vectors that are capable of transferring various genes to neurons. Using this system in experimental models of stroke, cardiac arrest, and excitotoxicity, we have found that it is possible to enhance neuron survival against such cerebral insults by overexpressing genes that target various facets of injury. These include energy restoration by the glucose transporter (GLUT-1), buffering calcium excess by calbindin, preventing protein malfolding or aggregation by stress proteins and inhibiting apoptotic death by BCL-2. We show that in some cases, gene therapy is also effective after the onset of injury, and also address whether successful gene therapy necessarily spares function. Although gene therapy is limited to the few hundred cells the vector is capable of transfecting, we consider the possibility of such gene therapy becoming relevant to clinical neurology in the future.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Isquemia Encefálica/terapia , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Proteína G de Unión al Calcio S100/metabolismo , Simplexvirus , Sistema de Transporte de Aminoácidos X-AG , Animales , Isquemia Encefálica/metabolismo , Calbindinas , Calcio/metabolismo , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Genes bcl-2/fisiología , Proteínas HSP70 de Choque Térmico/metabolismo , Humanos , Ratas
6.
Neurol Res ; 23(5): 543-52, 2001 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-11474812

RESUMEN

Significant advances have been made over the past few years concerning the cellular and molecular events underlying neuron death. Recently, it is becoming increasingly clear that some of the genes induced during cerebral ischemia may actually serve to rescue the cell from death. However, the injured cell may not be capable of expressing protein at levels high enough to be protective. One of the most exciting arenas of such interventions is the use of viral vectors to deliver potentially neuroprotective genes at high levels. Neurotrophic herpes simplex viral strains are an obvious choice for gene therapy to the brain, and we have utilized bipromoter vectors that are capable of transferring various genes to neurons. Using this system in experimental models of stroke, cardiac arrest and excitotoxicity, we have found that it is possible to enhance neuron survival against such cerebral insults by over-expressing genes that target various facets of injury. These include energy restoration by the glucose transporter (GLUT-1), buffering calcium excess by calbindin, preventing protein malfolding or aggregation by stress proteins and inhibiting apoptotic death by BCL-2. We show that in some cases, gene therapy is also effective after the onset of injury, and also address whether successful gene therapy necessarily spares function. Although gene therapy is limited to the few hundred cells the vector is capable of transfecting, we consider the possibility of such gene therapy becoming relevant to clinical neurology in the future.


Asunto(s)
Isquemia Encefálica/genética , Isquemia Encefálica/terapia , Muerte Celular/genética , Regulación de la Expresión Génica/genética , Terapia Genética , Vectores Genéticos/uso terapéutico , Degeneración Nerviosa/genética , Degeneración Nerviosa/terapia , Simplexvirus/genética , Animales , Humanos
7.
J Neurophysiol ; 85(4): 1377-83, 2001 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11287462

RESUMEN

Exposure to novel environments or behavioral training is associated with increased strength at hippocampal synapses. The present study employed quantal analysis techniques to examine the mechanism supporting changes in synaptic transmission that occur following differential behavioral experience. Measures of CA1 synaptic strength were obtained from hippocampal slices of rats exposed to novel environments or maintained in individual cages. The input/output (I/O) curve of extracellularly recorded population excitatory postsynaptic potentials (EPSPs) increased for animals exposed to enrichment. The amplitude of the synaptic response of the field potential was related to the fiber potential amplitude and the paired-pulse ratio, however, these measures were not altered by differential experience. Estimates of biophysical parameters of transmission were determined for intracellularly recorded unitary responses of CA1 pyramidal cells. Enrichment was associated with an increase in the mean unitary synaptic response, an increase in quantal size, and a trend for decreased input resistance and reduction in the stimulation threshold to elicit a unitary response. Paired-pulse facilitation, the percent of response failures, coefficient of variance, and estimates of quantal content were not altered by experience but correlated well with the mean unitary response amplitude. The results suggest that baseline synaptic strength is determined, to a large extent, by presynaptic release mechanisms. However, increased synaptic transmission following environmental enrichment is likely due to an increase in the number or efficacy of receptors at some synapses and the emergence of functional synaptic contacts between previously unconnected CA3 and CA1 cells.


Asunto(s)
Ambiente , Hipocampo/fisiología , Sinapsis/fisiología , Potenciales de Acción/fisiología , Animales , Umbral Diferencial , Potenciales Postsinápticos Excitadores/fisiología , Conducta Exploratoria/fisiología , Espacio Extracelular/fisiología , Teoría Cuántica , Ratas , Ratas Sprague-Dawley , Transmisión Sináptica/fisiología
8.
Exp Neurol ; 166(1): 180-9, 2000 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11031094

RESUMEN

Research shows that overexpression of cytoprotective genes can spare neurons from necrotic death, but few studies have addressed the functional status of surviving neurons. Overexpression of a brain glucose transporter, Glut-1, or the anti-apoptotic protein, Bcl-2, in rats decreases the size of hippocampal lesions produced by kainic acid (KA) treatment. In animals in which KA-induced lesions are reduced to similar extents by Glut-1 or Bcl-2 overexpression, spatial learning is spared by Glut-1, but not Bcl-2. We postulated that Glut-1 and Bcl-2 act differently to protect hippocampal function and investigated the effects of vector overexpression on synaptic physiology after KA treatment. Three days after KA and vector delivery to the dentate gyrus, mossy fiber-CA3 (MF-CA3) population excitatory postsynaptic potentials (EPSPs) were recorded in vitro. In addition to producing a lesion in area CA3, KA treatment reduced baseline MF-CA3 synaptic strength, posttetanic potentiation (PTP), and long-term potentiation (LTP). A similar reduction in the KA-induced lesion was produced by overexpression of Glut-1 or Bcl-2. Glut-1, but not Bcl-2, attenuated the impairments in synaptic strength and PTP. Overexpression of Glut-1 or Bcl-2 preserved LTP after KA treatment. Results indicate greater protection of MF-CA3 synaptic transmission with overexpression of Glut-1 compared to Bcl-2 and suggest that not all neuroprotective gene therapy techniques are equivalent in their ability to spare function.


Asunto(s)
Supervivencia Celular/genética , Terapia Genética/métodos , Hipocampo/fisiopatología , Degeneración Nerviosa/terapia , Fármacos Neuroprotectores/metabolismo , Neurotoxinas/efectos adversos , Transmisión Sináptica/fisiología , Animales , Proteínas Reguladoras de la Apoptosis , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Compuestos Cromogénicos , Giro Dentado/lesiones , Giro Dentado/patología , Giro Dentado/fisiopatología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Transportador de Glucosa de Tipo 1 , Hipocampo/lesiones , Hipocampo/patología , Ácido Kaínico/efectos adversos , Masculino , Proteínas de Transporte de Monosacáridos/genética , Proteínas de Transporte de Monosacáridos/metabolismo , Fibras Musgosas del Hipocampo/efectos de los fármacos , Fibras Musgosas del Hipocampo/fisiología , Fibras Musgosas del Hipocampo/ultraestructura , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/fisiopatología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Neurotoxinas/metabolismo , Ratas , Ratas Sprague-Dawley , Transmisión Sináptica/efectos de los fármacos
9.
Neurosci Lett ; 248(2): 138-40, 1998 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-9654362

RESUMEN

Depression of excitatory postsynaptic potentials (EPSPs) by the GABA(b) agonist, baclofen, was compared in hippocampal slices from juvenile (postnatal day (P) 15-21) and young adult (P28-35) rats. EPSP inhibition following baclofen application was not different between age groups, however, paired-pulse facilitation (PPF) increased more in young adults relative to juveniles. The differential effect of baclofen on PPF was not due to tonic receptor activity, since the GABA(b) antagonist, saclofen, did not differentially modify PPF. The baclofen-mediated increase in PPF for juvenile slices could be enhanced by first increasing transmitter release through an increased bath Ca2+ concentration. These findings suggests that ligand-mediated presynaptic depression is inversely related to the level of transmitter release and maturation of presynaptic inhibition is related to development of release.


Asunto(s)
Hipocampo/fisiología , Receptores de GABA-B/fisiología , Transmisión Sináptica/fisiología , Análisis de Varianza , Animales , Baclofeno/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Agonistas del GABA/farmacología , Agonistas de Receptores GABA-B , Hipocampo/efectos de los fármacos , Hipocampo/crecimiento & desarrollo , Hipocampo/ultraestructura , Técnicas In Vitro , Masculino , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Neurotransmisores/metabolismo , Ratas , Ratas Sprague-Dawley , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Sinapsis/fisiología , Transmisión Sináptica/efectos de los fármacos
10.
Brain Res Dev Brain Res ; 105(1): 137-9, 1998 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-9497087

RESUMEN

Paired-pulse facilitation (PPF) of CA3-CA1 excitatory postsynaptic potentials (EPSP) was compared in hippocampal slices from juvenile (postnatal day (P) 15-21) and young adult rats (P28-P35) following application of adenosine. Relative to juveniles, young adults expressed an increase in baseline synaptic strength that was accompanied by a decrease in PPF suggesting a developmental increase in transmitter release. While adenosine depressed the EPSP slope to a similar extent in juveniles and young adults, PPF increased during adenosine application only for young adults. The differential effect of adenosine on PPF was not due to differences in receptor function or in extracellular ligand levels, since the A1 antagonist cyclopentyltheophylline (CPT) did not differentially affect PPF across age. Adenosine could increase PPF in juvenile slices under conditions of enhanced transmitter release, through an increase in the bath Ca2+ concentration, or addition of forskolin to the bath. These data indicate that the ability to modify synaptic transmission through presynaptic adenosine A1 receptors increases across postnatal development with the maturation of release mechanisms.


Asunto(s)
Hipocampo/fisiología , Receptores Purinérgicos P1/fisiología , Transmisión Sináptica/fisiología , Envejecimiento , Animales , Calcio/farmacología , Colforsina/farmacología , Potenciales Postsinápticos Excitadores/fisiología , Espacio Extracelular/metabolismo , Hipocampo/crecimiento & desarrollo , Técnicas In Vitro , Neurotransmisores/metabolismo , Antagonistas de Receptores Purinérgicos P1 , Ratas , Ratas Sprague-Dawley , Receptores Purinérgicos P1/efectos de los fármacos , Teofilina/análogos & derivados , Teofilina/farmacología
11.
Neuroreport ; 8(13): 2919-24, 1997 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-9376531

RESUMEN

Modulation of hippocampal CA3-CA1 synaptic transmission during metabotropic glutamate receptor (mGluR) activation was investigated in juvenile (postnatal day (P) 15-21) and young adult rats (P28-35). The mGluR agonist 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (ACPD) depressed the EPSP slope more in young adults than juveniles. ACPD increased paired-pulse facilitation (PPF) at both ages. The group I mGluR antagonist (+)-alpha-methylcarboxyphenylglycine (MCPG) inhibited the ACPD-mediated depression of the EPSP slope and completely blocked the increase in PPF only in young adults. Minimal effects of MCPG on ACPD-dependent synaptic depression were observed in juveniles. These data suggest that presynaptic group I mGluR-mediated synaptic inhibition increases across late postnatal development. In addition, other mGluR subtypes, with the ability to depress presynaptic function, appear to be present in juveniles.


Asunto(s)
Potenciales Postsinápticos Excitadores/fisiología , Hipocampo/fisiología , Inhibición Neural/fisiología , Receptores de Glutamato Metabotrópico/fisiología , Transmisión Sináptica/fisiología , Animales , Benzoatos/farmacología , Cicloleucina/análogos & derivados , Cicloleucina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Glicina/análogos & derivados , Glicina/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/crecimiento & desarrollo , Técnicas In Vitro , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/efectos de los fármacos
12.
J Neurophysiol ; 73(5): 1821-8, 1995 May.
Artículo en Inglés | MEDLINE | ID: mdl-7623083

RESUMEN

1. We recorded extracellular and intracellular CA3-CA1 synaptic responses in hippocampal slices from neonatal rats [postnatal day (P) 15-21 and P29-35]. Presynaptic function was examined by measuring input-output relationships and paired-pulse facilitation and by quantal analysis of minimally evoked responses. 2. Extracellular recording revealed no difference in excitatory postsynaptic potential (EPSP) threshold or the fiber potential response for a given stimulus intensity between the two age groups. However, the slope of the field EPSP was consistently larger in older animals. The increase in EPSP slope was associated with a decrease in paired-pulse facilitation, suggesting an increase in presynaptic function with postnatal development. 3. Extracellular results were confirmed by intracellular recordings that revealed no difference in the minimal stimulation intensity needed to evoke a response, an increase in mean EPSP amplitude with development, and a decrease in paired-pulse facilitation. Quantal parameters were extracted by three separate methods including method of failures, coefficient of variance, and parameter optimization through noise deconvolution. All methods supported presynaptic mediation of facilitation. Comparison of quantal parameters during development indicated an increase in mean quantal content. 4. The results demonstrate that synaptic strength is altered over the course of development because of, at least in part, changes in presynaptic release mechanisms. Developmental differences in presynaptic function provide an explanation of differences in mechanisms for expression of long-term potentiation. The lower initial probability of transmitter release in neonates may permit increased presynaptic change.


Asunto(s)
Hipocampo/crecimiento & desarrollo , Terminales Presinápticos/fisiología , Células Piramidales/crecimiento & desarrollo , Animales , Animales Recién Nacidos , Estimulación Eléctrica , Electrofisiología , Potenciales Evocados , Hipocampo/fisiología , Masculino , Células Piramidales/fisiología , Ratas , Ratas Sprague-Dawley
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