RESUMEN
There is an ongoing controversy regarding the role of gender in modulating components of the human visual-evoked potential (VEP) and event-related potentials (ERPs). Our aim was to further characterize the role of gender on VEPs, ERPs and response performance in an object recognition task. We recorded VEPs and reaction time (RT) in a paradigm wherein subjects responded to a randomly presented "Relevant" stimulus, and did not respond when presented with "Irrelevant" or "Standard" visual stimuli. There was no effect of gender on early components of the VEP or RT to Relevant stimuli. Relevant and Irrelevant stimuli evoked distinct VEP components including the P300, N400 and late-positive (LP) ERPs that were well-discriminated from those of the Standard stimulus. Females were characterized by greater P300 and N400 responses than males for the Relevant stimulus, but exclusively greater N400 responses for the Irrelevant stimulus. There were no significant gender differences for the LP, or for the latency of any ERP component. Gender differences were not attributed to hemispheric asymmetry, as there were no significant differences in P300 and N400 VEP amplitudes between lateral occipital or parietal electrode positions. These results indicate that the N400 can be elicited in a task requiring the processing of irrelevant, but not unexpected, stimuli and that females process visual information differently than males, perhaps by increased allocation of attentional resources to distracting stimuli.
Asunto(s)
Potenciales Relacionados con Evento P300/fisiología , Potenciales Evocados Visuales/fisiología , Reconocimiento Visual de Modelos/fisiología , Caracteres Sexuales , Adolescente , Adulto , Atención/fisiología , Electroencefalografía , Femenino , Humanos , Masculino , Estimulación Luminosa/métodos , Tiempo de Reacción/fisiologíaRESUMEN
Axonal injury is considered the major cause of disability in patients with multiple sclerosis (MS), but the underlying effector mechanisms are poorly understood. Starting with a proteomics-based approach, we identified neurofascin-specific autoantibodies in patients with MS. These autoantibodies recognize the native form of the extracellular domains of both neurofascin 186 (NF186), a neuronal protein concentrated in myelinated fibers at nodes of Ranvier, and NF155, the oligodendrocyte-specific isoform of neurofascin. Our in vitro studies with hippocampal slice cultures indicate that neurofascin antibodies inhibit axonal conduction in a complement-dependent manner. To evaluate whether circulating antineurofascin antibodies mediate a pathogenic effect in vivo, we cotransferred these antibodies with myelin oligodendrocyte glycoprotein-specific encephalitogenic T cells to mimic the inflammatory pathology of MS and breach the blood-brain barrier. In this animal model, antibodies to neurofascin selectively targeted nodes of Ranvier, resulting in deposition of complement, axonal injury, and disease exacerbation. Collectively, these results identify a novel mechanism of immune-mediated axonal injury that can contribute to axonal pathology in MS.
Asunto(s)
Autoanticuerpos/inmunología , Axones/inmunología , Axones/patología , Moléculas de Adhesión Celular/inmunología , Factores de Crecimiento Nervioso/inmunología , Animales , Autoantígenos/inmunología , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Modelos Animales de Enfermedad , Electrofisiología , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Células HeLa , Humanos , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Vaina de Mielina/metabolismo , RatasRESUMEN
Several recent studies have established a role for estrogens in ameliorating specific neurodegenerative disorders, mainly those associated with the cholinergic neurons of the basal forebrain and their targets in the cortex and hippocampus. We have previously demonstrated that endogenous and exogenous application of the neurosteroid dehydroepiandrosterone sulfate (DHEAS) markedly reduces GABA-mediated recurrent inhibition and synchronizes hippocampal unit activity to theta rhythm (Steffensen (1995) Hippocampus 5:320-328). In this study, we evaluated the role of muscarinic receptors in mediating the effects of DHEAS and estrone sulfate (ES), the principal circulating estrogen in humans, on short-latency-evoked potential responses, paired-pulse inhibition (PPI), paired-pulse facilitation, and GABA interneuron activity in the dentate gyrus and CA1 subfields of the rat hippocampus. In situ microelectrophoretic application of the muscarinic M2 subtype cholinergic receptor agonist cis-dioxolane, DHEAS, and ES markedly reduced PPI in the dentate and CA1 that was blocked by the M2 receptor antagonist gallamine. Similar to DHEAS, microelectrophoretic administration of ES increased population spike amplitudes, without increasing excitatory transmission, but this effect was not blocked by gallamine. Microelectrophoretic application of cis-dioxolane and ES markedly increased the firing rate of dentate hilar interneurons and CA1 oriens/alveus interneurons and enhanced their synchrony to hippocampal theta rhythm. These findings suggest that select GABA-modulating neurosteroids and neuroactive estrogen sulfates alter septohippocampal cholinergic modulation of hippocampal GABAergic interneurons mediating recurrent, but not feedforward, inhibition of hippocampal principal cell activity.
Asunto(s)
Sulfato de Deshidroepiandrosterona/farmacología , Estrona/análogos & derivados , Hipocampo/citología , Inhibición Neural/efectos de los fármacos , Neuronas/efectos de los fármacos , Receptores Muscarínicos/fisiología , Ácido gamma-Aminobutírico/metabolismo , Potenciales de Acción/efectos de los fármacos , Análisis de Varianza , Animales , Interacciones Farmacológicas , Estimulación Eléctrica/métodos , Estrona/farmacología , Hipocampo/efectos de los fármacos , Masculino , Antagonistas Nicotínicos/farmacología , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Ritmo Teta/efectos de los fármacosRESUMEN
Paranodal junctions of myelinated nerve fibers are important for saltatory conduction and function as paracellular and membrane protein diffusion barriers flanking nodes of Ranvier. The formation of these specialized axoglial contacts depends on the presence of three cell adhesion molecules: neurofascin 155 on the glial membrane and a complex of Caspr and contactin on the axon. We isolated axonal and glial membranes highly enriched in these paranodal proteins and then used mass spectrometry to identify additional proteins associated with the paranodal axoglial junction. This strategy led to the identification of three novel components of the paranodal cytoskeleton: ankyrinB, alphaII spectrin, and betaII spectrin. Biochemical and immunohistochemical analyses revealed that these proteins associate with protein 4.1B in a macromolecular complex that is concentrated at central and peripheral paranodal junctions in the adult and during early myelination. Furthermore, we show that the paranodal localization of ankyrinB is disrupted in Caspr-null mice with aberrant paranodal junctions, demonstrating that paranodal neuron-glia interactions regulate the organization of the underlying cytoskeleton. In contrast, genetic disruption of the juxtaparanodal protein Caspr2 or the nodal cytoskeletal protein betaIV spectrin did not alter the paranodal cytoskeleton. Our results demonstrate that the paranodal junction contains specialized cytoskeletal components that may be important to stabilize axon-glia interactions and contribute to the membrane protein diffusion barrier found at paranodes.