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Oscillations in the cerebral cortex: mechanisms of control and alterations in a transgenic model of Down syndrome

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Universitat de Barcelona. Facultat de Medicina

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[spa] Esta Tesis aborda diferentes cuestiones acerca de la actividad oscilatoria espontánea en la corteza cerebral, incluyendo estudios comparativos funcionales, estudios de mecanismos que generan esta actividad y la evaluación de alteraciones en un modelo de discapacidad mental. La principal técnica que se ha usado es el registro electrofisiológico de señales de Potencial de Campo Local (LFP), el cual se ha usado en combinación con otras técnicas, y que responde principalmente a la actividad de una población local de neuronas. Este tipo de registros se ha obtenido tanto en rodajas de cerebro como in vivo. Además, se han obtenido registros de neurona única, que evalúan sus propiedades de disparo, que fueron obtenidas al mismo tiempo que registros de LFP. En el primer estudio, nuestro objetivo fue entender el rol de la corriente persistente de sodio en el control de la actividad oscilatoria, tanto en la generación y mantenimiento de estados UP en oscilaciones lentas como el control de las oscilaciones rápidas beta-gamma. Aquí, vimos que el bloqueo de esta corriente con fenitoína provocaba el alargamiento de los estados UP e incrementaba la tasa de disparo de la red durante los mismos, a la vez que evitaba la generación de nuevos estados UP. En otro estudio, llevamos a cabo una comparación de la actividad oscilatoria espontánea en diferentes áreas de la corteza in vivo. Vimos que la corteza prefrontal presentaba características distintas comparadas con áreas primarias, incluyendo mayor tasa de disparo de la red, frecuencias gamma aumentadas, una variabilidad menor de las duraciones de los estados UP y patrones de disparo de las neuronas distintos. Este estudio también incluye un análisis de los patrones de propagación de las ondas lentas en la corteza. Finalmente, hicimos un estudio de las alteraciones funcionales y anatómicas en la red cortical que subyacen los déficits cognitivos en un modelo transgénico de síndrome de Down, el ratón TgDyrk1A. Este trabajo se llevó a cabo en dos áreas corticales: prefrontal y somatosensorial primaria. En el estudio en la corteza prefrontal, los ratones transgénicos presentaron alteraciones en la actividad oscilatoria que eran compatibles con una mayor inhibición de la red. Este desbalance entre excitación e inhibición fue demostrado posteriormente a nivel anatómico, y explicaría los hallazgos de alteraciones de comportamiento en tareas cognitivas que requieren de la corteza prefrontal, como el puzzle box. En el estudio de la corteza somatosensorial, el análisis de potenciales evocados talamocorticales mostró un aumento de inhibición cortical. A pesar de ello, la actividad oscilatoria no se vio alterada, sugiriendo la existencia de mecanismos compensatorios. Todos estos fenómenos estudiados en esta Tesis se pueden entender en el marco de alteraciones en el balance excitación-inhibición de la corteza cerebral.

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[eng] The present Thesis addressed different questions concerning spontaneous oscillatory activity in the cerebral cortex, including functional comparative studies, studies of mechanisms generating this activity and the evaluation of alterations in a model of mental disability. The main technique used for this work is the recording of electrophysiological extracellular Local Field Potential signals, which mainly respond to the activity of local populations of neurons. This type of recordings was obtained both in brain slices and in vivo and was used in combination with other techniques. Single Unit recordings, which evaluate the firing properties of a single neuron, were also obtained in combination of LFP in some of the studies. In the first study, we aimed to disclose the role of persistent sodium current in controlling cortical oscillatory activity, either in the generation and maintenance of UP states in slow oscillations and the control of fast beta-gamma oscillations. Here, we saw that blocking this current with phenytoin provoked the elongation of UP states and increased firing rate of the network, while the generation of new UP states was prevented. In another study, we performed a comparison of the oscillatory activity along different cortical areas in vivo. Here, prefrontal cortex showed special features compared to primary areas, including increased firing rate and gamma oscillations, and firing patterns of single units. This study also included a measurement of the speed of propagation of UP states, because prefrontal cortex was found to present a reduced Coefficient of Variation of UP state duration, compatible with being an area of wave generation. Thus, we aimed to demonstrate a main pattern of propagation of slow waves from frontal areas to posterior areas, as previously described in humans. Finally, we performed a study of the functional and anatomical alterations in the cortical network underlying cognitive deficits in a transgenic model of Down syndrome, TgDyrk1A mice. This work was performed in two cortical areas: prefrontal and primary somatosensory cortex. In our study of prefrontal cortex, TgDyrk1A mice presented alterations in oscillatory activity that were compatible with as more inhibited network, such as decreased firing rate, decreased gamma oscillations and a slower speed of propagation. This unbalance between excitation and inhibition was later demonstrated at anatomical level, and may explain our findings of altered behavior in cognitive tasks that involved prefrontal cortex such as the puzzle box. In our study in somatosensory cortex, thalamocortical evoked potentials showed increased cortical inhibition. Although that, oscillatory activity, either in parameters of Slow waves or beta-gamma frequencies, remained unchanged, suggesting the existence of compensatory mechanisms. From the work of this Thesis, we demonstrated some mechanistic aspects that control the emergence of rhythmic patterns from cortical circuits, with a striking role on the mechanisms which control excitability or cortical connectivity that underlies oscillations. First, this study presents de dependence of slow and fast rhythms on an intrinsic mechanism of neurons that governs cortical oscillations which is the persistent sodium current. Secondly, here is presented the role of cortical excitability in the expression of those rhythms across different cortical areas. And finally, this study shows the changes in cortical network function in a model of Down syndrome by means of analyzing oscillatory activity, as this represents a network activity and reflects the altered cellular and connectivity elements which are critical for the expression of cortical rhythms. These findings can all be understood within frame of altered balance between excitation and inhibition.

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Oscillations in the cerebral cortex: mechanisms of control and alterations in a transgenic model of Down syndrome