Publication: Estudio de los circuitos neuronales responsables de ritmopatías y déficit cognitivo en modelos experimentales de epilepsia del lóbulo temporal
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2017-12-11
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Universidad Complutense de Madrid
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Abstract
En periodos de inmovilidad y sueño de ondas lentas emerge en el hipocampo el patrón de actividad más síncrono del cerebro de mamífero: los eventos sharp wave (SPW-r). Gran número de trabajos han demostrado que el reclutamiento celular durante tales eventos recopila secuencias neuronales computacionalmente relevantes, fenómeno que subyace al proceso de consolidación de la memoria. Todas las condiciones que cursan con déficit cognitivos han sido asociadas a alteraciones en los SPW-r, incluyendo el envejecimiento, la enfermedad de Alzheimer y la epilepsia del lóbulo temporal. No obstante, desconocemos a día de hoy los mecanismos que los determinan. El objetivo de esta tesis doctoral es comprender las reglas de reclutamiento de las células piramidales glutamatérgicas (PC) de CA1 durante los SPW-r, así como su alteración en los SPW-r epilépticos, con énfasis en los mecanismos que determinan su función cognitiva. Asimismo, se persiguió la posibilidad de utilizar este conocimiento básico en la búsqueda de estrategias de rescate funcional en epilepsia del lóbulo temporal (TLE). Para el abordaje de tales objetivos se empleó una combinación multi-disciplinar de métodos experimentales y analíticos, que incluyen: registros extracelulares durante paradigmas comportamentales de memoria, registros simultáneos de célula única y extracelulares in vivo, identificación histológica de entidades celulares registradas y estudios estereológicos de botones GABAérgicos perisomáticos, así como otras estrategias de neurofisiología clásica y análisis computacional. En oposición al modelo vigente, nuestros resultados muestran el comportamiento heterogéneo de las PC de CA1 durante los SPW-r, con correspondencia a su identidad celular como PC superficiales - próximas al stratum radiatum - y PC profundas - adyacentes al stratum oriens -. Ambos tipos celulares presentan inervación GABAérgica perisomática y conectividad glutamatértica intra-hipocampal diferencial, que a su vez explican la diferente selección de las PC por los eventos. Utilizando un método de agrupación no-supervisado se demostró que el control dinámico del balance excitación e inhibición subyace a la selectividad celular, y que su preciso antagonismo independiza la respuesta de células individuales respecto a la excitación general del circuito. Los eventos SPW-r que emergen en el hipocampo epiléptico presentaron una dinámica circuital distinta: el incremento del reclutamiento de las PC canceló la tendencia superficial-profunda y alteró las características espectrales de los SPW-r. Tales alteraciones estuvieron asociadas a la pérdida de selectividad celular en el hipocampo epiléptico y con déficit cognitivo. Manipulaciones farmacológicas que atenúan el reclutamiento excesivo de las PC restablecieron los parámetros circuitales relacionados con la selectividad celular y rescataron la función. Se concluye que las PC hipocampales exhiben heterogeneidad durante los SPW-r, y su reclutamiento está exquisitamente regulado como función de la dinámica interna del sistema, su contexto y su historia.
Hippocampal sharp wave-ripple (SPW-r) complexes emerge during immobility and slowwave- sleep, being the most synchronous activity patter of the mammalian brain. A number of studies have pointed out that cell recruitment during such events comprises relevant neuronal sequences during memory consolidation. Moreover, alterations of the SPW-r pattern have been related to memory impairment in normal aging and in several disorders, including Alzehimer's disease an temporal lobe epilepsy. The mechanisms however remain elusive. The major goal of this doctoral thesis is to understand the synaptic and cellular rules determining participation of CA1 glutamatergic pyramidal cells (PC) during SPW-r, as well as their distorsion in the epileptic hippocampus. To address these goals, we used a combination of experimental and analytical methods, including hippocampal muti-site silicon probe recordings in normal and epileptic rats during behavioural tasks, simultaneous single-cell and multi-site extracellular recording in vivo, unbiased histological profiling of recorded cells, and stereological studies of the GABAergic perisomatic boutons PC. In contrast to the current model, our results show a heterogeneous behaviour of CA1 PC during SPW-r according to their superficial PC – closer to stratum radiatum – or deep location PC – closer to stratum oriens. Circuit specific mechanisms, including perisomatic GABAergic and intra-hippocampal glutamatergic connectivity, explain the di↵erent selection of deep and superficial PC. An un-supervised clustering method discloses the role of the excitatory/inhibitory balance in determining cellular selectivity. SPW-r exhibited a di↵erent circuit dynamics in the epileptic hippocampuus with more PC recruited during events across the deep-superficial axis and higher frequency components characterizing SPW-r . Such spectral features were associated with a loss of selectivity and memory impairment in epileptic animals. Pharmacological manipulations that decrease excesive PC recruitment, improved cell and network parameters related to cell selectivity, and restored memory function...
Hippocampal sharp wave-ripple (SPW-r) complexes emerge during immobility and slowwave- sleep, being the most synchronous activity patter of the mammalian brain. A number of studies have pointed out that cell recruitment during such events comprises relevant neuronal sequences during memory consolidation. Moreover, alterations of the SPW-r pattern have been related to memory impairment in normal aging and in several disorders, including Alzehimer's disease an temporal lobe epilepsy. The mechanisms however remain elusive. The major goal of this doctoral thesis is to understand the synaptic and cellular rules determining participation of CA1 glutamatergic pyramidal cells (PC) during SPW-r, as well as their distorsion in the epileptic hippocampus. To address these goals, we used a combination of experimental and analytical methods, including hippocampal muti-site silicon probe recordings in normal and epileptic rats during behavioural tasks, simultaneous single-cell and multi-site extracellular recording in vivo, unbiased histological profiling of recorded cells, and stereological studies of the GABAergic perisomatic boutons PC. In contrast to the current model, our results show a heterogeneous behaviour of CA1 PC during SPW-r according to their superficial PC – closer to stratum radiatum – or deep location PC – closer to stratum oriens. Circuit specific mechanisms, including perisomatic GABAergic and intra-hippocampal glutamatergic connectivity, explain the di↵erent selection of deep and superficial PC. An un-supervised clustering method discloses the role of the excitatory/inhibitory balance in determining cellular selectivity. SPW-r exhibited a di↵erent circuit dynamics in the epileptic hippocampuus with more PC recruited during events across the deep-superficial axis and higher frequency components characterizing SPW-r . Such spectral features were associated with a loss of selectivity and memory impairment in epileptic animals. Pharmacological manipulations that decrease excesive PC recruitment, improved cell and network parameters related to cell selectivity, and restored memory function...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Biológicas, Departamento de Bioquímica y Biología Molecular I, leída el 15-09-2017