Rendimiento cognitivo en envejecimiento: efecto del sueño, del ejercicio y de la TMS en Octodon degus

La Enfermedad de Alzheimer (EA) es un trastorno neurodegenerativo progresivo cuya incidencia probablemente aumentara en los proximos anos. A pesar de los avances en investigacion y del gran volumen de datos que se obtienen a diario en relacion con la EA, el diagnostico de certeza solo se consigue en estudios postmortem. Los objetivos de esta tesis son: i) Evaluar el posible papel terapeutico de la TMS en la funcion cognitiva de Octodon degus jovenes, tras la privacion de sueno, mediante la evaluacion de la memoria de trabajo y espacial con los test conductuales de Radial Arm Maze, Barnes Maze y Novel Object Recognition, ii) Una vez comprobada la idoneidad de esta herramienta en este modelo, se estudio la aplicacion de TMS en Octodon degus de distintas edades: tras la privacion de sueno, analizando la memoria de trabajo y espacial con los paradigmas conductuales anteriormente mencionados, iii) Explorar si la acentuacion del deterioro cognitivo asociado a la edad y los niveles de cortisol, como marcador de estres, pueden mejorar con la modulacion de factores medioambientales como es la practica de ejercicio fisico voluntario, iv) Estudiar el efecto de la memantina, como farmaco empleado en la EA, para nuestro modelo animal de deficit cognitivo inducido por privacion de sueno, y v) Estudiar la posible diferencia en la actividad enzimatica tanto de AChE como de BuChE asociada a la edad y a la practica de actividad fisica voluntaria, en extractos de hipocampo de Octodon degus. Tras los estudios, observamos que el tratamiento con Estimulacion Magnetica Transcraneal (TMS) puede ser una herramienta terapeutica en el deterioro cognitivo. El tratamiento agudo con TMS mejora significativamente la memoria espacial en O. degus tras ser privados de sueno, mientras que para recuperar la memoria de trabajo, es necesario el tratamiento cronico con TMS. Asi mismo, este tratamiento tiene un efecto terapeutico tanto en O. degus jovenes y anosos. La administracion de memantina en O. degus, se observo la mejoria en el deterioro cognitivo transitorio inducido por la privacion de sueno, y la gran utilidad de este roedor como modelo en desordenes asociados a la edad. A pesar de los avances en investigacion y del gran volumen de datos que se obtienen a diario en relacion con la EA, el diagnostico de certeza solo se consigue en estudios postmortem. Los tratamientos farmacologicos para la EA tienen efectividad limitada, son caros y pueden inducir efectos secundarios. Las nuevas estrategias terapeuticas, como por la estimulacion magnetica, estan siendo utiles como tratamientos complementarios. El desarrollo de nuevos metodos no invasivos de estimulacion cerebral ha incrementado el interes en tecnicas neuromoduladoras como herramientas terapeuticas para rehabilitacion cognitiva en EA. Age-related cognitive deficiencies are extremely common and represent a considerable health risk in humans. The deterioration of cognition is one of the principal properties of the physiological consequences of aging. Although the initial effect of a degeneration process does not fundamentally suggest memory damage, age-related disturbances regularly emerge with diverse levels of cognitive dysfunction. Among these kind of disorders, Alzheimer's disease (AD) is of particular concern because of its predominance and drastic consequences. It is a progressive neurological disease which is the mark of an extreme accumulation of neurofibrillary tangles and the deposition of amyloid peptides in the cortical parenchyma and hippocampal area. It has long been accepted that sleep disturbances may impair normal physiological functions including the immune system, thermoregulation, tissue restoration and energy conservation. Sleep orchestrates brain plasticity during maturation, which enables learning and memory processes, neurogenesis and adult consolidation of hippocampal integrity and types of memories. The paradigm of sleep deprivation (SD) during the paradoxical sleep window has been widely used to induce memory impairments in animal models. SD produces an efficient transient cognitive impairment in both human and animals, pointing out that SD prior to learning may influence memory processes by limiting the ability of neuronal networks to process new information. In this sense, SD could be a non-invasive alternative to reproduce AD cognitive deficits. Preclinical research using animal models for the study of age-related disorders is crucial for the development and improvement of pharmacological strategies. O. degus is a diurnal rodent that provides an excellent opportunity for exploring the mechanisms underlying late developmental changes in the nervous system, and therefore, the behavioral and cognitive outcomes resulting from such changes. These animals develop spontaneously several physiopathological conditions has recently been identified as a very valuable animal model for research in several medical fields, especially those concerned with neurodegenerative diseases in which risk is associated with aging. The principal conclusions of the thesis are: i) TMS treatment may have a great therapeutic potential in cognitive impairment. Acute TMS treatment significantly improve spatial memory after SD insult in O. degus, while chronic TMS is required to additionally recover the working memory. Chronic TMS treatment has a therapeutic potential effect in both young and old O. degus. However, acute treatment is insufficient in old animals meanwhile is enough in the young ones. Old O.degus requires until 7 TMS applications to recover in comparison to 1 needed for the young ones, ii) The administration of memantine at 10 mg/kg prior to the SD challenge, showed the suitability of the O. degus model for the study of aging-related disorders such as in Alzheimer's disease, iii) Voluntary physical activity improved spatial memory functions and decreased cortisol level in no-SD animals, highlighting the benefits of sleep hygiene in the lifestyle. The insertion of exercise programs in addition to pharmacological tool might promote memory recovery functions in the prognosis of neurodegenerative disorders, such as Alzheimer's disease, and iv) The study of both ChEs activities AChE and BuChE in O. degus after 45 days performing voluntary physical exercise, revealed that the aging process affect differently at each enzyme after SD insult. While there is no changes in BuChE activity, in AChE there is a decrease in young animals just in fraction S1, and this reduction occurs at both ages in the supernatant S2 after exercise stimuli.