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RICERCA FINALIZZATA 2009 Ministero della Salute – Direzione Generale della Ricerca Scientifica e Tecnologica

1/12/2011 – 30/11/2014

“Induction of long-term synaptic plasticity in the human cerebellum byu repetitive TMS: cellular mechanisms and implications for rehabilitation in ataxia”

The cerebro-cerebellar loops are involved in numerous brain processes ranging from sensory-motor control to cognition. However, the functional properties of these circuits remain largely unknown. Beside the urge to better understand their functioning, it is becoming clear that dysfunction of the cerebro-cerebellar loops involves plastic changes that may play a central role in the functional recovery from various pathological states involving sensory-motor and cognitive processing, like stroke, which can cause cerebellar ataxia. In this project we will investigate the function of these loops in patients affected by cerebellar stroke and will compare the results with healthy subjects. The long-lasting modulation of the cerebro-cerebellar function will be obtained using repetitive transcranial magnetic stimulation (rTMS) in order to modify the learning processes occurring in the cerebellar cortex. This will allow at the same time to investigate memory deposition and retrival in the cerebellar circuits and to assess the effectiveness of rTMS as a rehabilitation tool. The cellular foundations of the underlying mechanisms will be investigated in the laboratory animal by using electrophysiological and imaging techniques in vitro and in vivo. A central hypothesis is that learning induced by theta-burst stimulation (TBS) in the cerebellum depends on the NMDA receptors, which are primarily expressed in the granular layer. Therefore, the impact of drugs active on these receptors (the agonist D-Serine and the antagonist memantine (REBIXA) will be investigated. These pharmacological tests will also be performed in humans in combination with rTMS in order to better understand the action mechanisms of rTBS on the cerebellar circuits. In this way, this project will provide a bridge between basic knowledge in cellular neurophysiology and central circuit operation in humans. This project, in addition to gain critical information on the plastic properties of cerebro-cerebellar loops, will allow to understand the impact of rTMS on long-term synaptic plasticity in brain circuits and will foster research of new pharmacological and rehabilitative tools for a spectrum of pathologies affecting cerebellar functioning and learning.