Towards new treatments for Alzheimer disease Modulating effect of cerebellum on hippocampal plasticity and hippocampal-dependent memory

Description

There is more and more evidence that hippocampus and cerebellum are functionally connected. Bidirectional modulation of their activity occurs during spatial navigation and time-dependent task in rodents influencing synaptic plasticity in both structures. Moreover, synchronization of network oscillations of hippocampus and cerebellum in the theta and gamma band has been recorded during learning tasks such as eyeblink conditioning and Morris water maze. Theta oscillation in the hippocampus was showed to be important for in vivo long-term potentiation and memory encoding, hippocampal high theta power being correlated with efficient learning. Moreover, theta rhythm dysfunction has been demonstrated in Alzheimer’s disease. On the other hand, beside its well-known role in motor control, there is more and more evidence that the cerebellum is involved in cognitive processes and could modulate information processing in cortical areas and in hippocampus. All these facts point towards the cerebellum as a new important target for brain activity modulation. Transcranial direct current stimulation (tDCS) is a well-established non-invasive brain stimulation technique able to modulate neural activity and the cerebellum is particularly suitable for transcranial stimulation due to the disposition of Purkinje cells aligned at the surface of the cortex. The tDCS stimulation of the cerebellum brings therefore a lot of hope for the treatment of neurological and psychiatric disorders. On the other hand, the transcranial alternating current stimulation (tACS) only differs from tDCS by the fact that sinusoidal currents are given at a specific frequency in place of DC currents. Due to the importance of network oscillations on neuronal processing, this technique could provide an even more powerful tool to modulate brain activity. However, very little is known on the direct and indirect effects of these stimulations on neuronal activity in the cerebellum and in remote connected areas. The aim of this project is to better understand the effects of tDCS/aDCS applied on the cerebellum on hippocampal electrical activity, synaptic plasticity and memory in mice. For this purpose, we will (1) study the immediate effect of tDCS/tACS applied on the cerebellum on the electrical activity of deep cerebellar nuclei in head-fixed animals; (2) study in freely moving animals the modulation of hippocampal activity (field potential) by direct local electrical stimulation of deep cerebellar nuclei mimicking tDCS/tACS stimulation; (3) analyze the delayed (long-term) effect of this stimulation on synaptic plasticity in acute slices and on memory with behavioral tests. In the second part of the project, we will (1) confirm the alteration of brain oscillations in a mouse model of Alzheimer’s disease; (2) apply the protocol of tDCS/aDCS tested in the first part to evaluate the potential rescue of impairments of synaptic plasticity and memory developed by these mice as they age. As an important outcome of this project, the same tACS approach could be made in the future on Alzheimer’s patients where specific rhythmic alterations of the ongoing EEG were reported. Positive outcomes could promote a new type of non-invasive electrical and behavioral prevention, retardation and therapy against the devastating tendency to fall from SCD, MCI to fatal AD. Industrial partners have already shown their interest in the development of a new portable technology allowing elderly people to train their brain abilities in order to reinforced memory outcome and prevent its deterioration.

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