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Final Activity Report Summary - ITFCIL (Imaging the transfer function of a cortical input layer)

The functional properties of local neuronal microcircuits determine the computational capacity of specialised brain structures and drive animal behaviour. A top-down approach to understanding brain function consists of recording neurons or neuronal populations in the intact animal and relating the neuronal activity to the execution of an identified behaviour. A bottom-up approach consists of identifying all the cell types in the neuronal microcircuits, characterising their synaptic and non-synaptic interconnections and studying the physiological properties of all these components. The present project has attempted to begin to bridge the gap between bottom-up and top-down approaches in the cerebellar cortex.

Towards this goal we first developed a reduced preparation in which physiological synaptic inputs of the cerebellar microcircuit are mimicked in vitro by taking advantage of the peculiar synaptic organization of the vestibulo-cerebellum, the part of the cerebellum involved with the treatment of vestibular inputs. Specifically, by selectively activating group 1 metabotropic glutamate receptors on unipolar brush cells (UBCs), an interneuron that provides intrinsic mossy fibre inputs in the vestibular cerebellum, we were able to mimic asynchronous physiological synaptic inputs of the cerebellar microcircuit, including high-frequency bursts.

Concurrently, we have monitored the pattern of activity of many identified neurons of the microcircuit in situ electrophysiologically. We have shown that mossy fibre inputs are relayed by granule cells to Purkinje cells in the output layer of the cerebellum. Furthermore, we have shown that granule cells are driven synaptically by our stimulation paradigm and that granule cell activity relies on the activation of NMDA receptors. This NMDA-dependent integration acts as a high-pass filter that relays only salient high-frequency activity of the mossy fibres. Although frequency dependent NMDA receptor activity has been shown to be involved in synaptic plasticity in other parts of the brain, our work studying the role of NMDA receptors during high frequency integration represents an original result.

In addition to NMDA receptor activity, inhibitory inputs from the Golgi cell network within the granule layer may gate the transfer of activity from mossy fibres to the Purkinje cell layer. In parallel studies to those described above, we have also demonstrated that synchronized Golgi cell oscillations lead to rhythmic inhibition and disinhibiton of the granule cells. These results have been published in the journal Neuron as part of a manuscript describing gap junction mediated Golgi cell oscillations in the granule layer (Dugue et al. 2008). Together, the development of the in vitro physiological stimulus of intrinsic UBC mossy fibers in conjunction with the observation of synchronised inhibitory oscillations impinging on the granule, will allow us to test the role of inhibitory Golgi cell oscillations on the throughput of the cerebellar neuron circuit in vitro.

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