Dynamic control of sensory processing by an active network of interneurons

? DESCRIPTION (provided by applicant): Inhibitory interneurons crucially control information processing in neuronal networks, but their vast molecular and anatomical diversity has made it difficult to dissect their functional roles. The cerebellar cortex with its relatively simple architecture and few neuron subtypes constitutes an ideal model circuit to study interneuron function. In the cerebellar cortex, mossy fibers (MFs) relay sensory information to granule cells (GCs) that send their axons to the molecular layer to excite Purkinje cells (PCs). As the only interneurons of the cerebellar input layer, Golgi cells (GoCs) are strategically positioned to control the propagation of sensory information to the cerebellar output layer. Spontaneously active GoCs inhibit GCs with two distinct time courses: rapid phasic inhibition that narrows the time window for excitatory input integration, and persistent tonic inhibition that controls the gai of incoming signals. Moreover, GoCs are thought to mediate the slow oscillations observed in the GC layer prior to the onset of motor behaviors. Strong electrical coupling between GoCs permits these oscillations that coordinate large assemblies of GCs. Although it is well established that GoCs crucially determine the flow of information within the cerebellar cortex, less is known about the mechanisms that orchestrate GoC firing, regulate GoC activity, and dynamically control GC excitability. Contrary to current beliefs in the field, preliminary data supports the hypothesis that active GoC dendrites enhance electric coupling. This proposal thus seeks to determine the cellular mechanisms that enable GoCs to fire synchronously using two-photon calcium imaging, patch clamp electrophysiology, voltage imaging and array tomography. Preliminary results also suggest that GoC activity dictates dendritic calcium concentration. The planned experiments will therefore examine the functional relationship between GoC activity and dendritic calcium dynamics, and determine the consequences for synaptic plasticity of excitatory PF and MF input. Preliminary data indicates that activation of metabotropic receptors on GoCs suppresses firing, and that this suppression is accompanied by a decrease in tonic inhibition of GCs. With the help of electrophysiology and optogenetics, this proposal will therefore test the hypothesis that dynamic modulation of GoC firing rate controls GC excitability and MF input integration. Completion of the outlined work will elucidate the mechanisms that control integration of sensory information by varying the activity of a single interneuron subtype in the cerebellar cortex. It will also extend our general understanding of how inhibition governs computational processes in neural networks.