Unraveling modular information processing in cerebellar microcircuits – MicroCer

Several approaches were developed in order to stimulate and record cerebellar neural networks and identify functional unitary modules:
-We have transgenic mice in which cells can be identified by the green fluorescent protein (GFP), These tools allowed us to target specific cells and record their synaptic inputs. Combined with anatomical markers highlighting cerebellar modules, we can study the organization of information processing.
- A photoactivation technique releasing neurotransmitter at a given position allow a rapid mapping of the organization of synaptic inputs.
-We also used a new transgenic strain of mice that we have generated in which a photoactivable protein, the channelrhodopsin, has been expressed specifically in Purkinje cell. We use this optogenetic tool in order to activate Purkinje cells in vitro and in vivo

Our findings demonstrate explicitely the existence of a modular information processing in the cerebellar cortex and refine the limits of the modules. Modules can be characterized either by the expression of biochemical markers in Purkinje cells or by the topographical organization of mossy fiber inputs, one of the major input of the cerebellum. We showed that Golgi cells process information from local mossy fiber more powerfully than from mossy fiber projecting in adjacent modules. We also showed that informations can be transmitted to Purkinje cells reliability in a wide range of frequencies. We now work on the development of a method to stimulate specifically a group of identified mossy fibers.
Finally, our new strain of transgenic mice will now allowed us to selectively photostimulate Purkinje cells, the output of the cerebellum, and then control in vivo individual cerebellar modules

Our results will give insights on the organization of information processing in cerebellar modules. Modular organization and parallel processing in the cerebellum are the base of motor coordination. A dysfunction in information processing in cerebellar modules lead to movement disorders or tremor. The tools that we have developed will allow new compensatory strategies to be developed on mice and new hypotheses on the role of the cerebellum in motor coordination

2 articles in peer reviewed journals were published, one in the Journal of Neuroscience. 3 articles are in preparation. Also several poster presentations were presented in international meetings.

To understand the progressive emergence of complex functions at the molecular level, it is essential to bridge the gap between global brain function and molecular neuroscience. Fortunately, the brain is modular: neuronal networks of the cerebral cortex are organized in local circuits or modules that serve different functions in specific brain regions, from the forebrain to the spinal cord. A given cortical area is composed of many functional modules that allow a parallel processing of incoming information. Ocular dominance columns in the visual cortex, glomeruli in the olfactory bulb and the barrel of the somato-sensoricortex are considered as paradigms of the modular organization of information processing in the brain. One major challenge of current neuroscience is to unravel the operational modes of these modules or ‘microcircuits’ .
The cerebellum plays a major role in the control and learning of skilled movements. Recent evidence has demonstrated that the cerebellar cortex plays a role in the precise timing of individual components of the motor program and is involved in the synchronization of cerebello-thalamo-cortical oscillations observed during motor tasks. To understand, and ultimately manipulate, the integrative role of the cerebellum in the motor circuit its input/output transformation needs to be elucidated. Although the cellular organization of the cerebellar cortex looks homogeneous across lobules and folia, anatomical and molecular data have shown that the cerebellum is also organized in modules. Functional studies have demonstrated that task-related modules can be identified and selectively modified. The organization of the basic microcircuit of the cerebellar cortex is now well described; however rules governing how incoming information is channelled through the microcircuitry and how the specific processing of one given input is carried out by the microcircuit are still poorly understood. Furthermore, the functional connectivity within and across individual modules has not yet been characterized.
The major goal of this project is to identify operational modes of the unitary functional module in the cerebellar cortex. We will study intrinsic synaptic connections within a given module, intermodular synaptic connections between neighboring modules and Purkinje cell output to deep cerebellar nuclei, the actual output stage of the cerebellum. Since this requires isolating both individual modules and its specific inputs, we will then combine two recent optical tools. (1) The use of transgenic mice in which modules can be identified by GFP expression. (2) An optical genetically-targeted stimulation technique that permits the selective activation of identified input pathways targeting specific modules of the cerebellar cortex and pathways projecting to the output stage of the cerebellum. We postulate that targeting and identifying individual cerebellar modules will clarify the fundamental rules determining functional synaptic organization of the cerebellar modular system.