Optical, behavioral and electrical probing of the inhibitory cerebellar circuit during a reward-oriented task – RewInhib

Clinical studies showing that cerebellar lesions are associated with major cognitive and emotional deficits suggest a pivotal role of the cerebellar cortex in integrating cognitive and emotional aspects of behavior. In this context, a recent report using calcium imaging showed that a population of cerebellar granule cells encodes the reward content of motor tasks. This work raises the question of how reward affects the cellular activity of the cerebellar cortex, and as a result influences behavior. In the present project, we ask how information processing by the cerebellar cortex depends on the reward context of a motor task. Our aims are (i) to examine and manipulate the activity of GABA-releasing neurons of the cerebellar cortex during behaviors with different reward contents and (ii) to identify synaptic mechanisms that sub-serve the activity patterns observed during the behavioral paradigms. We will address these aims through (i) activity-dependent two-photon calcium imaging, single unit recordings and closed loop opto- and chemo-genetic manipulations in behaving mice and (ii) patch-clamp and imaging studies combined with pharmacological interference directed to silencing specific glutamate receptors in anesthetized mice and in cerebellar slices.
The behavioral task studied is rhythmic licking in water-deprived mice, a behavior accompanied by changes in the spike pattern of Purkinje cells and shown to engage/trigger calcium rises in populations of Purkinje cells as well as molecular layer interneurons. Licking is a periodic, stereotyped and well-timed behavior that can be easily quantified and analyzed and it suits well our aims since it is a reward-oriented task. This will allow for the timing of Purkinje cells and molecular layer interneurons activation to be precisely compared to that of licking. Importantly, imaging work in cortex shows that licking undergoes a learning process, and pilot work from one of the project teams indicates that this learning can be altered by cerebellar manipulations.
The project involves 3 teams, with complementary expertise. Team 1, from the CNRS/University Paris 5 laboratory of Cerebral Physiology, has a rich track record of signaling studies of cerebellar circuitry at the slice level and recently in behaving mice. Team 2, from the CNRS/Sorbonne University laboratory of Cerebellum Navigation and Memory, has pioneered behavioral tests of cerebellar function and has also more recently developed expertise in electrophysiological recordings during behavior. Team 3, from the University of Colorado at Denver, has pioneered new optics to study neuronal population activity without the constraint of head fixation, namely two-photon fiber coupled microscopy. The third team joins the present project as part of an NINDS Brain Initiative grant geared to implement advanced optical techniques in different laboratories.