The cerebellar cortex is a highly organized structure necessary for fine control of voluntary movements. Understanding the signal transformations carried out by this structure is essential to understand motor function. The cerebellar cortex processes sensory and motor information arriving through mossy and climbing fibers, and sends its output to target nuclei through Purkinje cells. Within the cerebellar cortex exists a rich network of interneurons that play a key role in the sensorimotor transformations carried out by this structure;however, the role of these interneurons in the alert animal is largely unknown. In fact, our current understanding of cerebellar cortex function in the alert animal is largely based on comparing the input signals (mossy and climbing fibers) with the output signal (Purkinje cell activity), bypassing the rich network of interneurons. We propose a different approach that specifically questions the role of the cerebellar cortex interneurons during well-control behaviors using a combination of single unit recordings and pharmacological manipulation. Our model system is the ventral paraflocculus of the cerebellum (VPFL), a structure that participates in the generation of eye movements and helps stabilize images on the retina during visual behaviors. We hypothesize that interneurons perform temporal and spatial signal transformations that shape the output of the cerebellar cortex (Purkinje cell discharge). This hypothesis is supported by recent experiments, our previous studies in the cerebellar Nodulus-Uvula, and our preliminary data. To test our hypothesis we have designed a series of experiments that take advantage of the highly organized architecture of the cerebellar cortex and the fact that the majority of interneuron classes in the cerebellar cortex are inhibitory. Specifically, we will study the computations carried out by inhibition at the output layer by recording Purkinje cells, the sole output of the cerebellum, and at the input layer processing by recording Golgi cells, which directly control the input to the cerebellar cortex (mossy fiber granular cell synapses).
Our aims are:
AIM 1. To study the effect of inhibition on output layer processing. We will unveil the sensorimotor transformations carried out by GABAergic interneurons in the molecular and Purkinje cell layer through recording the response of Purkinje cells in the VPFL during well-controlled oculomotor tasks with and without application of antagonist drugs to GABA-A receptors.
AIM 2. To study the effect of inhibition on input layer processing. Specifically, we will record the response of Golgi cells during well-controlled oculomotor tasks with and without application of GABA-A receptor antagonist in the molecular layer in order to study the role of VPFL Golgi cells and how their response is shaped by molecular layer inhibition.

Public Health Relevance

Understanding the function of the cerebellar cortex is essential to understand the behavioral consequences of cerebellar dysfunction and develop therapies for rehabilitation. The majority of cerebellar cortex neurons are inhibitory interneurons that form local circuit networks, but their functional role is not understood. In this proposal we have designed experiments that directly question the role of these interneurons during normal behaviors, allowing us to provide essential data not available today.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Central Visual Processing Study Section (CVP)
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Gnadt, James W
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Washington University
Schools of Medicine
Saint Louis
United States
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Blazquez, Pablo M; Kim, GyuTae; Yakusheva, Tatyana A (2017) Searching for an Internal Representation of Stimulus Kinematics in the Response of Ventral Paraflocculus Purkinje Cells. Cerebellum 16:817-826
Blazquez, Pablo M; Yakusheva, Tatyana A (2015) GABA-A Inhibition Shapes the Spatial and Temporal Response Properties of Purkinje Cells in the Macaque Cerebellum. Cell Rep 11:1043-53
Van Dijck, Gert; Van Hulle, Marc M; Heiney, Shane A et al. (2013) Probabilistic identification of cerebellar cortical neurones across species. PLoS One 8:e57669
Laurens, Jean; Heiney, Shane A; Kim, Gyutae et al. (2013) Cerebellar cortex granular layer interneurons in the macaque monkey are functionally driven by mossy fiber pathways through net excitation or inhibition. PLoS One 8:e82239
Heiney, Shane A; Blazquez, Pablo M (2011) Behavioral responses of trained squirrel and rhesus monkeys during oculomotor tasks. Exp Brain Res 212:409-16
Heine, Shane A; Highstein, Stephen M; Blazquez, Pablo M (2010) Golgi cells operate as state-specific temporal filters at the input stage of the cerebellar cortex. J Neurosci 30:17004-14