Experimental lesions and blunt force traumas to the cerebellum result in behavioral abnormalities that indicate this brain region plays an important role in controlling smooth coordinated movement and motor memory (Fine, Ionita, &Lohr, 2002). Specifically, researchers believe the cerebellum evaluates the disparities between intention and action, and then adjusts the motor output to correct for these disparities in order to generate a desired, smooth-motor behavior. Experiments suggest these corrections arise from dynamic changes in the strength of synaptic connections in both the cerebellar cortex and deep nuclei. In addition, these changes are likely driven by the association or coincident detection of signals from two specific pathways, one by way of the mossy fibers (MF, carrying sensory information) and the other by way of the climbing fibers (CF, indicating a disparity or error in the motor command). Originating in the inferior olive the climbing fiber delivers a unique and powerful input that generates a "complex spike" in the sole output of the cerebellar cortex, the Purkinje cells (PCs). This input, when paired with parallel fiber (PF;mossy fiber relay) activation decreases the somatosensory receptive fields of PCs (Jvrntell &Ekerot, 2002). This change in receptive field is due to the depression of a subset of PF-PC synapses, a mechanism believed to remove sensory signals producing undesired motor behaviors. Similar experiments also demonstrate CFs drive associative changes in the receptive fields of molecular layer inhibitory interneurons (MLI) that synapse onto PCs. However, the nature of the CF-MLI connection remains unclear, nor are the mechanisms driving the associative plasticity that result in receptive field changes known. This deficiency in the current state of cerebellar knowledge is the result of an inability to reliably stimulate CFs without activating neighboring axons from other neuron types. To overcome this technical challenge, a novel optogenetic approach has been developed to allow robust stimulation of isolated CFs.
The first aim of this proposal will further confirm preliminary results demonstrating the reliability and specificity of photostimulating CFs expressing Channelrhodopsin 2 by systematically exploring the optical stimulation and viral injection parameters necessary for robust CF stimulation. Using this technique, I propose to describe both the nature of CF-MLI transmission as well as the mechanisms and rules governing the CF- driven associative plasticity between parallel fibers and MLIs. This will be accomplished through whole-cell patch clamp recordings from MLIs in acute slices during selective CF photostimulation. These experiments will be the first of their kind to illustrate the effectiveness of optogenetic techniques in exploring the cerebellar cortex. In the end results from these experiments will allow for better predictions of how the cerebellar cortex evaluates and corrects for disparities between intention and action.
Cerebellar dysfunction, which usually results from disease, blunt force trauma or the effects of aging, often presents itself as deficits in motor control and/or motor memory. The goal of this proposal is to examine the basic cellular properties and mechanisms governing motor control and memory in the cerebellar cortex using a novel technique to stimulate neurons in the brain. With a more informed knowledge base of cerebellar function at the cellular level researchers will be better prepared to design therapies to cure or alleviate the symptoms of cerebellar dysfunctions.
|Lee, Ka Hung; Mathews, Paul J; Reeves, Alexander M B et al. (2015) Circuit mechanisms underlying motor memory formation in the cerebellum. Neuron 86:529-40|
|Otis, Thomas S; Mathews, Paul J; Lee, Ka Hung et al. (2012) How do climbing fibers teach? Front Neural Circuits 6:95|
|Mathews, Paul J; Lee, Ka Hung; Peng, Zechun et al. (2012) Effects of climbing fiber driven inhibition on Purkinje neuron spiking. J Neurosci 32:17988-97|