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The Cerebellar Circuit: From Synapse to Behavior

Research Summary

Megan Carey is interested in how individual cellular and synaptic mechanisms work together within neural circuits to control behavior.

Every movement we make is the result of patterned activity within neural circuits that is precisely orchestrated to allow us to act with millimeter and millisecond precision. In turn, neural activity is shaped by a multitude of molecular and cellular mechanisms that act at the level of individual neurons and synapses. Understanding how these mechanisms interact within neural circuits to control behavior is a fundamental goal of neuroscience. To achieve that goal, we need a thorough understanding of behavior as well as a detailed knowledge of the underlying neural circuit. With this in mind, we currently focus our research on the cerebellum, a brain area that is critical for coordinated motor control and motor learning and whose circuitry is relatively simple and well understood.

Our lab takes advantage of genetic tools to dissect cerebellar circuit function in mice. The cerebellar circuit is highly organized and consists of identified cell types with known synaptic connectivity. Many of the neuron types in the cerebellum are molecularly identifiable, and existing technologies allow us to target transgenes to specific neuronal populations. By comparing specific aspects of behavior and neural activity across mice in which we have targeted genetic perturbations to different cell types, we hope to determine links between cellular function, circuit activity, and behavior. We take a multifaceted approach, including quantitative analysis of cerebellum-dependent behaviors, in vivo measurements of neural activity, and in vitro studies of synaptic transmission and plasticity.

Currently, we are conducting research to (1) identify molecular mechanisms of learning by perturbing the expression of genes known to be important for cellular plasticity, (2) dynamically control neural activity by using optogenetics, and (3) develop novel cerebellum-dependent behavioral paradigms in mice.

Molecular Mechanisms of Learning
Cannabinoids are neuromodulators that mediate several forms of synaptic plasticity, as well as being responsible for the psychotropic effects of marijuana. Recent work has suggested a role for endocannabinoids in cerebellum-dependent behaviors and provided hypotheses regarding the sites and mechanisms of their action. In the cerebellum, both short- and long-term plasticity at several synapses depend on activation of cannabinoid receptors. During my postdoctoral studies (with Wade Regehr at Harvard Medical School), I used cell type–specific cannabinoid receptor knockout mice to show that cannabinoid receptors on cerebellar parallel fibers are required for several forms of synaptic plasticity. We are now using a similar approach to determine in which cell types, and through which mechanisms, cannabinoid receptors regulate motor learning.

Dynamic Control of Neural Activity
A wealth of behavioral, electrophysiological, and lesion experiments in model systems such as eye movements and classical eyeblink conditioning have generated working hypotheses for the role of the cerebellum in these learned behaviors. Full tests of these hypotheses require the ability to control activity in specific neural populations on rapid time scales. The emerging field of optogenetics allows the control of activity in genetically specified neurons with light. We are using this approach to try to establish links between neural activity and behavior. In particular, we are interested in how activity in individual cell types leads to long-term changes in circuit activity and behavior.

Mouse Behavioral Paradigms
The many technological tools for manipulating neural circuits in mice have led to a growing number of transgenic mouse lines with defects in cerebellar circuit function and motor control. As these genetic manipulations become more and more subtle, a need arises for increasingly sensitive behavioral assays, to assess the effects of the manipulations and to distinguish between them. We are working to establish new, quantitative measures of cerebellar motor control that are natural to mice and that relate to the symptoms of cerebellar dysfunction. By combining these behavioral assays with genetic tools to manipulate gene expression and activity in identified classes of cerebellar neurons, we will dissect the contributions of distinct neural populations to specific aspects of coordinated movement.

This work was supported in part by the Champalimaud Foundation, the Helen Hay Whitney Foundation, and the Foundation for Science and Technology (Fundação para a Ciência e a Tecnologia) of Portugal.

As of January 17, 2012