Understanding how cellular and synaptic 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 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. 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.

Mouse behavioral paradigms

The many technological tools for manipulating neural circuits in mice have led to a growing number of transgenic lines with defects in cerebellar circuit function and motor control. As these genetic manipulations become more and more subtle, there is a need for increasingly sensitive behavioral assays, to assess the effects of the manipulations and also to distinguish between them. We are working to establish new, quantitative measures of cerebellar motor control that are natural to mice and mindful of 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.

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. We have recently 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 timescales. 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.

Megan Carey, PhD
Principal Investigator
megan.carey@neuro.fchampalimaud.org

Biography

Ana Machado
MIT PhD Student
ana.machado@neuro.fchampalimaud.org

Carla Matos
Research Technician
carla.matos@neuro.fchampalimaud.org

Catarina Albergaria
PhD Student
catarina.albergaria@neuro.fchampalimaud.org

Dana Darmohray
Research Assistant
dana.darmohray@neuro.fchampalimaud.org

João Fayad, PhD
Postdoctoral Fellow
joao.fayad@neuro.fchampalimaud.org

Carey MR (2011) Synaptic mechanisms of sensorimotor learning in the cerebellum. Curr. Opin. Neurobiol. 21 , 609-15 (doi:10.1016/j.conb.2011.06.011)

Carey MR, Myoga MH, McDaniels KR, Marsicano G, Lutz B, Mackie K, Regehr WG (2011) Presynaptic CB1 receptors regulate synaptic plasticity at cerebellar parallel fiber synapses. J. Neurophysiol. 105 , 958-63 (doi: 10.1152/jn.00980.2010)

Carey MR, Regehr WG (2010) Phosphatase activity controls the ups and downs of cerebellar learning. Neuron 67 , 525-6 (doi:10.1016/j.neuron.2010.08.015)

Kim JC, Cook MN, Carey MR, Shen C, Regehr WG, Dymecki SM (2009) Linking genetically defined neurons to behavior through a broadly applicable silencing allele. Neuron 63 , 305-315 (doi:10.1016/j.neuron.2009.07.010)

Regehr WG, Carey MR, Best AR (2009) Activity-dependent regulation of synapses by retrograde messengers. Neuron 63 , 154-170 (doi:10.1016/j.neuron.2009.06.021)

Carey MR, Regehr WG (2009) Noradrenergic control of associative synaptic plasticity by selective modulation of instructive signals. Neuron 62 , 112-122 (doi:10.1016/j.neuron.2009.02.022)

Carey MR, Medina JF, Lisberger SG (2005) Instructive signals for motor learning from visual cortical area MT. Nat. Neurosci. 8 , 813-819 (doi:10.1038/nn1470)

Medina JF, Carey MR, Lisberger SG (2005) The representation of time for motor learning. Neuron 45 , 157-167 (doi:10.1016/j.neuron.2004.12.017)

Carey MR, Lisberger SG (2004) Signals that modulate gain control for smooth pursuit eye movements in monkeys. J. Neurophysiol. 91 , 623-631 (doi:10.1152/jn.00525.2003)

Carey M, Lisberger S (2002) Embarrassed, but not depressed: eye opening lessons for cerebellar learning. Neuron 35 , 223-226 (doi:10.1016/S0896-6273(02)00771-7)

Bodznick D, Montgomery JC, Carey M (1999) Adaptive mechanisms in the elasmobranch hindbrain. J. Exp. Biol. 202 , 1357-1364