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.

If you are interested in joining our group, please contact Megan at the email address above.

Cerebellar contributions to coordinated locomotion in mice

Gait ataxia, or uncoordinated walking, is one of the most prominent symptoms of cerebellar damage, but the mechanisms through which the cerebellum contributes to coordinated locomotion are not well understood. Both ataxic mouse mutants and the sophisticated genetic tools available for manipulating neural circuits in mice have the potential to help shed light on this problem. However, analyses of mouse gait have typically lacked the kind of detail about the precision and timing of limb movements that would be required for a full analysis of coordination. We have built a custom video tracking system (LocoMouse) for measuring and analysing overground locomotion in freely walking mice. The LocoMouse system automatically detects the position of paws, snout, tail, and body centre in all three spatial dimensions with high spatiotemporal resolution. We have used this system to establish a quantitative framework for coordinated locomotion in mice (Machado et al. 2015). This approach allows us to identify specific, cerebellum-dependent features of locomotor coordination and to probe circuit mechanisms supporting complex, whole-body movements.

Neural mechanisms of locomotor adaptation

Locomotor patterns are constantly adapted for changing environments but the neural mechanisms underlying this basic form of learning are not well understood. Locomotor adaptation has been studied in humans using a motorized split-belt treadmill in which the limbs on opposite sides of the body move at different speeds. Subjects adapt to split-belt walking over time by changing spatial and temporal gait parameters, which show negative after- effects in post- adaptation. This type of motor learning is thought to involve the cerebellum, as previous studies have indicated that patients with cerebellar lesions cannot adapt to the perturbation (Morton & Bastian, 2006). However, the circuit mechanisms within the cerebellum that support this adaptation are not known. We have built a split-belt treadmill for mice and are using it in combination with genetic and electrophysiological tools to investigate the neural basis of locomotor adaptation.

Behavioral state modulation of associative learning in mouse cerebellum

Delay eyeblink conditioning is a relatively simple form of cerebellum-dependent associative learning. Recent work has demonstrated, however, that neither the learned behavior nor its underlying neural circuitry are as simple as once thought. We have recently found that locomotor activity modulates delay eyeblink conditioning through mechanisms that act on the mossy fiber pathway within the cerebellar cortex. These results suggest a novel role for behavioral state modulation in associative learning and provide a potential mechanism through which engaging in movement can improve an individual’s ability to learn. Ongoing experiments are investigating the mechanisms and consequences of this modulation.

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

Biography

Ana Gonçalves
2016 INDP PhD Student
ana.goncalves@neuro.fchampalimaud.org

Ana Machado, PhD
Postdoctoral Researcher
ana.machado@neuro.fchampalimaud.org

Catarina Albergaria, PhD
2011 INDP PhD Student
catarina.albergaria@neuro.fchampalimaud.org

Catarina Almeida
Research Technician
catarina.almeida@research.fchampalimaud.org

Dana Darmohray
2012 INDP PhD Student
dana.darmohray@neuro.fchampalimaud.org

Hugo Marques, PhD
Postdoctoral Researcher
hugo.marques@neuro.fchampalimaud.org

Jorge Ramírez, PhD
Postdoctoral Researcher
jorge.ramirez@research.fchampalimaud.org

Jovin Jacobs
2013 INDP PhD Student
jovin.jacobs@neuro.fchampalimaud.org

Marta Maciel
Masters Student
marta.maciel@research.fchampalimaud.org

Rita Félix
2012 INDP PhD Student
rita.felix@neuro.fchampalimaud.org

Tatiana Silva
2014 INDP PhD Student
tatiana.silva@neuro.fchampalimaud.org

Virginia Casasnovas
Research Technician
virginia.casasnovas@research.fchampalimaud.org

Lab Administration

Margarida Nunes
Lab Administrator
margarida.nunes@research.fchampalimaud.org

Machado AS, Marques HG, Duarte DF, Darmohray DM, Carey MR (2020) Shared and specific signatures of locomotor ataxia in mutant mice eLife

Darmohray DM, Jacobs JR, Marques HG, Carey MR (2019) Spatial and Temporal Locomotor Learning in Mouse Cerebellum Neuron (doi:10.1016/j.neuron.2019.01.038)

Albergaria C; Silva NT; Pritchett DL; Carey MR (2018) Locomotor activity modulates associative learning in mouse cerebellum Nat. Neurosci. (doi:10.1038/s41593-018-0129-x)

Correia PA, Lottem E, Banerjee D, Machado AS, Carey MR, Mainen ZF (2017) Transient inhibition and long-term facilitation of locomotion by phasic optogenetic activation of serotonin neurons eLife , pii: e20975 (doi:10.7554/eLife.20975)

Machado AS, Darmohray DM, Fayad J, Marques HG, Carey MR. (2015) A quantitative framework for whole-body coordination reveals specific deficits in freely walking ataxic mice. eLife (doi:10.7554/eLife.07892)

Pritchett DL, Carey MR (2014) A matter of trial and error for motor learning Trends Neurosci. 37 (9), 465–466 (doi:10.1016/j.tins.2014.08.001)

Catarina Albergaria, Megan R Carey (2014) Neural circuits: All Purkinje cells are not created equal eLife (3), e03285 (doi:10.7554/eLife.03285)

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