Grant: Discovery Grants Program - Individual

Importance: Synaptic plasticity underlies learning in the mammalian brain. Mastering actions that benefit the learner is crucial, and requires associating the new action with a beneficial outcome, then consolidating the series of movements required to produce that outcome. My lab seeks to understand molecular/cellular mechanisms underlying skilled motor learning. Evidence suggests a key site for this is plasticity at synapses between glutamate-releasing cortical neurons and striatal projection neurons. My lab has uncovered mechanisms of synaptic plasticity in brain slice and neuronal culture, and begun to explore dynamic changes at corticostriatal synapses after motor learning in mice. We and others showed that endocannabinoids (eCBs) - modulatory transmitters that suppress release of fast neurotransmitters like glutamate (GLU) - mediate forms of synaptic plasticity in ex vivo brain slice. However, the role of changes in GLU release and eCBs in specific brain regions at different stages of motor learning, and relationship to synaptic plasticity in brain slice from untrained animals, remain a gap in knowledge. Investigating these questions is enabled by advanced imaging techniques and optogenetic probes, tools we have embraced in our program of research. Our recent work developing automated home-cage operant motor learning platforms facilitates linking dynamic changes in brain connections with behavioural outcomes. Theory: The long-term goal is to discover mechanisms of corticostriatal synaptic plasticity underpinning motor learning in mice. I hypothesize that eCB control of plasticity at corticostriatal synapses is a key contributor to how the brain learns motor skills and adapts to compensate for unexpected perturbations. We will compare two skilled motor learning tasks - rotarod and lever-pull for reward, in these three 5-year goals: Objective 1: Monitor striatal GLU and eCB levels in vivo during stages of skilled motor learning, and determine whether modulating eCB levels alters this learning. Objective 2: Investigate a potential link between eCB release and corticostriatal synaptic plasticity at different stages of motor learning, using ex vivo slice recording and imaging. Objective 3: Develop an automated, home-cage reward-based motor learning task that includes a component requiring cognitive/motor flexibility to compensate for sudden perturbations. Impact: I expect this research program to train >14 HQP and enhance understanding of fundamental mechanisms of learning motor skills. My program will determine the contribution of presynaptic plasticity (regulation of cortical GLU release to striatum) including the role of eCBs, adding fundamental knowledge of how the brain encodes goal-directed learning and skill acquisition. I will train the next generation of HQP in state-of-the-art techniques to study dynamic changes in brain connectivity during motor learning and development of automated behavioural assessment tools.