Investigating corticostriatal synaptic plasticity in motor learning

重要性：突触的可塑性是哺乳动物大脑学习的基础。掌握有利于学习者的行动是至关重要的，需要将新的行动与有益的结果联系起来，然后巩固产生该结果所需的一系列动作。我的实验室试图了解熟练运动学习背后的分子/细胞机制。有证据表明，谷氨酸释放皮质神经元和纹状体投射神经元之间突触的可塑性是这一现象的关键部位。我的实验室已经在脑片和神经元培养中发现了突触可塑性的机制，并开始探索小鼠运动学习后皮质纹状体突触的动态变化。我们和其他人证明了内源性大麻素(ECB)--抑制谷氨酸(GLU)等快速神经递质释放的调制递质--在体外脑片中介导了突触可塑性的形式。然而，在运动学习的不同阶段，特定脑区GLU释放和ECB的变化所起的作用，以及与未经训练的动物脑片突触可塑性的关系，仍然是一个知识空白。研究这些问题是通过先进的成像技术和光遗传学探测器实现的，我们在研究计划中采用了这些工具。我们最近开发的自动化家庭笼子操作运动学习平台有助于将大脑连接的动态变化与行为结果联系起来。理论：长期目标是发现支持小鼠运动学习的皮质纹状体突触可塑性的机制。我推测，欧洲央行对皮质纹状体突触可塑性的控制是大脑学习运动技能和适应意外干扰的关键因素。在这三个五年目标中，我们将比较两种熟练的运动学习任务-旋转和杠杆-拉动奖励：目标1：在熟练的运动学习阶段监测体内纹状体GLU和ECB水平，并确定调节ECB水平是否改变这种学习。目的：利用体外脑片记录和成像技术，研究运动学习不同阶段大脑皮质纹状体突触可塑性与ECB释放之间的关系。目标3：开发一个自动化的、基于家庭笼子奖励的运动学习任务，其中包括一个需要认知/运动灵活性来补偿突然干扰的组成部分。影响：我希望这项研究计划将培训14名HQP，并加强对学习运动技能的基本机制的理解。我的程序将确定突触前可塑性(调节纹状体皮质GLU释放)的贡献，包括ECB的作用，增加大脑如何编码目标导向学习和技能获得的基础知识。我将对下一代HQP进行最先进的技术培训，以研究运动学习期间大脑连接的动态变化，并开发自动行为评估工具。

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.