Dendritic Integration and Cerebellar Synaptic Plasticity

描述（申请人提供）：小脑是所有脊椎动物的大脑结构，被认为具有许多感觉-运动协调功能。特别是，几十年的证据表明，小脑指导基于感觉输入的运动学习。一个被认为与小脑有关的运动学习的实验室例子是这样一个任务，在这个任务中，一个条件刺激（如可听到的音调）与一个无条件刺激（如向眼睛吹气）相关联。最终，受试者学会对单独播放的音调做出眨眼反应。要使学习发生，声调必须是第一位的，这表明小脑可以检测到事件发生的顺序。在被认为与这一任务的顺序依赖性相匹配的突触活动条件下，一个分子事件是小脑浦肯野神经元内钙的升高，钙是一种广泛使用的信号离子。反过来，钙诱发长期抑郁，这是浦肯野神经元平行纤维突触的一种突触可塑性，可能是运动学习的基础。本研究将验证以下观点：(1)通过平行纤维突触传入的条件刺激信息由化学信使肌醇-1,4,5-三磷酸（IP3）编码。(2)通过攀爬纤维突触传递的无条件刺激信息被少量的启动钙编码，并在动作电位期间进入。(3)当IP3和启动钙同时产生时，小脑突触从内部储存中产生大量的钙释放。(4)钙信号的顺序依赖性是由IP3、钙和钙释放机制的动力学引起的。这一假设将使用多光子激光扫描荧光显微镜进行验证，这种技术可以在单个突触上测量钙信号；以及光敏“笼”化合物，可用于控制小脑浦肯野神经元中的生化事件。这些实验将提供关于突触可塑性和运动学习过程中在毫秒到秒的时间尺度上发生的分子事件的关键基础知识，并可能最终有助于理解小脑功能缺陷。

DESCRIPTION (provided by applicant): The cerebellum, a brain structure found in all vertebrates, is thought to serve many sensory-motor coordinating functions. In particular, decades of evidence suggest that the cerebellum guides motor learning based on sensory inputs. One laboratory example of motor learning thought to involve the cerebellum is a task in which a conditional stimulus, such as an audible tone, is associated with an unconditional stimulus, such as an airpuff delivered to the eye. Eventually the subject learns to blink in response to the tone played alone. For learning to occur the tone must come first, suggesting that the cerebellum can detect the order in which events occur. Under synaptic activity conditions thought to match the order-dependence of this task, one molecular event is elevation of calcium, a widely used signaling ion, inside cerebellar Purkinje neurons. Calcium, in turn, induces long-term depression, a form of synaptic plasticity at parallel fiber synapses to the Purkinje neuron that may underlie motor learning. This proposal will test the following ideas: (1) Conditional stimulus information coming in through parallel fiber synapses is encoded by the chemical messenger inositol-1,4,5-trisphosphate (IP3). (2) Unconditional stimulus information coming through the climbing fiber synapse is encoded by a small amount of priming calcium that enters during the action potential. (3) Synapses in the cerebellum generate large amounts of calcium release from internal stores when both IP3 and priming calcium are generated. (4) The order-dependence seen in calcium signaling is caused by dynamics in IP3, calcium, and calcium release mechanisms. This hypothesis will be tested using multiphoton laser scanning fluorescence microscopy, a technique that allows calcium signals to be measured at single synapses; and light-sensitive "caged" compounds, which can be used to control biochemical events in cerebellar Purkinje neurons. These experiments will provide crucial basic knowledge regarding the molecular events that occur on a time scale of milliseconds to seconds during synaptic plasticity and motor learning, and may eventually help in understanding defects in cerebellar function.