Dendritic Integration and Cerebellar Synaptic Plasticity

描述（由申请人提供）：小脑是在所有脊椎动物中发现的脑结构，被认为具有许多感觉-运动协调功能。特别是，数十年的证据表明，小脑根据感觉输入指导运动学习。一个被认为涉及小脑的运动学习的实验室例子是一项任务，其中有条件刺激（如可听音）与无条件刺激（如向眼睛输送空气）相关联。最终，受试者学会了眨眼来回应单独播放的音调。为了学习发生，音调必须先出现，这表明小脑可以检测事件发生的顺序。在突触活动条件下，被认为是匹配这个任务的顺序依赖性，一个分子事件是小脑浦肯野神经元内钙离子的升高，钙离子是一种广泛使用的信号离子。反过来，钙又会诱导长期抑制，这是浦肯野神经元平行纤维突触的一种突触可塑性形式，可能是运动学习的基础。这个建议将测试以下的想法：（1）条件刺激信息通过平行的纤维突触是由化学信使肌醇-1，4，5-三磷酸（IP 3）编码。(2)通过攀爬纤维突触传递的无条件刺激信息是由在动作电位过程中进入的少量启动钙编码的。(3)当产生IP 3和启动钙时，小脑中的突触产生大量的钙从内部储存释放。(4)在钙信号传导中看到的顺序依赖性是由IP 3、钙和钙释放机制中的动力学引起的。这一假设将使用多光子激光扫描荧光显微镜进行测试，该技术允许在单个突触处测量钙信号;和光敏“笼状”化合物，其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发生在毫秒到秒的时间尺度上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的缺陷。

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.