Dendritic Integration and Cerebellar Synaptic Plasticity

描述(申请人提供)：小脑，一种在所有脊椎动物中发现的大脑结构，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，小脑在感觉输入的基础上引导运动学习。一个被认为涉及小脑的运动学习的实验室例子是一个任务，在这个任务中，一个条件刺激，如可听得见的音调，与一个无条件刺激有关，如送到眼睛的喷气。最终，受试者学会了对单独演奏的音调做出反应而眨眼。为了学习发生，音调必须是第一位的，这表明小脑可以检测到事件发生的顺序。在被认为与这项任务的顺序依赖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广泛使用的信号离子钙的升高。钙反过来会导致长期抑郁，这是一种形式的突触可塑性，位于与浦肯野神经元平行的纤维突触上，可能是运动学习的基础。这一提议将检验以下想法：(1)通过平行纤维突触进入的条件刺激信息由化学信使三磷酸肌醇(IP3)编码。(2)来自攀升纤维突触的无条件刺激信息是由动作电位过程中进入的少量启动钙编码的。(3)当IP3和启动钙同时产生时，小脑中的突触从内部储备处产生大量的钙释放。(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(一种允许在单个突触上测量钙信号的技术)和光敏的“笼式”化合物来验证，这种化合物可以用来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，并最终可能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.