Intrinsic plasticity and information storage in cerebellar Purkinje cells

小脑浦肯野细胞的内在可塑性和信息存储

• 批准号: 7694361
• 负责人: Christian Robert Hansel
• 金额: $ 32.78万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7694361
• 关键词: Action Potentials; Address; Affect; Animals; Behavioral; Biology; Blinking; Brain; Calcineurin; Calcium; Calcium Channel; Calcium Signaling; Calcium Spikes; Cells; Cerebellar Ataxia; Cerebellum; Chelating Agents; Chemosensitization; Complement; Complex; Confocal Microscopy; Conotoxin; Data; Dendrites; Dimensions; Down-Regulation; Environment; Event; Fiber; Image; Information Storage; Injection of therapeutic agent; Ion Channel; Knockout Mice; Laboratories; Learning; Long-Term Depression; Long-Term Potentiation; Mediating; Membrane; Memory; Memory Disorders; Metaplastic; Mibefradil; Microscope; Modeling; Molecular; Monitor; Motor; Mus; Mutant Strains Mice; Neurons; Nimodipine; Noise; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Potassium Channel; Probability; Protein phosphatase; Purkinje Cells; Research; Rest; Rodent; Role; Signal Transduction; Slice; Sodium; Speed; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Tilia; Transgenic Mice; Transgenic Organisms; Vertebral column; attenuation; base; calmodulin-dependent protein kinase II; charge coupled device camera; conditioning; experience; iberiotoxin; inhibitor/antagonist; motor learning; mouse model; neural circuit; neuronal cell body; neuronal excitability; novel; patch clamp; promoter; public health relevance; research study; theories

DESCRIPTION (provided by applicant): One of the hallmark features of the brain is its enormous degree of plasticity, which is evident in the ability to learn and store information throughout lifetime. It is generally assumed that memory storage rests on changes in synaptic strength, such as long-term potentiation (LTP) and long-term depression (LTD). For example, Marr-Albus-Ito theories suggest that cerebellar motor learning is mediated by LTD at parallel fiber (PF) synapses onto Purkinje cells. PF-LTP might function as a reversal mechanism (Jvrntell and Hansel, 2006). "Synaptic memories" are optimally suited as cellular learning correlates, because they are experience-dependent and can be synapse-specific, allowing for selective information storage. However, over the last years it has become clear that synaptic plasticity is not the only player on the scene. Forms of intrinsic plasticity (alterations in neuronal excitability) have been described and might play a role in information storage as well (Hansel et al., 2001; Zhang and Linden, 2003; Frick and Johnston, 2005). But how does intrinsic plasticity interact with LTD and LTP, and what role does it play in learning and memory? We plan to address these questions in cerebellar Purkinje cells. A crucial advantage of the cerebellum in learning research is that the underlying circuitry is simple and well-characterized, which is helpful when studying the interaction of different types of plasticity in information storage (Hansel et al., 2001). Our preliminary data demonstrate an activity-dependent increase in Purkinje cell excitability, which depends on the activation of protein phosphatases (PP1/2A and PP2B) and is partially mediated by a down-regulation of SK-type calcium-sensitive K channels. We observed that the enhanced excitability upregulates spontaneous spike firing in Purkinje cells, which does not alter the tonic spike rate of the target DCN neurons, but lowers the impact of PF synapses onto Purkinje cells by reducing the signal-to-noise ratio. Here, we propose four specific aims to further characterize Purkinje cell intrinsic plasticity. First, we plan to examine the signaling cascades involved in the induction of excitability changes, including calcium signaling, phosphatases and kinases (including the use of mutant mice deficient in PKC, 1CaMKII and PP2B, respectively). Second, we plan to search for additional types of ion channels (next to SK channels) mediating the excitability enhancement. Third, we wish to examine whether this potentiation of Purkinje cell excitability subsequently alters calcium signaling in dendritic shafts and spines (using confocal microscopy) and affects the probabilities for LTD / LTP induction. Fourth, using a combination of somato-dendritic double-patching and calcium imaging, we plan to determine the spatial dimension of excitability changes. The suggested project is part of our long-term objective to reveal underlying mechanisms of (motor) learning and to develop novel modes for the treatment of motor learning deficits and memory disorders in general. To this end, we will also test genetically altered mice (SK channel transgenics and PP2B knock-outs) in behavioral learning tasks to study the role of intrinsic plasticity in cerebellar motor learning. PUBLIC HEALTH RELEVANCE it is widely believed that learning and memory are mediated by long-term alterations in the efficacy of synaptic transmission, such as long-term potentiation (LTP) and long-term depression (LTD). Abnormalities in the signaling cascades triggering LTP and LTD can cause learning deficits, such as in cerebellar ataxias, in which the fine-adjustment of motor coordination and motor learning are disturbed. Here, we suggest to characterize a novel type of non-synaptic plasticity, which is associated with an increase in the intrinsic membrane excitability of cerebellar Purkinje cells, and to describe its involvement in motor learning (and related cerebellar learning deficits).

描述(由申请人提供)：大脑的一个标志性特征是其巨大的可塑性，这在一生学习和存储信息的能力中显而易见。一般认为，记忆存储依赖于突触强度的变化，如长时程增强(LTP)和长时程增强(LTD)。例如，Marr-Albus-Ito理论认为，小脑运动学习是由LTD在平行纤维(PF)突触到浦肯野细胞上介导的。PF-LTP可能起到逆转机制的作用(Jvrntell和Hansel，2006)。“突触记忆”最适合与细胞学习相关，因为它们依赖于经验，可以是突触特有的，允许选择性的信息存储。然而，在过去的几年里，突触可塑性并不是唯一的参与者。已经描述了内在可塑性的形式(神经元兴奋性的改变)，并可能在信息存储中发挥作用(Hansel等人，2001；Zhang和Linden，2003；Frick和Johnston，2005)。但内在可塑性如何与LTD和LTP相互作用，以及它在学习和记忆中扮演什么角色？我们计划在小脑浦肯野细胞中解决这些问题。小脑在学习研究中的一个关键优势是其基本电路简单且特征良好，这有助于研究信息存储中不同类型可塑性的相互作用(Hansel等人，2001)。我们的初步数据表明，浦肯野细胞兴奋性的增加依赖于活性，这依赖于蛋白磷酸酶(PP1/2A和PP2B)的激活，部分是由SK-型钙敏感K通道的下调介导的。我们观察到，兴奋性的增强上调了浦肯野细胞的自发放电，这不会改变靶DCN神经元的紧张性峰率，但通过降低信噪比来降低PF突触对浦肯野细胞的影响。在这里，我们提出了四个具体目标，以进一步表征浦肯野细胞的内在可塑性。首先，我们计划研究参与兴奋性变化诱导的信号级联反应，包括钙信号、磷酸酶和激酶(包括使用分别缺乏PKC、1CaMKII和PP2B的突变小鼠)。第二，我们计划寻找更多类型的离子通道(紧挨着SK通道)来调节兴奋性增强。第三，我们希望检验这种浦肯野细胞兴奋性的增强是否会随后改变树突茎和棘中的钙信号(使用共聚焦显微镜)，并影响LTD/LTP诱导的可能性。第四，结合体树突双斑贴和钙离子成像，我们计划确定兴奋性变化的空间维度。建议的项目是我们长期目标的一部分，目的是揭示(运动)学习的潜在机制，并开发治疗运动学习缺陷和记忆障碍的新模式。为此，我们还将在行为学习任务中测试基因改变的小鼠(SK通道转基因和PP2B基因敲除)，以研究内在可塑性在小脑运动学习中的作用。公众健康相关性人们普遍认为，学习和记忆是由突触传递效率的长期变化所调节的，如长时程增强(LTP)和长时程增强(LTD)。触发LTP和LTD的信号级联异常可导致学习障碍，如小脑性共济失调，其中运动协调和运动学习的微调受到干扰。在这里，我们建议描述一种新型的非突触可塑性，它与小脑浦肯野细胞固有的膜兴奋性增加有关，并描述它参与运动学习(以及相关的小脑学习障碍)。