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）：大脑的标志性特征之一是其巨大的可塑性，这在整个生命周期的学习和存储信息的能力中很明显。通常假定记忆存储基于突触强度的变化，例如长期增强（LTP）和长期抑郁症（LTD）。例如，Marr-Albus-Ito理论表明，小脑运动学习是由LTD在平行纤维（PF）突触上介导的Purkinje细胞上的。 PF-LTP可能是一种逆转机制（Jvrntell and Hansel，2006）。 “突触记忆”最适合于蜂窝学习相关，因为它们是经验依赖性的，并且可以特定于突触，从而可以选择性信息存储。但是，在过去的几年中，显然突触可塑性并不是现场的唯一玩家。已经描述了内在可塑性（神经元兴奋性的改变）的形式，并且可能也可能在信息存储中发挥作用（Hansel等，2001； Zhang和Linden，2003； Frick和Johnston，2005）。但是，内在可塑性如何与LTD和LTP相互作用，并且它在学习和记忆中起什么作用？我们计划在小脑Purkinje细胞中解决这些问题。小脑在学习研究中的关键优势是，基础电路是简单且特征良好的，在研究信息存储中不同类型的可塑性的相互作用时，这很有帮助（Hansel等，2001）。我们的初步数据表明，浦肯野细胞兴奋性的活性依赖性增加，这取决于蛋白质磷酸酶的激活（PP1/2A和PP2B），并部分由SK型钙敏感K通道的下调部分介导。我们观察到，增强的兴奋性上调了Purkinje细胞中自发的尖峰发射，这不会改变靶DCN神经元的刺激性尖峰速率，但通过降低信号透射率的比率降低了PF突触对Purkinje细胞的影响。在这里，我们提出了四个特定的目标，以进一步表征浦肯野细胞的内在可塑性。首先，我们计划检查参与诱导兴奋性变化的信号传导级联反应，包括钙信号传导，磷酸酶和激酶（包括分别在PKC，1CAMKII和PP2B中使用突变小鼠）。其次，我们计划搜索介导兴奋性增强的其他类型的离子通道（SK通道旁边）。第三，我们希望检查Purkinje细胞兴奋性的增强是否会随后改变树突状轴和脊柱中的钙信号传导（使用共聚焦显微镜），并影响LTD / LTP诱导的概率。第四，使用somato树枝状双绘制和钙成像的组合，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，旨在揭示（运动）学习的潜在机制，并开发出一种新型模式，以治疗运动缺陷和记忆障碍。为此，我们还将在行为学习任务中测试遗传改变的小鼠（SK通道转基因和PP2B敲除），以研究内在可塑性在小脑运动学习中的作用。公共卫生相关性是人们普遍认为，学习和记忆是由长期变化的长期变化（例如长期增强（LTP）和长期抑郁症（LTD））介导的。信号传导级联触发LTP和LTD的异常会导致学习缺陷，例如小脑共济失调，其中运动配位和运动学习的精细调整受到干扰。在这里，我们建议表征一种新型的非突触可塑性，这与小脑Purkinje细胞的内在膜兴奋性的增加有关，并描述了其参与运动学习（以及相关的小脑学习缺陷）。