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

基本信息

  • 批准号:
    7590708
  • 负责人:
  • 金额:
    $ 30.26万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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,这在一生中学习和存储信息的能力中是显而易见的。一般认为,记忆储存依赖于突触强度的变化,如长时程增强(LTP)和长时程抑制(LTD)。例如,Marr-Albus-Ito理论认为小脑运动学习是由LTD在浦肯野细胞上的平行纤维(PF)突触介导的。PF-LTP可能作为逆转机制发挥作用(Jvrntell和Hansel,2006)。“突触记忆”最适合作为细胞学习相关物,因为它们依赖于经验,并且可以是突触特异性的,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,这一点变得越来越清楚。已经描述了内在可塑性的形式(神经元兴奋性的改变),并且也可能在信息存储中起作用(Hansel等人,2001; Zhang和林登,2003;弗里克和约翰斯顿,2005)。但是内在可塑性是如何与LTD和LTP相互作用的,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至关重要的优势是,底层电路简单且特征良好,这在研究信息存储中不同类型可塑性的相互作用时很有帮助(Hansel et al.,2001年)。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,这取决于蛋白磷酸酶(PP 1/2A和PP 2B)的激活,并部分介导的SK型钙敏感性K通道的下调。我们观察到,增强的兴奋性upregulates浦肯野细胞的自发放电,这并不改变目标DCN神经元的强直性放电率,但降低PF突触对浦肯野细胞的影响,通过降低信噪比。在这里,我们提出了四个具体的目标,以进一步表征浦肯野细胞的内在可塑性。首先,我们计划研究参与兴奋性变化诱导的信号级联,包括钙信号,磷酸酶和激酶(包括使用突变小鼠缺乏PKC,1CaMKII和PP 2B,分别)。其次,我们计划寻找其他类型的离子通道(旁边的SK通道)介导的兴奋性增强。第三,我们希望研究浦肯野细胞兴奋性的增强是否随后改变树突状细胞和棘中的钙信号(使用共聚焦显微镜),并影响LTD / LTP诱导的概率。第四,使用体-树突双修补和钙成像的组合,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,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遗传改变的小鼠(SK通道转基因小鼠和PP 2B敲除小鼠),以研究小脑运动学习中内在可塑性的作用。公共卫生相关性人们普遍认为,学习和记忆是由突触传递功效的长期改变介导的,如长时程增强(LTP)和长时程抑制(LTD)。触发LTP和LTD的信号级联的异常可导致学习缺陷,例如在小脑共济失调中,运动协调和运动学习的微调受到干扰。在这里,我们建议表征一种新型的非突触可塑性,这是与小脑浦肯野细胞的内在膜兴奋性增加,并描述其参与运动学习(和相关的小脑学习缺陷)。

项目成果

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会议论文数量(0)
专利数量(1)

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Christian Robert Hansel其他文献

Christian Robert Hansel的其他文献

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{{ truncateString('Christian Robert Hansel', 18)}}的其他基金

Multiple climbing fiber innervation of Purkinje cells in the adult cerebellum
成人小脑浦肯野细胞的多重攀爬纤维神经支配
  • 批准号:
    10315621
  • 财政年份:
    2021
  • 资助金额:
    $ 30.26万
  • 项目类别:
The effects of alcohol on cerebellar synaotic transmission and plasticity
酒精对小脑突触传递和可塑性的影响
  • 批准号:
    7753907
  • 财政年份:
    2009
  • 资助金额:
    $ 30.26万
  • 项目类别:
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:
    10532150
  • 财政年份:
    2008
  • 资助金额:
    $ 30.26万
  • 项目类别:
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:
    8807947
  • 财政年份:
    2008
  • 资助金额:
    $ 30.26万
  • 项目类别:
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:
    10057278
  • 财政年份:
    2008
  • 资助金额:
    $ 30.26万
  • 项目类别:
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:
    9244852
  • 财政年份:
    2008
  • 资助金额:
    $ 30.26万
  • 项目类别:
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:
    10311479
  • 财政年份:
    2008
  • 资助金额:
    $ 30.26万
  • 项目类别:
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
  • 财政年份:
    2008
  • 资助金额:
    $ 30.26万
  • 项目类别:
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:
    8694825
  • 财政年份:
    2008
  • 资助金额:
    $ 30.26万
  • 项目类别:
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:
    9043954
  • 财政年份:
    2008
  • 资助金额:
    $ 30.26万
  • 项目类别:

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