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
• 负责人: Christian Robert Hansel
• 金额: $ 47.45万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057278
• 关键词: Apamin; Auditory; Axon; Calcineurin; Calcium; Calcium Signaling; Calcium Spikes; Cells; Cerebellar Nuclei; Cerebellum; Chemosensitization; Closure by clamp; Complement; Conditioned Reflex; Conditioned Stimulus; Dendrites; Depressed mood; Disinhibition; Dissection; Event; Excitatory Postsynaptic Potentials; Eyelid structure; Fiber; Funding; Generations; Glutamates; Hippocampus (Brain); Image; Impairment; In Vitro; Information Storage; Interneurons; Knock-out; Laboratories; Learning; Light; Long-Term Depression; Long-Term Potentiation; Maps; Measurement; Measures; Mediating; Membrane; Membrane Potentials; Memory; Mental Depression; Modality; Modeling; Monitor; Motor output; Mus; Output; Pattern; Penetrance; Pharmacology; Potassium Channel; Prevalence; Process; Purkinje Cells; Rest; Role; Signal Transduction; Slice; Stimulus; Structure of molecular layer of cerebellar cortex; Structure of purkinje fibers; Supervision; Synapses; Techniques; Testing; Tilia; Time; Vibrissae; Visual; Weight; awake; base; calmodulin-dependent protein kinase II; classical conditioning; experience; experimental study; eyeblink conditioning; in vivo; in vivo calcium imaging; inhibitory neuron; metabotropic glutamate receptor 7; motor learning; neuronal cell body; place fields; prevent; regenerative; response; sensory input; teacher; theories; two-photon

Project Summary: Associative learning rests on the strengthening of synaptic inputs that show coincident activity over extended periods of time. A notable exception is provided by supervised associative learning in the cerebellum. Parallel fiber (PF) - Purkinje cell synapses, whose activity predicts a climbing fiber (CF)-mediated error signal, undergo long-term depression (LTD). Since Purkinje cells are inhibitory neurons, classic Marr-Albus-Ito theories of cerebellar function state that LTD at glutamatergic PF inputs causes disinhibition of target cells in the cerebellar nuclei, thus enabling motor learning. However, more recent evidence challenges the notion of LTD as the only, or the predominant, cellular mechanism underlying associative motor learning. For example, findings from our laboratory show that in mice Purkinje cell excitability is enhanced after eyeblink conditioning (delay EBC), and that mice with a Purkinje cell-specific knockout of SK2-type K+ channels show reduced EBC. SK2 channels are small conductance, calcium-dependent K+ channels that are downregulated in a form of non-synaptic (‘intrinsic’) plasticity, which enhances Purkinje cell excitability. Intrinsic plasticity is co-induced with long-term potentiation (LTP) at PF synapses. A scenario emerges, in which an intrinsic plasticity-assisted potentiation of those PF inputs that warn of an upcoming error signal (without contributing to it) enables EBC learning, possibly in parallel with depression at other PF synapses, whose activity continues to predict the error signal throughout learning. This scenario is in line with an adaptive filter model of cerebellar learning, in which bidirectional synaptic weight adjustment under supervision of a teacher signal is crucial for the fine-tuning of motor output. Here, we plan to use two-photon measurements of GCaMP6f-encoded, dendritic calcium signals in Purkinje cells of awake mice to test the hypothesis that during EBC the dendritic input map is restructuring. We predict that this map plasticity does not only consist of depression of response amplitudes at some PF synapses, but also the emergence of responses at other PF inputs, whose activity shifts from predicting the unconditioned stimulus (US; periorbital airpuff) to predicting the occurrence of the developing eyelid closure during EBC. We will examine how SK2-dependent intrinsic plasticity contributes to response strengthening, with a focus on possible roles of dendritic calcium spikes in synapse stabilization and clustering, motifs that have been identified as important cellular mechanisms in hippocampal place field formation. Using genetically modified mice with blockade of intrinsic plasticity (L7-SK2 knockout), LTP (L7-PP2B) and LTD (CaMKII T305D), respectively, we will further delineate the specific roles of these plasticity mechanisms in map re-organization and motor learning. Finally, using double-patch recordings from Purkinje cell dendrites and somata in vitro, we will examine the mechanisms of interaction between LTP and intrinsic plasticity that both seem to co-exist and complement each other in EBC. We will test the hypothesis that LTP stabilizes synaptic inputs, while intrinsic plasticity regulates synaptic penetrance, i.e. the predictive control of the EPSP amplitude over the spike output.

项目摘要： 联想学习依赖于突触输入的加强，这些突触输入显示出同步活动， 很长时间一个值得注意的例外是小脑中的监督联想学习。 平行纤维（PF）-浦肯野细胞突触，其活动预测攀爬纤维（CF）介导的错误信号， 长期抑郁症（LTD）由于浦肯野细胞是抑制性神经元，经典的Marr-Albus-Ito 小脑功能的理论认为，在小脑能PF输入时，LTD引起靶细胞的去抑制， 小脑核团，从而使运动学习。然而，最近的证据挑战了 LTD作为唯一的，或占主导地位的，细胞机制的联想运动学习。比如说， 我们实验室的研究结果表明，小鼠浦肯野细胞的兴奋性在眨眼条件反射后增强 （延迟EBC），并且具有SK 2型K+通道的浦肯野细胞特异性敲除的小鼠显示出降低的EBC。 SK2通道是小电导、钙依赖性K+通道，其以一种形式下调。 非突触（“内在”）可塑性，增强浦肯野细胞兴奋性。内禀塑性是共诱导的 在PF突触处具有长时程增强（LTP）。一个场景出现了，其中一个内在的可塑性辅助 增强那些警告即将到来的错误信号（而不会导致错误信号）的PF输入，从而启用EBC 学习，可能与其他PF突触的抑郁并行，其活动继续预测错误 信号贯穿学习始终。这种情况符合小脑学习的自适应滤波器模型，其中 在教师信号的监督下的双向突触权重调整对于 电机输出在这里，我们计划使用双光子测量GCaMP 6 f编码的树突状钙信号 在清醒小鼠的浦肯野细胞中，以检验在EBC期间树突输入图正在重构的假设。 我们预测，这种地图可塑性不仅包括在某些PF的反应幅度的抑郁症 突触，但也出现在其他PF输入的反应，其活动从预测 非条件刺激（US;眶周喷气）预测眼睑闭合的发生 在EBC期间。我们将研究SK2依赖的内在可塑性如何有助于反应强化， 重点是树突状钙峰在突触稳定和聚集中的可能作用， 已被确定为海马位置场形成的重要细胞机制。使用基因 阻断内在可塑性（L7-SK 2敲除）、LTP（L7-PP 2B）和LTD（CaMK II T305 D）的修饰小鼠， 我们将进一步阐明这些可塑性机制在地图重组中的具体作用 和运动学习。最后，利用离体浦肯野细胞树突和胞体的双斑记录， 将研究LTP和内在可塑性之间的相互作用机制，两者似乎共存， 在EBC中相互补充。我们将测试LTP稳定突触输入的假设，而内在的 可塑性调节突触的突触传递，即EPSP振幅对尖峰输出的预测控制。