Synaptic plasticity in the cerebellar nuclei

描述(申请人提供)：小脑是一个高度保守的大脑结构，与运动学习和行为有关。这项研究计划的目的是阐明小脑输出核团突触可塑性的细胞机制。这项研究将支持更广泛的长期目标，即了解小脑依赖行为中学习和记忆的细胞机制。损伤研究表明，这些核团是学习和记忆的场所，特别涉及携带感觉信息的苔藓纤维传入。我们建议研究两种不同形式的苔藓纤维突触可塑性-增强和抑制-是如何在单个神经元水平上协调的。这些相反形式的突触可塑性是在传入刺激模式下产生的，这些模式只是略有不同，因此可能至少部分汇聚在相同的信号通路上。具体地说，兴奋和抑制同时发生后，增强作用才出现，而抑制作用仅在激发后发生。增强方案中对抑制的要求使这种形式的可塑性有别于大脑其他地方研究的其他形式，因此有望拓宽我们对不同类型神经细胞如何产生突触可塑性的理解。我们的特定目标是针对h/vo水平的机械性组织：酶信号和递质受体递送到突触。全细胞电压和电流钳记录是从急性小鼠脑片制备的神经元中获得的，并使用电刺激来诱发突触电流。各种药理学试剂将被用来测试分子级联调节可塑性的作用。公共卫生相关性：几种人类病理与小脑功能障碍有关，如共济失调、肌张力障碍、自闭症和某些形式的精神发育迟缓。了解小脑回路是如何支持健康行为的，对于破译神经病理的根源至关重要。通过靶向可能构成行为基础的细胞功能所涉及的特定酶和蛋白质，我们为将基因突变与可观察到的病理联系起来奠定了基础。

DESCRIPTION (provided by applicant): The cerebellum is a highly conserved brain structure involved in motor learning and behavior. The aim of this research proposal is to elucidate the cellular mechanisms underlying synaptic plasticity in the cerebellar nuclei, the output of the cerebellum. This research will support the broader long-term goal of understanding the cellular mechanisms of learning and memory in cerebellum-dependent behaviors. Lesion studies suggest that the nuclei are a locus of learning and memory which specifically involve mossy fiber afferents carrying sensory information. We propose to investigate how two disparate forms of mossy fiber synaptic plasticity - potentiation and depression - are coordinated at the level of single neurons. These opposing forms of synaptic plasticity are generated following afferent stimulation patterns that differ only slightly, and thus likely converge on at least partly the same signaling pathways. Specifically, potentiation follows coincident excitation and inhibition while depression occurs after excitation alone. The requirement for inhibition in the potentiation protocol sets this form of plasticity apart from others investigated elsewhere in the brain and therefore promises to broaden our understanding of how synaptic plasticity is generated across different neuronal cell types. Our specific aims target h/vo levels of mechanistic organization: enzymatic signaling and transmitter receptor delivery to synapses. Whole cell voltage- and current-clamp recordings are made from neurons in an acute mouse brain slice preparation and electrical stimulation is used to elicit synaptic currents. Various pharmacological agents will be used to test the roles of molecular cascades mediating plasticity. PUBLIC HEALTH RELEVANCE: Several human pathologies are linked to cerebellar dysfunction such as ataxias, dystonias, autism and some forms of mental retardation. Understanding how cerebellar circuitry supports healthy behavior is essential to decipher the roots of neural pathologies. By targeting specific enzymes and proteins involved in a cellular function that likely underlies behavior, we lay the groundwork for linking gene mutations to observable pathologies.