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，涉及运动学习和行为。本研究计划的目的是阐明小脑输出的小脑核突触可塑性的细胞机制。这项研究将支持理解小脑依赖行为中学习和记忆的细胞机制这一更广泛的长期目标。损伤研究表明，核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。我们建议研究苔藓纤维突触可塑性的两种不同形式-增强和抑制-如何在单个神经元水平上协调。这些相反形式的突触可塑性是在传入刺激模式下产生的，这些传入刺激模式只是略有不同，因此可能至少部分地集中在相同的信号通路上。具体来说，增强发生在同时兴奋和抑制之后，而抑制发生在单独兴奋之后。增强方案中对抑制的要求将这种形式的可塑性与大脑其他地方的研究区分开来，因此有望拓宽我们对突触可塑性如何在不同神经元细胞类型中产生的理解。我们的具体目标是机械组织的h/vo水平：酶信号和递质受体传递到突触。整个细胞的电压和电流钳记录来自急性小鼠大脑切片准备中的神经元，并使用电刺激来引发突触电流。各种药物将被用来测试分子级联介导可塑性的作用。公共卫生相关性：一些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智力迟钝。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。通过靶向与细胞功能相关的特定酶和蛋白质，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.