Plasticity of Neuronal Function and Form in Drosophila

描述(申请人提供)：果蝇的神经遗传学研究对我们理解各种形式的行为可塑性和潜在的分子机制做出了很大贡献。这个项目是我们长期努力的继续，通过阐明神经元功能和结构以及神经电路性能的相关修改来弥合这两个水平的方法之间的差距。神经和神经回路的发育和功能可塑性将使用遗传、分子、形态和生理技术的组合，对一组已发现分子缺陷的突变体进行分析。 CAMP水平(DNC和RUT)和PKA激酶活性(DC0，PKARI)的遗传变化会导致学习障碍，而PKG活性的自然变异(For)与觅食行为模式有关。在这些第二信使通路突变中，我们证明了神经元放电模式和突触可塑性的改变，以及习惯性行为的异常过程。K通道控制神经元的放电特性，影响突触传递。有趣的是，我们发现不同K通道亚基Sh、Slo、HK和EAG的突变对突触可塑性的影响和习惯化过程的改变与DNC、RUT和For一样频繁，这表明K通道是神经元可塑性背后的第二信使调节的潜在中介。学习的基础突触修改依赖于神经元之间突触前和突触后活动的精确时间相关性。根据信息处理的局部突触活动，神经元树枝内的不同终末分支可以被单独修改。利用第二信使级联缺陷突变体和K通道亚基，我们将剖析幼虫神经肌肉接头中控制末梢支兴奋性和突触输出水平和时序的机制。我们将进一步发展行为和生理范式来研究成人逃避反射回路中的这两类突变，以揭示非关联条件反射过程、习惯化、去习惯化和敏化之间的分子差异，这些过程尚未得到很好的确立。这类研究可以扩展我们对神经传递的精确度和幅度以及不同形式的行为可塑性背后的发育和细胞过程的知识，并可能为学习/记忆过程中的功能障碍提供新的治疗方法。

DESCRIPTION (provided by applicant): Neurogenetic studies in Drosophila have contributed much to our understanding of the various forms of behavioral plasticity and the underlying molecular mechanisms. This project is a continuation of our long-term efforts to bridge the gap between these two levels of approach by elucidating the associated modification in neuronal function and structure and in neural circuit performance. Developmental and functional plasticity of neurons and neural circuits will be analyzed using a combination of genetic, molecular, morphological and physiological techniques on a collection of mutants with identified molecular defects. Genetic alterations of cAMP levels (dnc and rut) and PKA kinase activity (DC0, PKARI) cause learning disabilities, while naturally occurring variants in PKG activity (for) correlate with patterns of foraging behavior. We demonstrated in these second messenger pathway mutants altered neuronal firing pattern and synaptic plasticity, as well as abnormal processes underlying habituation behavior. K channels control neuronal firing properties and affect synaptic transmission. Interestingly, we found that mutations of different K channel subunits, Sh, slo, Hk and eag, affect synaptic plasticity and alter the habituation process often as extremely as dnc, rut, and for, suggesting that K channels are potential mediators of second messenger modulation underlying neuronal plasticity. Synaptic modification underlying learning relies on precise temporal correlations of the pre- and post-synaptic activities between neurons. Different terminal branches within a neuronal arbor can be separately modified depending on local synaptic activities for information processing. Using mutants defective in second messenger cascades and K channel subunits, we will dissect the mechanisms controlling terminal branch excitability and synaptic output level and timing in the larval neuromuscular junction. We will further develop behavioral and physiological paradigms to study these two categories of mutations in the adult escape reflex circuit to reveal molecular distinctions among the non-associative conditioning processes, habituation, dishabituation, and sensitization, which have not been well established. Such studies can extend our knowledge of the developmental and cellular processes underlying the precision and amplitude of neurotransmission and different forms of behavioral plasticity, and may suggest new therapeutical approaches to dysfunction in learning/memory processes.