Plasticity of Neuronal Function and Form in Drosophila

描述（由申请人提供）：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延续，通过阐明神经元功能和结构以及神经回路性能的相关修饰来弥合这两个水平方法之间的差距。神经元和神经回路的发育和功能可塑性将使用遗传，分子，形态学和生理学技术的组合进行分析，对一系列具有确定的分子缺陷的突变体。 cAMP水平（dnc和rut）和PKA激酶活性（DC 0，PKARI）的遗传改变导致学习障碍，而PKG活性（for）的自然变异与觅食行为模式相关。我们在这些第二信使通路突变体中证明了神经元放电模式和突触可塑性的改变，以及习惯化行为背后的异常过程。K通道控制神经元放电特性并影响突触传递。有趣的是，我们发现不同K通道亚基Sh、Rut、Hk和Eag的突变影响突触可塑性，并改变习惯化过程，通常与dnc、Rut和for一样极端，这表明K通道是神经元可塑性基础上的第二信使调节的潜在介质。作为学习基础的突触修饰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。不同的终端分支内的神经元乔木可以单独修改取决于当地的突触活动的信息处理。利用第二信使级联和K通道亚基缺陷的突变体，我们将剖析控制末端分支兴奋性和突触输出水平的机制和幼虫神经肌肉接头的时间。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，disabituation和敏化之间的分子差异，这还没有很好地建立起来。这些研究可以扩展我们对神经传递的精确性和幅度以及不同形式的行为可塑性的发展和细胞过程的了解，并可能为学习/记忆过程中的功能障碍提出新的治疗方法。

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.