Neurogenetic Analysis of a Visual Working Memory in Drosophila melanogaster

除了简单的反射之外，动物的适应性行为是无法想象的，如果它们没有记住外部刺激、自己的行为及其后果的能力。昆虫在一次短途旅行中采用不同的策略，以找到返回巢穴或起点。例如，自己的位置可以存储在一个参考点，并在一个地标从视野中消失的情况下自动更新。事实上，我们已经在遗传模式生物黑腹果蝇中发现了这种视觉定向的工作记忆。对大脑结构突变体椭圆体开放（ebo）的分析使我们认为果蝇中央脑的椭球体是与定向记忆相关的结构。对ebo突变体的分子分析表明，转录激活因子血清反应因子（dSRF）的果蝇同源性对于成年椭球体的功能性工作记忆至关重要。此外，觅食编码的cGMP调节蛋白激酶（PKG）和无知编码的S6激酶II （RSK2）在果蝇椭球体环状神经元的共同通路中都是必不可少的。遗传相互作用研究表明，觅食PKG正调控无知激酶的活性。本基金申请的目标是利用遗传学和神经解剖学方法以及行为生理学来详细了解果蝇的视觉定向记忆。我们的目标是解开完整的信号转导途径，其中两种蛋白激酶共同作用。初步结果表明，转录激活因子CREB （cAMP响应元件结合蛋白）及其靶基因构成了这一途径的终点。对于神经元来说，各自的基因表达似乎是不可避免的，因为它们能够保持仅仅几秒钟的记忆；它的瞬态底物还有待确定。此外，我们旨在了解转录因子dSRF与PKG-RSK2信号通路之间的相互作用。总体目标是揭示学习的基本分子机制，特别是短期工作记忆的分子机制，这需要从急性视觉信息中建立方位记忆。我们期望发现，至少在一定程度上，与那些控制嗅觉条件作用的短期、中期和长期记忆形式相比，新的和可替代的原理和信号传导途径。

Apart from simple reflexes adaptive behavior of animals is not imaginable without their ability to remember external stimuli, own actions and the consequences thereof. Insects employ different strategies during an excursion in order to find back to a nest or just their starting point. For instance, the own position can be stored in relation to a point of reference and updated idiothetically in cases where a landmark gets out of view. Indeed, we have identified such a working memory for visual orientation in the genetic model organism Drosophila melanogaster. Analysis of the brain structure mutant ellipsoid-body open (ebo) led us to the ellipsoid body in the central brain of Drosophila as the relevant structure for the orientation memory. Molecular analysis of the ebo mutant showed that the Drosophila ortholog of the transcription activator Serum Response Faktor (dSRF) is essential for a functional working memory in the adult ellipsoid body. Moreover, the cGMP regulated protein kinase (PKG) encoded by foraging and the S6 Kinase II (RSK2) encoded by ignorant are both essential in a common pathway in the ring neurons of the Drosophila ellipsoid body. Genetic interaction studies indicate that foraging PKG positively regulates the activity of the ignorant kinase. It is the goal of this grant application to understand the visual orientation memory of Drosophila in detail using genetic and neuroanatomical methods as well as behavioral physiology. We aim to unravel the complete signal transduction pathway in which both protein kinases act together. First results indicate that the transcription activator CREB (cAMP responsive element binding protein) and its target genes form the endpoint of this pathway. The respective gene expression seems inevitable for the neurons to be able to hold this memory of just a few seconds; its transient substrate remains to be identified. In addition, we aim to understand the interaction between the transcription factor dSRF and the PKG-RSK2 signaling pathway. The overarching goal is to unravel the fundamental molecular mechanisms of learning and particularly those of a short-lived working memory, required to establish an orientation memory from acute visual information. We expect to find, at least in part, novel and alternative principles and signaling pathways as compared to those governing olfactory conditioning with its short-, middle-, and long-term memory forms.