Identifying Neural Substrates of Behavior in Drosophila Melanogaster

识别果蝇行为的神经基础

基本信息

项目摘要

Insect ecdysis sequences represent a simple, robust, and tractable model for studying the neuromodulatory mechanisms that govern behavior. Because initiation of an ecdysis sequence involves a profound shift in behavioral priorities, study of these sequences offers the opportunity to understand the neuromodulatory mechanisms that govern changes in behavioral state. In addition, because ecdysis behaviors are inherently sequential, they permit the systematic investigation of how motor programs are assembled and serially executed by the nervous system. Finally, the study of ecdysis sequences promises insight into how neural circuits can be variably configured to generate immensely different behaviors. In Drosophila, for example, the motor sequences performed at pupal and adult ecdysis are completely different. This is because of the profound differences in the pupal and adult body plans. Despite these anatomical differences, the two behavioral sequences are governed by a common set of neuromodulatory/hormonal inputs. By analogy to computing, these inputs can be regarded as instructions written in a higher programming language that are then compiled into different outputs. Exposing the mechanisms of neural compilation in ecdysis is likely to deeply inform our understanding of how neuromodulators contribute to neurocomputation by reconfiguring the activity of neural networks. To investigate these issues, my laboratory seeks to elucidate the circuitry that governs both the pupal and adult ecdysis sequences in Drosophila. Our efforts over the last year have been more or less evenly divided between study of these two circuits. In addition, we have completed development of a novel methodology for genetically targeting small subsets of neurons in the fly brain for manipulation. We are now applying this method to further fine-map neuronal circuits underlying adult ecdysis. With regard to pupal ecdysis, the work conducted over the past year has focused on describing the pupal ecdysis sequence at the highest possible level of resolution, namely the activity of each of the individual muscles of the animal. This work was motivated by the realization that if we are to understand in detail how the fly brain generates a pupal ecdysis sequence, we must first understand in detail what, exactly, it is generating. Using our previously derived map of the entire pupal musculature together with tools for monitoring muscle activity throughout the animal, we completed a comprehensive description of the pupal ecdysis sequence that spans multiple levels. Surprisingly, we found considerable stochasticity in muscle activation throughout the course of the behavior, but identified specific muscle ensembles with overlapping activity that form basic units of movement. A major observation was that release of the ecdysis hormones coincided with a reduction in variability of muscle activity and progressive changes in muscle ensemble identity. Ecdysis hormones also ensured behavioral coherence by coordinating muscle activity across multiple body axes. A manuscript describing this work is in preparation. Our study of the adult ecdysis circuit has focused on the action of two ecdysis hormones: Eclosion Hormone (EH) and Bursicon. Our research on EH resolved a long-standing discrepancy in the action of this hormone, which was previously thought to be expressed by only two large neuroendocrine cells in the fly brain. Paradoxically, ablation of these cells failed to block adult ecdysis even though the hormone itself appeared to be required for that process. Using the Trojan exon technology that we developed in 2015 (Diao et al., 2015, Cell Rep. 10:1410-21. doi: 10.1016/j.celrep.2015.01.059), we identified two small populations of EH-expressing neurons that are distinct from the previously known neuroendocrine cells and which are required for adult ecdsysis. This work was published in the journal iScience. We likewise used the Trojan exon method to investigate targets of the hormone Bursicon. Our previous work had shown that Bursicon released from a single pair of neurons (called the BSEG) was important in helping flies decide whether to expand their wings after adult ecdysis depending on environmental conditions. Expanding under adverse conditions risks permanently damaging the wings and flies will generally delay wing expansion and seek better conditions rather than risk damage (Luan et al., 2012, J Neurosci. 32: 880889). We have now found that a key component of the decision-making circuitry is a set of cholinergic neurons targeted by Bursicon that signal back to the BSEG via a positive feedback loop. This feedback loop is critical for initiating and maintaining wing expansion in an environmentally sensitive manner. This work has recently been submitted for publication. The novel technology that we developed and published last year involves the use of split inteins, which are recently discovered proteins that can join two protein fragments fused to them. Split inteins lend themselves naturally to applications in which a protein molecule is divided into inert fragments that must be joined together to reconstitute activity. Our method divides the Cre recombinase into three fragments fused to two distinct pairs of split inteins. The three components can thus be independently targeted to different cell groups and only those cells that express all three Cre components will generate active Cre. Cre itself is used to activate a transcription factor, Gal4, thus allowing expression of other transgenes in the targeted cells so that they can be manipulated to determine their function. The manuscript describing this technology has now been published in the journal eLIFE. We are currently using the technique to map ecdysis circuits and have shared our reagents with numerous colleagues to facilitate their circuit-mapping efforts. In summary, we have made good progress during the last year in advancing research on the principal questions of interest to the laboratory. At the same time, we have continued to contribute tools that support not only our own circuit mapping efforts, but also those of other members of the Drosophila research community. As we use these tools to extend and refine our analysis of the circuitry underlying ecdysis sequences, our work should provide insight into the principles that govern the development and function of behavioral circuits in all organisms, including humans.
昆虫蜕皮序列为研究控制行为的神经调节机制提供了一个简单、稳健和易于处理的模型。由于蜕化序列的启动涉及行为优先级的深刻转变,因此对这些序列的研究为理解控制行为状态变化的神经调节机制提供了机会。此外,由于内分泌行为固有的顺序性,它们允许系统地研究运动程序是如何由神经系统组装和顺序执行的。最后,对催化序列的研究有望深入了解神经回路如何可变地配置以产生巨大不同的行为。以果蝇为例,蛹和成虫蜕皮时的运动序列是完全不同的。这是因为蛹和成虫的身体结构有很大的不同。尽管存在这些解剖学上的差异,但这两种行为序列是由一套共同的神经调节/激素输入控制的。通过类比计算,这些输入可以被看作是用高级编程语言编写的指令,然后被编译成不同的输出。揭示神经编译的机制可能会深刻地告知我们神经调节剂如何通过重新配置神经网络的活动来促进神经计算的理解。

项目成果

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Benjamin H White其他文献

Benjamin H White的其他文献

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{{ truncateString('Benjamin H White', 18)}}的其他基金

Identifying Neural Substrates of Behavior in Drosophila Melanogaster
识别果蝇行为的神经基础
  • 批准号:
    10703918
  • 财政年份:
  • 资助金额:
    $ 236.92万
  • 项目类别:
Identifying Neural Substrates of Behavior in Drosophila Melanogaster
识别果蝇行为的神经基础
  • 批准号:
    9357278
  • 财政年份:
  • 资助金额:
    $ 236.92万
  • 项目类别:
Identifying Neural Substrates of Behavior in Drosophila
识别果蝇行为的神经基础
  • 批准号:
    6982718
  • 财政年份:
  • 资助金额:
    $ 236.92万
  • 项目类别:
Identifying Neural Substrates of Behavior in Drosophila Melanogaster
识别果蝇行为的神经基础
  • 批准号:
    8556937
  • 财政年份:
  • 资助金额:
    $ 236.92万
  • 项目类别:
Identifying Neural Substrates of Behavior in Drosophila Melanogaster
识别果蝇行为的神经基础
  • 批准号:
    7969372
  • 财政年份:
  • 资助金额:
    $ 236.92万
  • 项目类别:
Identifying Neural Substrates of Behavior in Drosophila
识别果蝇行为的神经基础
  • 批准号:
    7136784
  • 财政年份:
  • 资助金额:
    $ 236.92万
  • 项目类别:
Identifying Neural Substrates of Behavior in Drosophila Melanogaster
识别果蝇行为的神经基础
  • 批准号:
    8939969
  • 财政年份:
  • 资助金额:
    $ 236.92万
  • 项目类别:
Identifying Neural Substrates of Behavior in Drosophila Melanogaster
识别果蝇行为的神经基础
  • 批准号:
    10929811
  • 财政年份:
  • 资助金额:
    $ 236.92万
  • 项目类别:
Identifying Neural Substrates of Behavior in Drosophila Melanogaster
识别果蝇行为的神经基础
  • 批准号:
    8158104
  • 财政年份:
  • 资助金额:
    $ 236.92万
  • 项目类别:
Identifying Neural Substrates of Behavior in Drosophila Melanogaster
识别果蝇行为的神经基础
  • 批准号:
    8342135
  • 财政年份:
  • 资助金额:
    $ 236.92万
  • 项目类别:

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