权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Identifying Neural Substrates of Behavior in Drosophila Melanogaster

识别果蝇行为的神经基础

基本信息

批准号：
10929811
负责人：
Benjamin H White
金额：
$ 233.43万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10929811
关键词：
Achievement Adult Alleles Anatomy Animals Anxiety Disorders Back Behavior Behavioral Biological Metamorphosis Bipolar Disorder Brain Cells Collaborations Communities Custom Decision Making Depressive disorder Derivation procedure Development Drosophila genus Drosophila melanogaster Environment Exclusion Exercise Exhibits Exons Face Feedback Genes Genetic Transcription Goals Hormonal Hormones Human Insecta Instruction Investigation Knowledge Laboratories Light Manuscripts Maps Mediating Mental disorders Methods Microscope Molting Motivation Motor Motor Neurons Motor output Movement Muscle Nervous System Neuromodulator Neurons Neurophysiology - biologic function Obsessive-Compulsive Disorder Organism Output Paper Pattern Pharmaceutical Preparations Phase Play Preparation Process Programming Languages Protein Truncation Proteins Publishing Recurrence Regulation Research Research Personnel Resolution Risk Role Schizophrenia Signal Transduction Stochastic Processes Study models System Techniques Technology Temperature Time Transcriptional Regulation Wing Work Writing bursicon cholinergic cholinergic neuron exoskeleton fly follow-up hormonal signals inhibitor insight intein interest neural neural circuit neural network neuromechanism neuron component neuronal patterning neuroregulation neurotransmission operation programs receptor response technology development tool transcription factor transgene expression

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. With regard to pupal ecdysis, we have continued to follow up on our description of the pupal ecdysis sequence at single muscle resolution (Elliott et al., eLife 2021;10:e68656). The motivation for that study, which to our knowledge constituted the first muscle-level description of a complicated behavioral sequence in any animal, was to facilitate a similar investigation of the neuronal activity that drives pupal ecdysis. This is in line with the laboratory's central interest in understanding how a simple hormonal signal (i.e. ETH) is transformed in the brain into the execution of a specific motor sequence characterizing a particular behavioral state. To study the patterns of neuronal activity that transform the ETH signal into a pupal ecdysis sequence, we are using the excised pupal brain preparation that we and others have previously shown exhibits fictive pupal ecdysis activity in response to ETH (Diao et al., 2017, doi.org/10.7554/eLife.29797). We are currently using a custom-built light-sheet microscope to establish the patterns of ETH-evoked motor neuron activity in the excised brain and compare them with the previously established patterns of pupal ecdysis muscle activity. We will then use the motor neuron activity patterns to identify the pre-motor neurons likely to drive them based on their patterns of activity. Using correlated activity and functional manipulations as our guide, we will identify neurons at progressively higher levels that participate in generating the movements of the pupal ecdysis sequence, up to and including the neurons that respond to ETH. Adult ecdysis immediately follows metamorphosis and consists of two major behavioral phases. In the first, the animal extricates itself from the puparium and in the second, it stops to expand and harden its wings. Each of these phases involves the execution of specific motor patterns that are under hormonal control. Over the past year, we laid the groundwork for identifying the hormonal targets mediating eclosion by characterizing the patterns of muscle activity underlying that process. These patterns show selective sensitivity to distinct hormones indicating the multifactorial regulation eclosion. Second, we have continued to investigate the dual roles of the hormone Bursicon in wing expansion. 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. Using the Trojan exon technology that we developed in 2015 (Diao et al., 2015, Cell Rep. 10:1410-21) to investigate targets of Bursicon, we established that a key component of the decision-making circuitry is a set of cholinergic neurons that express the Bursicon receptor. These neurons signal back to the BSEG via a positive feedback loop to initiate and maintain wing expansion in an environmentally sensitive manner. Our efforts over the last year have focused on resolving the minimal subset of neurons in the feedback loop using a variety of directed and stochastic methods for restricting neuronal expression. In technology development, my laboratory has continued to refine methods for targeted transgene expression that exploit the use of split inteins. In collaboration with the Perrimon lab at Harvard, we have adapted split inteins for use in a modified version of the Split Gal4 method introduced by my laboratory in 2006 (Neuron 52:425-436). The modified version has the advantage of being compatible with the temperature-sensitive Gal4 inhibitor tsGal80, and therefore permits temporal control of transcriptional activity of the new Split Gal4 system. In addition, we developed a split intein version of the drug-inducible GeneSwitch molecule, which similarly permits Gal4-mediated transcription of downstream targets. Our split intein GeneSwitch thus provides a second method for exercising temporal control of a split transcription factor. This work is described in a recently published paper in PNAS (https://doi.org/10.1073/pnas.2304730120). In addition, we are also using split inteins to modify our Trojan exon method. That method necessarily truncates the allele of the gene into which the Trojan exon is inserted, essentially cutting the encoded protein in half. To obviate this, we have devised a strategy in which split inteins are used to re-unite the two halves of the truncated protein thereby restoring its function. This method is proving useful in creating new Split Gal4 drivers to identify the cholinergic feedback neurons described above. More generally, we expect that it will be a valuable tool to the Drosophila research community by extending the range of problems that can be tackled using the Trojan exon technique. A manuscript is currently in preparation. In summary, during the last year we have advanced research on the principal questions of interest to the laboratory. At the same time, we have continued to develop technology that supports not only our own circuit mapping efforts, but also those of other researchers. 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.

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neural and hormonal control of postecdysial behaviors in insects.

DOI：
10.1146/annurev-ento-011613-162028
发表时间：
2014
期刊：
Annual review of entomology
影响因子：
23.8
作者：
White BH;Ewer J
通讯作者：
Ewer J

Command and compensation in a neuromodulatory decision network.

DOI：
10.1523/jneurosci.3707-11.2012
发表时间：
2012-01-18
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Luan H;Diao F;Peabody NC;White BH
通讯作者：
White BH

Enteric neurons increase maternal food intake during reproduction.

DOI：
10.1038/s41586-020-2866-8
发表时间：
2020-11
期刊：
Nature
影响因子：
64.8
作者：
Hadjieconomou D;King G;Gaspar P;Mineo A;Blackie L;Ameku T;Studd C;de Mendoza A;Diao F;White BH;Brown AEX;Plaçais PY;Préat T;Miguel-Aliaga I
通讯作者：
Miguel-Aliaga I

Bursicon functions within the Drosophila CNS to modulate wing expansion behavior, hormone secretion, and cell death.

DOI：
10.1523/jneurosci.2842-08.2008
发表时间：
2008-12-31
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Peabody NC;Diao F;Luan H;Wang H;Dewey EM;Honegger HW;White BH
通讯作者：
White BH

Neurotrapping: cellular screens to identify the neural substrates of behavior in Drosophila.