A multisensory-motor integration circuit; from synapse to behavior

自然行为是引起自我诱导的感觉激活的运动行为的协调交响曲。感觉神经元只发出感觉线索的存在和大小的信号；他们无法区分自我诱导和外部诱导的输入（例如，听到你的声音和别人的声音）。然而，动物很容易区分这些感觉信号的来源；这是适当决策和适应性行为结果的基础。神经系统通过推论放电回路来区分感觉信号的来源，推论放电回路是一类广泛的神经回路，它向感觉神经系统传递运动命令的“推论”，修改感觉处理。然而，关于使必然放电回路起作用的细胞和分子机制知之甚少。本项目的目的是表征一对相关的必然放电回路的结构和功能，由两对已识别的组胺能神经元组成。建立一个机制框架，通过该框架，必然放电修改感觉功能以优化感觉运动表现，将解决神经系统如何整合感觉运动信息方面长期存在的知识空白。这项研究将有助于在动物、机器人、无人驾驶车辆和其他运动可以与传感器功能相互作用的工程应用中更广泛地研究目标导向和感官引导决策。此外，该提案还包含更广泛的社会影响，西弗吉尼亚州本科生和研究生的STEM培训，以及下一代神经解剖学研究课程的开发。该项目旨在解决驱动必然放电回路活动的细胞和突触机制，以及这种活动对感觉-运动表现的影响。为了实现这一目标，实验将进行：1)利用基于序列切片电镜的苍蝇大脑和腹侧神经索体积重建结合分子遗传技术，识别2对组胺能神经元的上游和下游伙伴；2)利用光遗传学和Ca2+成像技术确定在高度受限的行驶路线中，上下游伙伴如何与组胺神经元相互作用；3)在行为分析中确定组胺神经元在塑造感觉运动表现中的作用。工作的假设是，组胺神经元主要被下行的运动命令神经元激活，导致下游抑制大脑中不同但相关的感觉网络。该项目的基本原理是，通过精确解剖特定行为背景下组胺神经元与其突触伙伴之间的相互作用，更好地理解在复杂的自然行为中，必然放电回路如何整合和分配信息，以微调多感觉-运动相互作用。通过建立一个机制框架，通过该机制框架，必然放电改变感觉功能以优化感觉-运动表现，该项目提供了神经系统如何整合感觉-运动信息的知识，并有助于研究目标导向和感觉导向的决策，这可以应用于生物学和工程应用。这个项目将让学生接触到STEM培训，并为新兴的连接组学领域提供新的课件。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Natural behaviors are a coordinated symphony of motor acts which cause self-induced sensory activation. Sensory neurons only signal presence and magnitude of a sensory cue; they cannot disambiguate self-induced from externally-induced inputs (e.g. hearing your voice versus someone else’s voice). Nevertheless, animals readily differentiate between these sources of sensory signals; this is fundamental to appropriate decision making and adaptive behavioral outcomes. Nervous systems differentiate sources of sensory signals via corollary discharge circuits, which are a broad class of neural circuits that convey a “corollary” of motor commands to sensory neural systems, modifying sensory processing. However, little is known about the cellular and molecular mechanisms that make corollary discharge circuits work. The objective of this project is to characterize the structure and function of a pair of related corollary discharge circuits, comprised of two pairs of identified histaminergic neurons. Establishing a mechanistic framework by which corollary discharges modify sensory function to optimize sensory-motor performance will address long standing gaps in knowledge of how the nervous system integrates sensory-motor information. The research will contribute to the broader study of goal-directed and sensory-guided decision making in animals, robotics, unmanned vehicles, and other engineering applications where movement can interact with sensor function. Additionally, this proposal contains broader societal impacts, STEM training for undergraduate and graduate students in West Virginia, and the development of curriculum for next generation neuroanatomical studies.This project seeks to resolve the cellular and synaptic mechanisms that drive the activity of corollary discharge circuits and the consequences of this activity for sensory-motor performance. To achieve this, experiments will be conducted to: 1) identify upstream and downstream partners of 2 pairs of histaminergic neurons using serial section electron microscopy-based volumetric reconstructions of fly brain and ventral nerve cord coupled with molecular genetic techniques; 2) determine how up- and downstream partners interact with the histamine neurons using optogenetics and Ca2+ imaging during ongoing behavior in highly restricted driver lines, and 3) determine the role of the histamine neurons in shaping sensory-motor performance in behavioral assays. The working hypothesis is that the histamine neurons are primarily activated by descending motor command neurons resulting in downstream suppression of distinct but related sensory networks in the brain. The rationale for this project is that by precisely dissecting interactions between the histamine neurons and their synaptic partners in specific behavioral contexts, a better understand of how corollary discharge circuits integrate and distribute information to fine-tune multisensory-motor interactions during complex natural behaviors. By establishing a mechanistic framework by which corollary discharges modify sensory function to optimize sensory-motor performance, this project provides knowledge of how nervous systems integrate sensory-motor information and contributes to the study of goal-directed and sensory-guided decision making, that can be applied in both biological and engineered applications. This this project will expose students to STEM training and provide new courseware for the emerging field of connectomics.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.