Understanding the role of descending neuromodulation in flexible control of behavior

1神经调节剂通过对不同细胞过程的影响来改变神经回路的输出，并 2在灵活控制行为方面发挥着特别重要的作用。神经调节剂的遗传操作 在体内，毫无疑问，它们对行为产生了强大的影响。但是，很难准确地确定一个 4给定的神经调节神经元群体，因为它们的整体影响是通过它们对多个 5脑和脊髓的环路。特别是，神经调节性下行神经元的特殊作用 6(NM-DNS)-其胞体驻留在大脑中并将轴突发送到脊髓的神经元-in 7对马达输出的调节知之甚少。迫切需要填补我们知识上的这一空白 8因为NM-DNS是脊髓神经调节剂的主要来源，在形成过程中起着至关重要的作用 9电机输出。本研究的长期目标是了解NM-DNS在以下方面的作用 10种需要控制多关节肢体的行为。这项提案的总体目标是评估 11使用胺能神经递质--多巴胺(DA)、章鱼胺(OA)和5-羟色胺的NM-DN的作用 12(5HT)--在一个完全完整的动物体内。中心假设是，NM-DN是由调解 13种感觉运动转换，我们称之为感觉神经网络(SDNS)，SDNS启动运动 14同时通过轴突侧支招募NM-DN。NM-DNS不启动移动，但 15通过调节腿部的频率、幅度和持续时间，在下行运动控制中起主要作用 16个动作。这项研究的基本原理是，全面理解下行 17在多关节肢体的情况下，完整系统中的神经调节对这两个基本问题都是至关重要的 18复杂行为的神经控制，以及当这种控制受到影响时的治疗策略。这个 19.拟议项目有三个具体目标：1)衡量国家管理--域名系统和专家组的活动之间的关系 20运动学。2)建立下行神经调节的电路结构。3)了解 扰乱神经调节对苍蝇运动的影响。我们的方法是多学科的：它雇佣了一名 22结合机器视觉技术提取腿部运动学，一种新的分析框架 23条腿的运动，在活体全细胞膜片钳记录中提取NM活动之间的关系-- 24个域名和腿部运动学，以及用于识别和干扰NM-域名以建立因果关系的遗传工具 25 NM-DNS和电机输出之间。关于结果，我们希望阐明三个方面如何 26种胺能神经递质单独和共同作用于塑造运动输出 27条多关节肢体。这样的结果意义重大，因为它们有望在垂直方向上促进理解 28 NM-DNS的作用，因为人们对它们在体内发挥作用的电路机制知之甚少。 29同样重要的是，结果将对改善发动机控制丧失的努力产生积极影响 30在脊髓损伤期间通过恢复神经调节器。

1 Neuromodulators transform the output of neural circuits through their effects on diverse cellular processes and 2 play a particularly important role in the flexible control of behavior. Genetic manipulations of neuromodulators 3 in vivo leave no doubt that they exert a powerful influence on behavior. But it is difficult to pinpoint the role of a 4 given population of neuromodulatory neurons because their overall effect arises through their role on multiple 5 circuits in the brain and spinal cord. In particular, the specific role of neuromodulatory descending neurons 6 (NM-DNs)—neurons whose cell bodies reside in the brain and which send their axons to the spinal cord—in 7 modulating motor outputs is poorly understood. There is an urgent need to fill this gap in our knowledge 8 because NM-DNs are the major source of neuromodulators in the spinal cord and play a crucial role in shaping 9 motor output. The long-term aim of this research is to understand the role of NM-DNs in the context of 10 behaviors that require control over multi-jointed limbs. The overall objective in this proposal is to assess the 11 role of NM-DNs that use aminergic neurotransmitters—dopamine (DA), octopamine (OA) and serotonin 12 (5HT)—in a completely intact animal. The central hypothesis is that NM-DNs are recruited by DNs that mediate 13 sensorimotor transformations, which we refer to as sensory DNs (SDNs), and that SDNs initiate movement 14 while at the same time recruiting NM-DNs through their axon collaterals. NM-DNs do not initiate movement but 15 play a major role in descending motor control by modulating frequency, amplitude and duration of leg 16 movements. The rationale for this study is that a comprehensive understanding of descending 17 neuromodulation in an intact system in the context of multi-jointed limbs is essential to both the basic question 18 of neural control of complex behaviors, and to treatment strategies when such control is affected. The 19 proposed project has three specific aims: 1) To measure the relation between activities in NM-DNs and leg 20 kinematics. 2) To establish the circuit architecture underlying descending neuromodulation. 3) To understand 21 the effect of perturbing neuromodulation on a fly’s movement. Our approach is multidisciplinary: It employs a 22 combination of machine vision techniques to extract leg kinematics, a novel analytical framework for analyzing 23 leg movements, in vivo whole-cell patch clamp recordings to extract the relationship between activities in NM- 24 DNs and leg kinematics, and genetic tools to identify and perturb NM-DNs to establish a causal relationship 25 between NM-DNs and motor output. With regard to outcomes, we expect to elucidate how each of three 26 aminergic neurotransmitters functions individually and together in shaping motor output resulting from multiple 27 multi-jointed limbs. Such results are significant because they are expected to vertically advance understanding 28 of the role of NM-DNs because little is known about the circuit mechanisms by which they function in vivo. 29 Equally importantly, the results will have a positive effect on efforts to ameliorate the loss of motor control 30 during spinal injury by restoring neuromodulators.