Understanding the role of descending neuromodulation in flexible control of behavior

了解下行神经调节在灵活控制行为中的作用

• 批准号: 10024929
• 负责人: Vikas Bhandawat
• 金额: $ 30.89万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10024929
• 关键词: Understanding; role; descending; neuromodulation; flexible

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.

1神经调质通过影响不同的细胞过程来改变神经回路的输出， 2.在灵活控制行为方面起着特别重要的作用。神经调质的基因操作 毫无疑问，它们对行为产生了强大的影响。但很难确定一个 4给定的神经调节神经元群体，因为它们的总体效应是通过它们在多个神经元上的作用而产生的。 大脑和脊髓中的5个回路。特别是，神经调节下行神经元的特定作用 6（NM-DNs）-其细胞体驻留在大脑中并将其轴突发送到脊髓的神经元-in 7调制电机输出了解甚少。迫切需要填补我们知识上的这一空白 8因为NM-DNs是脊髓中神经调质的主要来源，并且在塑造神经元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-DN在以下背景下的作用： 10行为，需要控制多关节四肢。本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（5 HT）-在完全完整的动物中。核心假设是NM-DN被介导NM-DN的DN招募， 13感觉运动转换，我们称之为感觉DN（SDNs），SDNs启动运动 同时通过轴突侧支募集NM-DN。NM-DN不启动移动， 15通过调节腿的频率、幅度和持续时间在下行运动控制中起主要作用 16个动作本研究的理论基础是，全面了解下行 17在多关节肢体的情况下，完整系统中的神经调节对于基本问题 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。的 19.拟议的项目有三个具体目标：1）衡量国家管理指定国家的活动与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回路结构。3)了解 图21扰乱神经调节对苍蝇运动的影响。我们的方法是多学科的：它采用了 22结合机器视觉技术提取腿部运动学，一种新颖的分析框架， 23腿运动，在体内全细胞膜片钳记录，以提取NM- 24 DN和腿部运动学，以及识别和干扰NM-DN以建立因果关系的遗传工具 NM-DN和电机输出之间为25。关于结果，我们希望阐明三个方面中的每一个 26种胺能神经递质单独或共同作用于由多种神经递质引起的运动输出 27个多关节肢体。这些结果意义重大，因为它们有望纵向推进理解 28的NM-DNs的作用，因为很少有人知道的电路机制，他们在体内发挥作用。 29同样重要的是，这些结果将对改善运动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质。