The rodent central pattern generator for locomotion

用于运动的啮齿动物中央模式发生器

• 批准号: 7895760
• 负责人: Ronald M Harris-Warrick
• 金额: $ 36.07万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895760
• 关键词: Affect; Animals; Axon; Calcium; Crustacea; Development; Ganglia; Glutamates; Goals; Image; Injury; Interneurons; Invertebrates; Label; Learning; Left; Lesion; Locomotion; Methods; Modeling; Molecular; Molecular Genetics; Motor; Movement; Mus; Myxoid cyst; N-Methylaspartate; Neonatal; Neuromodulator; Neurons; Pathway interactions; Pattern; Play; Preparation; Property; Research; Rodent; Role; Sensory; Serotonin; Shapes; Signal Transduction; Spinal; Spinal Cord; Spinal Cord Lesions; Spinal cord injury; Synapses; Testing; Time; Transgenic Mice; Transgenic Organisms; Walking; Whole-Cell Recordings; Work; base; central pattern generator; neuron component; postnatal; public health relevance; response; voltage clamp

DESCRIPTION (provided by applicant): In the neonatal rodent spinal cord, the combination of serotonin and NMDA is adequate to activate the central pattern generator (CPG) networks for locomotion, but the cellular and biophysical mechanisms by which these transmitters organize and activate the CPG are poorly understood. We propose that these neuromodulators reconfigure the intrinsic properties of the CPG neurons and the strengths of network synapses to organize the network into a functional "idling" state, so that descending glutamatergic or sensory input can rapidly initiate locomotion. The neonatal mouse spinal cord is an excellent preparation to test these hypotheses: several neuronal candidates for the CPG have been identified using transgenic and anatomical methods to label specific interneuron types. Two identified classes of interneurons are thought to play important roles in the organization of the mouse spinal locomotor CPG: commissural interneurons (CINs) which coordinate left-right movements, and the Hb9 interneurons which may participate in the rhythm-generating component of the CPG. Following a research approach we have pursued for many years in the crustacean stomatogastric ganglion, we propose to study how the intrinsic cellular properties of these neurons shape their activity patterns during fictive locomotion, and how serotonin and NMDA affect those intrinsic properties. Our first aim is at the cellular level: using a combination of whole cell recording and calcium imaging, we will study the intrinsic firing properties of synaptically isolated interneurons, their modulation by serotonin, and its interaction with NMDA. The goal of this aim is to better understand how modulators can alter the neurons' activity to activate the motor pattern. Second, at the biophysical level, we will use voltage clamp methods to identify the ionic currents affected by serotonin and NMDA in CINs and Hb9 interneurons, to understand the biophysical basis for modulatory changes in the neurons' intrinsic firing properties. Third, we will begin to explore the plasticity of the intrinsic properties of these spinal interneurons by studying how they change during postnatal development, during the time the animal learns to walk, and following spinal cord injury. These projects will elucidate some of the cellular and molecular mechanisms that neuromodulators use to shape the locomotor CPG. Spinal cord injury causes loss not only of the rapid activating signals for locomotion, but also of the slower modulatory inputs that enable the network to function at all. To learn how to restore movement after spinal cord injury, we must understand both the modulatory mechanisms that enable the network to function and the rapid activating mechanisms in the locomotor CPG. PUBLIC HEALTH RELEVANCE We hypothesize that serotonin and other modulators modify the firing properties of locomotor network neurons and their synapses to enable the spinal network to produce the commands for locomotion. When these inputs are lost following spinal cord lesions, the network becomes non-functional. An eventual goal of our work is to provide a rational basis for post-injury neuromodulator therapy, to help maintain the locomotor networks in a functional state until regrowth of axons can be accomplished across the lesion.

描述（由申请人提供）：在新生的啮齿动物脊髓中，血清素和NMDA的结合足以激活中枢模式发生器（CPG）网络进行运动，但这些递质组织和激活CPG的细胞和生物物理机制尚不清楚。我们提出，这些神经调节剂重新配置CPG神经元的内在特性和网络突触的强度，使网络进入功能性的“空转”状态，从而使下降的谷氨酸能或感觉输入能够迅速启动运动。新生小鼠脊髓是测试这些假设的极好准备：使用转基因和解剖方法确定了CPG的几个候选神经元，以标记特定的中间神经元类型。两类已确定的中间神经元被认为在小鼠脊髓运动CPG的组织中起重要作用：协调左右运动的联合中间神经元（CINs）和可能参与CPG节律产生成分的Hb9中间神经元。根据我们多年来对甲壳类动物口胃神经节的研究方法，我们提出研究这些神经元的内在细胞特性如何在实际运动中塑造其活动模式，以及血清素和NMDA如何影响这些内在特性。我们的第一个目标是在细胞水平上：使用全细胞记录和钙成像的组合，我们将研究突触分离的中间神经元的内在放电特性，血清素对它们的调节，以及它与NMDA的相互作用。这项研究的目的是为了更好地理解调制器是如何改变神经元的活动来激活运动模式的。其次，在生物物理水平上，我们将使用电压钳法识别CINs和Hb9中间神经元中5 -羟色胺和NMDA影响的离子电流，以了解神经元内在放电特性调节变化的生物物理基础。第三，我们将开始探索这些脊髓中间神经元内在特性的可塑性，通过研究它们在出生后发育、动物学习行走期间以及脊髓损伤后的变化。这些项目将阐明神经调节剂用于塑造运动CPG的一些细胞和分子机制。脊髓损伤不仅会导致运动的快速激活信号的丢失，还会导致使神经网络正常运作的较慢的调节输入的丢失。为了了解如何在脊髓损伤后恢复运动，我们必须了解使网络功能的调节机制和运动CPG的快速激活机制。我们假设血清素和其他调节剂改变运动网络神经元及其突触的放电特性，使脊髓网络能够产生运动命令。当这些输入在脊髓损伤后丢失时，神经网络就会失去功能。我们工作的最终目标是为损伤后神经调节剂治疗提供合理的基础，以帮助维持运动网络处于功能状态，直到轴突可以在病变中再生。

项目成果

Neuromodulation and flexibility in Central Pattern Generator networks.

• DOI: 10.1016/j.conb.2011.05.011
• 发表时间: 2011-10
• 期刊: Current opinion in neurobiology
• 影响因子: 5.7
• 作者: Harris-Warrick RM

A comparison of serotonin neuromodulation of mouse spinal V2a interneurons using perforated patch and whole cell recording techniques.

使用穿孔斑块和全细胞记录技术对小鼠脊髓V2A中间神经元的5-羟色胺神经调节的比较。

• DOI: 10.3389/fncel.2012.00039
• 发表时间: 2012
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Dietz S;Husch A;Harris-Warrick RM
• 通讯作者: Harris-Warrick RM

Spinal cord injury induces serotonin supersensitivity without increasing intrinsic excitability of mouse V2a interneurons.

• DOI: 10.1523/jneurosci.2995-12.2012
• 发表时间: 2012-09-19
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Husch A;Van Patten GN;Hong DN;Scaperotti MM;Cramer N;Harris-Warrick RM
• 通讯作者: Harris-Warrick RM