Functions and connections of inhibitory reticulospinal locomotor systems

抑制性网状脊髓运动系统的功能和连接

基本信息

批准号：
9052844
负责人：
Veronique VanderHorst
金额：
$ 38.06万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9052844
关键词：
Acute Affect Area Binding Brain Stem Cholinergic Fibers Chronic Clozapine Complex Contralateral Data Designer Drugs Development Disinhibition Dorsal Etiology Feedback Freezing Functional disorder G-Protein-Coupled Receptors Gait Gait abnormality Generations Genes Glutamates Goals Institutionalization Interneurons Knock-out Knockout Mice Lead Length Ligands Locomotion Medial Mediating Midbrain structure Motor Activity Motor Neurons Movement Mus Muscarinics Mutate Nature Neurobiology Neurodegenerative Disorders Neurologic Neurons Neuropathy Oxides Parkinson Disease Pathway interactions Pattern Peripheral Nervous System Diseases Phenotype Pilot Projects Posture Prosencephalon Quality of life Role Sensory Signal Transduction Source Speed Spinal Spinal Cord Stroke System Techniques Technology Testing Viral Vector aging population base central pattern generator density designer receptors exclusively activated by designer drugs disability effective therapy human disease inhibitory neuron insight locomotor control nervous system disorder new technology novel receptor research study sensory feedback tumor vesicular GABA transporter

项目摘要

DESCRIPTION (provided by applicant): Gait disorders are a common problem in the aging population. Etiologies include neurological problems from neuropathies to neurodegenerative disorders, to strokes that affect locomotor circuitries. These circuitries are poorly understood, but the impact of the problem in terms of quality of life, and need for institutionalization is enormous. Locomotion is a complex function, requiring control of initiation of movement, speed, and rhythm. These functions are mediated via spinal central pattern generators (CPG), which are steered by sensory and supraspinal input. A major source of supraspinal input is from reticulospinal neurons in the medial medulla, in the lower brainstem. This region in turn receives input from mid- and forebrain locomotor regions from which locomotion is controlled. Inhibitory systems are crucial for locomotor control at spinal levels, but roles of inhibitory neurons could not be dissected in the medulla due to contributions from admixed serotonergic/glutamatergic reticulospinal neurons. Novel techniques now allow us to selectively study the functions and connectivity of inhibitory reticulospinal neurons. In our pilot studies we focally deleted the vesicular GABA transporter (vgat) from subregions in the medial medulla in conditional knockout mice and reconstructed connections of these regions to the spinal cord. Based upon our results we hypothesize that: 1) a dorsal inhibitory system is involved in initiation of movement. When this system is excited by locomotor regions, movement is initiated via disinhibition of spinal neurons. 2) a ventral inhibitory system regulates speed via projections to motoneurons and interneurons that modulate sensory feedback. We will test these hypotheses rigorously using Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology. This novel technology makes use of mutated receptors which can be built into selected groups of neurons. These receptors can then be selectively activated by administering an otherwise pharmacologically inert designer drug. This allows to reversibly inhibit or stimulate neurons, depending on the type of mutated receptor that was built in. This technology is suitable to functionally and anatomically dissect complex circuitries, and the overall approach has potential for applications in human disease. In Aim 1, we will assess the functions of inhibitory neurons in the medulla using DREADD technology. In Aim 2, we will selectively visualize the pathways from the various groups of inhibitory neurons in the medial medulla to the spinal cord, and will characterize classes of spinal neurons that are targeted by these systems. In Aim 3, we will use these same techniques to assess the nature and density of connections from putative locomotor regions in the fore- and midbrain to these inhibitory medullary systems. Our results will change current paradigms of locomotor control, will help understand how dysfunction of locomotor systems alters gait in neurological disorders, and may lead to new treatment options.

描述（由申请人提供）：步态障碍是老龄化人群中的常见问题。病因包括从神经病到神经退行性疾病的神经系统问题，再到影响运动电路的中风。这些电路的理解很少，但是问题在生活质量方面的影响和制度化的需求是巨大的。运动是一个复杂的功能，需要控制运动，速度和节奏的启动。这些功能是通过脊柱中央模式发生器（CPG）介导的，该功能是通过感觉和脊柱上输入来指导的。脊柱上输入的主要来源来自脑干下部延髓的网状脊髓神经元。该区域依次从控制运动的中部和前脑运动区域接收输入。抑制系统对于在脊柱水平上的运动控制至关重要，但是由于混合性血清素能/谷氨酸能网域神经元的贡献，抑制性神经元的作用不能在髓质中解剖。现在，新型技术使我们能够选择性地研究抑制性网状神经元的功能和连通性。在我们的试点研究中，我们从条件敲除小鼠的内侧延髓中的子区域置换了囊泡GABA转运蛋白（VGAT），并重建了这些区域与脊髓的连接。根据我们的结果，我们假设：1）背侧抑制系统参与运动的开始。当该系统受到运动区域的激发时，将通过抑制脊柱神经元来开始运动。 2）腹侧抑制系统通过投影对运动神经元和调节感觉反馈的中间神经元进行调节。我们将使用设计器药物（Dreadd）技术专门激活的设计器受体严格测试这些假设。这项新型技术利用了可以内置在选定的神经元组中的突变受体。然后，可以通过施用原本具有药理惰性的设计器药物来选择性地激活这些受体。这允许可逆地抑制或刺激神经元，具体取决于所内置的突变受体的类型。该技术适合于功能和解剖学上剖析复杂的循环系统，并且总体方法具有在人类疾病中应用的潜力。在AIM 1中，我们将使用Dreadd技术评估延髓中抑制性神经元的功能。在AIM 2中，我们将选择性地可视化从内侧髓质中各个抑制性神经元到脊髓的途径，并将表征这些系统靶向的脊柱神经元类别。在AIM 3中，我们将使用这些相同的技术来评估这些抑制性髓质系统的前脑和中脑的推定运动区域的连接性质和密度。我们的结果将改变当前的运动控制范式，有助于了解运动系统的功能障碍如何改变神经系统疾病的步态，并可能导致新的治疗选择。