Control of sensory function in mammalian spinal cord

哺乳动物脊髓感觉功能的控制

基本信息

批准号：
8627658
负责人：
SHAWN HOCHMAN
金额：
$ 37.45万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-15 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8627658
关键词：
Acetylcholine Alanine Bicuculline Caliber Cells Complement Coupled Cutaneous Muscle Depressed mood Drug effect disorder Family Feedback Fiber Figs - dietary Functional disorder Gated Ion Channel Genes Glycine In Situ In Vitro Interneurons Knock-out Lasers Ligands Mammals Measures Mediating Molecular Molecular Profiling Movement Mus Nature Nerve Neurons Neurotransmitters Nicotinic Receptors Pathway interactions Peripheral Nerves Pharmacology Population Process Sensory Spinal Cord Spinal Ganglia Synapses Synaptic Transmission Taurine Testing Time Touch sensation Transgenic Organisms base biophysical properties dorsal horn gamma-Aminobutyric Acid information processing knockout gene neural circuit neurotransmission novel postsynaptic presynaptic public health relevance receptor research study response sensory mechanism sensory stimulus somatosensory spinal nerve posterior root

项目摘要

DESCRIPTION (provided by applicant): Sensory neurotransmission is the fundamental first step in the central processing of sensory stimuli. It is controlled by pre- and post-synaptic inhibitory mechanisms. Presynaptic inhibition (PSI) is more powerful than postsynaptic inhibition in depressing the central excitatory actions of almost all primary afferent sensory fibers. A major mechanism producing afferent PSI is via a counterintuitive channel-mediated depolarization of their intraspinal terminals which, conveniently, can be recorded as a dorsal root potential. It is thought that, via a trisynaptic pathway, GABAergic inhibitory interneurons release GABA as the neurotransmitter to produce PSI of large-diameter (low threshold) muscle and cutaneous sensory afferents. However to this day there is little 'squeaky clean' evidence. We have heretical evidence suggesting instead that much of this afferent stimulation-evoked PSI is generated by more direct synaptic pathways that may be; (i) independent of classical GABAA receptors and (ii) independent of GABA. A mechanistic proof of these assertions require a coalescence of pioneering electrophysiological studies in the in vitro nerves-attached mouse spinal cord (P10-14) and includes transgenic lines that identify and knockout specific genes in larger- diameter sensory afferent subpopulation. Specifically, we will test the following two hypotheses: 1. GABA is not the only transmitter producing PSI. Alternates include acetylcholine, taurine and 2-alanine, and these are found in discrete afferent and interneuronal subpopulations. 2. GABAA receptor subunits are not the only subunits in activated receptors. Alternates are nicotinic and glycinergic subunits and these may be assembled in unique heteromeric compositions. If successful, a decades-old view of mechanisms producing PSI will require dramatic conceptual revision. This new perspective broadens our understanding of somatosensory information processing, and may introduce novel control strategies for sensory dysfunction.

描述（由申请人提供）：感觉神经传递是感觉刺激中央处理的基本第一步。它由突触前和突触后抑制机制控制。突触前抑制（PSI）在抑制几乎所有初级传入感觉纤维的中枢兴奋作用方面比突触后抑制更有效。产生传入 PSI 的主要机制是通过违反直觉的通道介导的椎内末梢去极化，可以方便地记录为背根电位。人们认为，通过三突触途径，GABA 能抑制性中间神经元释放 GABA 作为神经递质，产生大直径（低阈值）肌肉和皮肤感觉传入的 PSI。然而直到今天，还没有什么“绝对干净”的证据。我们有异端证据表明，这种传入刺激诱发的 PSI 大部分是由更直接的突触通路产生的，这些通路可能是： (i) 独立于经典 GABAA 受体和 (ii) 独立于 GABA。这些断言的机械证明需要在体外神经附着的小鼠脊髓（P10-14）中整合开创性的电生理学研究，并包括识别和敲除较大直径感觉传入亚群中特定基因的转基因系。具体来说，我们将测试以下两个假设： 1. GABA 不是唯一产生 PSI 的递质。替代品包括乙酰胆碱、牛磺酸和 2-丙氨酸，这些存在于离散的传入神经元和中间神经元亚群中。 2. GABAA受体亚基并不是激活受体中唯一的亚基。替代物是烟碱和甘氨酸亚基，这些亚基可以组装成独特的异聚组合物。如果成功的话，几十年前关于 PSI 产生机制的观点将需要进行重大的概念修改。这一新视角拓宽了我们对体感信息处理的理解，并可能为感觉功能障碍引入新的控制策略。