Control of sensory function in mammalian spinal cord

哺乳动物脊髓感觉功能的控制

• 批准号: 8426151
• 负责人: SHAWN HOCHMAN
• 金额: $ 36.5万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8426151
• 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; 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

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心处理的基本第一步。它受到突触前和突触后抑制机制的控制。突触前抑制（PSI）比突触后抑制更强大，以抑制几乎所有主要传入的感觉纤维的中心兴奋作用。产生传入PSI的主要机制是通过其载体内末端的违反直觉通道介导的去极化，可以方便地将其记录为背根电位。人们认为，通过三突触途径，GABA能抑制性中间神经元将GABA释放为神经递质，以产生大直径（低阈值）肌肉和皮肤感觉传递的PSI。但是，到目前为止，几乎没有“吱吱作响”的证据。我们有异端证据表明，这种传入刺激引起的PSI的大部分是由可能是更直接的突触途径产生的。 （i）独立于古典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）中合并开创性的电生理研究，并包括转基因线，这些线条在较大直径的感觉传入亚群中识别和敲除特定基因。具体来说，我们将测试以下两个假设：1。GABA并不是唯一产生PSI的发射器。替代物包括乙酰胆碱，牛磺酸和2-丙氨酸，它们在离散传入和神经间亚群中发现。 2。GABAA受体亚基不是活化受体中的唯一亚基。替代品是烟碱和糖脂亚基，这些亚基可以组装成独特的杂体组成。如果成功，几十年来产生PSI的机制的观点将需要戏剧性的概念修订。这种新的观点扩大了我们对体感信息处理的理解，并可能引入新颖的控制策略，以实现感官功能障碍。