Control of sensory function in mammalian spinal cord

描述（由申请人提供）：感觉神经传递是感觉刺激中枢处理的基本第一步。它受突触前和突触后抑制机制控制。突触前抑制比突触后抑制更能抑制几乎所有初级传入感觉纤维的中枢兴奋作用。一个产生传入PSI的主要机制是通过反直觉的通道介导的椎管内终末的去极化，这可以方便地记录为背根电位。GABA能抑制性中间神经元通过三突触通路释放GABA作为神经递质，产生大直径（低阈值）肌肉和皮肤感觉传入神经的PSI。然而，直到今天，几乎没有“干净的”证据。我们有异端的证据表明，传入刺激诱发的PSI大部分是由更直接的突触通路产生的，这可能是；(i)不依赖经典GABAA受体，（ii）不依赖GABA。这些断言的机制证明需要在体外神经附着的小鼠脊髓（P10-14）中进行开创性的电生理研究，并包括在大直径感觉传入亚群中识别和敲除特定基因的转基因系。具体来说，我们将检验以下两个假设：1。GABA并不是唯一产生PSI的递质。替代物质包括乙酰胆碱、牛磺酸和2-丙氨酸，这些物质存在于离散的传入神经和神经元间亚群中。2. GABAA受体亚基不是激活受体中唯一的亚基。替代物是烟碱和甘氨酸能亚基，它们可以组装成独特的异质成分。如果成功，几十年来关于PSI产生机制的观点将需要大幅度的概念修正。这一新观点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。

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. PUBLIC HEALTH RELEVANCE: We propose to undertake a detailed characterization of the mechanisms responsible for presynaptic inhibition of primary afferents in the mammal.