Mechanisms of Large-scale Reorganization in Rat Forepaw Barrel Subfiels Cortex

描述（由申请人提供）：有超过160万截肢者生活在美国，估计每周有3000人加入他们的行列。截肢的原因包括疾病、创伤事故、先天缺陷和战争，通常伴有慢性疼痛、运动障碍和无法进行双手操作。肢体丧失可能导致长期残疾、失业，并且是一个主要的全球性健康问题。截肢也会导致大量的皮层重组。了解截肢后的中枢神经系统后果对于设计治疗方法和开发替代策略以补偿肢体损失至关重要。对前肢截肢对中枢神经系统处理的影响的不完全理解限制了我们改善这些缺陷或开发用于恢复功能的假体装置的能力。皮质重组通常与慢性肢体疼痛有关;通过测试有关大脑重组的结构和功能基础的假设，我们可以希望更好地理解和控制慢性肢体疼痛。本研究的目的是了解前肢截肢后延迟的大规模皮质重组的机制。以大鼠第一躯体感觉皮层前爪桶形亚区、腹后外侧核、丘脑网状核和楔状核为模型系统。通过使用一个模型系统和技术，我们是专家，我们将阐明前肢截肢的核心后果，并研究潜在的机制，皮层重组的基础。这项建议的目标是：a）测试延迟的大规模皮层重组是由皮层下回路的变化引起的假设，B）测试消除GABA能抑制是皮层重组的机制的假设，c）测试RTN和CN为长期皮层重组中的延迟成分提供底物的假设，和d）测试前肢截肢改变完整皮质并导致完整肢体精细运动缺陷的假设。该提案结合了我们实验室常规使用的生理脑映射，微刺激，解剖追踪，免疫细胞化学和原位杂交组织化学技术。提出了四个目标：目标1：检验前肢截肢导致VPL和CN重组延迟的假设，以及重组受GABA能控制的假设。目的2：验证将新输入传递到FBS的前爪VPL投射神经元也为去传入皮质的新输入提供通路的假设。目的3：验证RTN对VPL提供延迟抑制控制的假设。目的4：测试前肢截肢也改变了非去传入皮质，并导致在完好的肢体精细运动控制的缺陷的假设。

DESCRIPTION (provided by applicant): There are over 1.6 million amputees living in the US and it is estimated that 3000 join their ranks each week. Limb amputation results from disease, traumatic accident, birth defects, and warfare, and often is accompanied by chronic pain, impaired locomotion, and inability to conduct bimanual tasks. Limb loss may lead to long-term disability, job loss, and represents a major worldwide health problem. Limb amputation also results in massive cortical reorganization. Understanding the central neurological consequences that follow amputation is crucial for devising therapies and developing alternative strategies to compensate for loss of limb. Incomplete understanding of the effects of forelimb amputation on central nervous system processing limits our ability to ameliorate these deficits or to develop prosthetic devices for restoration of function. Cortical reorganization is often associated with chronic limb pain; by testing hypotheses about the structural and functional bases of brain reorganization, we can hope to better understand and control chronic limb pain. The goals of this proposal are to understand the mechanisms that underlie delayed large-scale cortical reorganization that follows forelimb amputation. The rat forepaw barrel subfield in first somatosensory cortex, ventral posterior lateral nucleus (VPL), thalamic reticular nucleus (RTN), and cuneate nucleus (CN) will serve as our model systems. By using a model system and techniques in which we are expert, we will elucidate the central consequences of forelimb amputation and examine potential mechanisms that underlie cortical reorganization. The objectives of this proposal are: a) test hypotheses that delayed large-scale cortical reorganization results from changes in subcortical circuitry, b) test hypotheses that removal of GABAergic inhibition is a mechanism for cortical reorganization, c) test hypotheses that RTN and CN provide substrates for the delay component in long-term cortical reorganization, and d) test hypotheses that forelimb amputation alters intact cortex and results in deficits in fine movement in the intact limb. The proposal incorporates techniques in physiological brain mapping, microstimulation, anatomical tracing, immunocytochemistry, and in-situ hybridization histochemistry that are routinely used in our laboratories. Four Aims are proposed: Aim 1: Test hypotheses that forelimb amputation results in delayed reorganization in VPL and CN, and reorganization is under GABAergic control. Aim 2: Test hypotheses that forepaw VPL projection neurons that relay new input to FBS also provide the pathway for new input to deafferented cortex. Aim 3: Test hypotheses that RTN provides delayed inhibitory control of VPL. Aim 4: Test hypotheses that forelimb amputation also alters non-deafferented cortex and leads to deficits in fine motor control in the intact limb.