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

描述(由申请人提供)：美国有超过160万截肢者，据估计每周有3000人加入截肢者行列。截肢是由疾病、创伤事故、出生缺陷和战争引起的，通常伴随着慢性疼痛、运动障碍和无法执行双手作业。肢体丧失可能导致长期残疾、失业，并代表着一个重大的世界性健康问题。截肢还会导致大量的皮质重组。了解截肢后的中枢神经后果对于设计治疗方法和开发替代策略来补偿肢体丧失至关重要。对前肢截肢对中枢神经系统处理的影响的不完全了解限制了我们改善这些缺陷或开发用于恢复功能的假体设备的能力。皮质重组通常与慢性肢体疼痛有关；通过检验关于大脑重组的结构和功能基础的假说，我们可以希望更好地理解和控制慢性肢体疼痛。这项建议的目标是了解前肢截肢后延迟的大规模皮质重组背后的机制。大鼠第一躯体感觉皮层、腹后外侧核(VPL)、丘脑网状核(RTN)和楔状核(CN)的前爪桶状亚区将作为我们的模型系统。通过使用我们擅长的模型系统和技术，我们将阐明前肢截肢的主要后果，并检查皮层重组的潜在机制。这项建议的目标是：a)检验皮质下回路改变导致延迟大规模皮质重组的假说，b)检验移除GABA能抑制是皮质重组的机制的假说，c)检验RTN和CN为长期皮质重组中延迟成分提供底物的假说，以及d)检验前肢截肢改变完整皮质并导致完整肢体精细运动障碍的假说。该提案结合了我们实验室常规使用的生理脑图、微刺激、解剖示踪、免疫细胞化学和原位杂交组织化学等技术。提出四个目标：目标1：验证假设：前肢截肢导致VPL和CN延迟重组，重组受GABA能控制。目的2：验证前爪VPL投射神经元将新的信息传递到FBS的假说，也是向去传入皮层传递新信息的途径。目的3：验证RTN对VPL提供延迟抑制控制的假设。目的4：验证前肢截肢也改变非传入皮质并导致完整肢体精细运动控制缺陷的假说。

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.