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。肢体截肢是由疾病、创伤性事故、出生缺陷和战争造成的，通常伴有慢性疼痛、运动障碍和无法进行双手工作。肢体丧失可能导致长期残疾和失业，是一个主要的全球健康问题。截肢也会导致大量的皮质重组。了解截肢后的中枢神经系统后果对于设计治疗方法和制定替代策略来补偿肢体损失至关重要。对前肢截肢对中枢神经系统加工的影响的不完全了解限制了我们改善这些缺陷或开发修复功能的假肢装置的能力。皮质重组常与慢性肢体疼痛有关；通过对大脑重组的结构和功能基础的假设进行检验，我们有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大面积皮层重组延迟的机制。大鼠第一体感觉皮层前爪桶状亚区、腹侧后外侧核（VPL）、丘脑网状核（RTN）和楔状核（CN）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，并研究皮层重组的潜在机制。本研究的目的是：a)验证皮层大规模延迟重组源于皮层下回路改变的假说；b)验证gaba能抑制的去除是皮层重组机制的假说；c)验证RTN和CN为长期皮层重组的延迟成分提供底物的假说；d)验证前肢截肢改变完整皮层并导致完整肢体精细运动缺陷的假说。该方案结合了生理脑测绘、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，这些技术在我们的实验室中经常使用。目的1：验证前肢截肢导致VPL和CN的重组延迟，且重组受gaba能控制的假设。目的2：验证前爪VPL投射神经元将新输入传递到FBS的假设，也为新输入到去传入皮层提供了途径。目的3：验证RTN提供VPL延迟抑制控制的假设。目的4：验证前肢截肢也会改变非传入皮质并导致完整肢体精细运动控制缺陷的假设。

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.