AXON PLASTICITY AND RECOVERY OF FUNCTION AFTER TRAUMATIC BRAIN INJURY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 创伤性脑损伤(TBI)会导致严重的急性神经行为障碍，尽管有一些自发恢复，但在更慢性的时候仍然存在。至少有530万美国人--占美国人口的2%--目前患有脑外伤所致的残疾。然而，除了急性干预外，目前还没有被普遍接受的治疗方法来减少继发性神经病变和促进脑损伤后的功能恢复。拟议研究的中心假设是：(1)脑外伤后功能恢复有限，至少部分原因是轴突发芽不足，(2)有限的发芽是生长抑制分子(Growth-IMS)增加的结果，(3)减少生长-IMS的治疗将改善功能结局，(4)减少生长-IMS和激活细胞生长的联合治疗将进一步增强发芽和功能结局。我们根据受控皮质撞击(CCI)损伤后的观察结果提出这一假说，这是一个临床相关的脑创伤模型：1)尽管功能成像数据显示新的损伤区被激活，但仍出现持续性的行为缺陷，2)自发轴突出芽仅发生在生长抑制抑制硫酸软骨素蛋白多糖(CSPGs)减少的区域，3)CSPG的药物减少增加了伤区周围的出芽，4)同样的治疗诱导出芽是脊髓损伤后增强功能结果的解剖学基础，这也延长了暗饲养猫的可塑性关键期。基于这些观察，这项建议的重点是CSPG的生长抑制活性及其对脑损伤后失败的轴突可塑性的贡献。其具体目的是：(1)确定CCI损伤后CSPG表达与自发性轴突萌发的关系。我们将研究是否仅在CSPG低表达和CSPG神经周网络组织减少的区域发生自发轴突萌发，(Ii)确定减弱CSPG蛋白表达是否增强随后的轴突萌发。我们将使用软骨素酶ABC来降低自身CSPG蛋白以促进和维持轴突萌发，(Iii)确定轴突萌发是否是损伤后前肢诱发功能激活的新区域的局部和时间特异性。我们将评估轴突萌发是否为同一动物的功能恢复提供解剖学基础，(Iv)确定减弱CSPG表达是否改善功能和神经行为结果。我们将使用功能microPET成像和前肢功能的行为测试来确定增强发芽是否可以改善结果，(V)确定通过注射BDNF激活细胞生长状态和减弱CSPG表达是否会进一步增加发芽和改善行为结果。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Traumatic brain injury (TBI) results in significant acute neurobehavioral deficits that, despite some spontaneous recovery persist at more chronic times. At least 5.3 million Americans - 2% of the U.S. population currently lives with disabilities resulting from TBI. However, beyond acute interventions there are currently no generally accepted medical treatments for reducing secondary neuropathology and promoting functional recovery after TBI. The central hypotheses of the proposed research are that: (1) limited functional recovery after TBI is due, at least in part, to inadequate axonal sprouting, (2) limited sprouting is a result of an increase in growth-inhibitory molecules (growth-IMs), (3) treatment to reduce growth-IMs will improve functional outcome, and (4) combined treatments to reduce growth-IMS and to activate cellular growth will further enhance sprouting and functional outcome. We base this hypothesis on observations after controlled-cortical impact (CCI) injury, a clinically relevent model of TBI that: 1) a persistent behavioral deficit occurs, despite functional imaging data showing activation in novel ipsi-lesional regions, 2) spontaneous axon sprouting occurs only in regions of reduced growth-inhibitory chondroitin sulphate proteoglycans (CSPGs), 3) pharmacological reduction of CSPGs increases perilesional sprouting and 4) the same treatment-induced sprouting is the anatomical substrate for enhanced functional outcome after spinal cord injury which also prolongs the critical period for plasticity in dark-reared cats. Based on these observations the focus of this proposal is on the growth-inhibitory activity of the CSPGs and their contribution to failed axon plasticity after TBI. The specific aims are to: (i) Determine the relationship between CSPG expression and spontaneous axon sprouting after CCI injury. We will examine whether spontaneous axon sprouting occurs only in regions where CSPG expression is low and where perineuronal net organization of CSPGs is reduced, (ii) Determine whether attenuating CSPG protein expression enhances subsequent axonal sprouting. We will use chondroitinase ABC to reduce ipsi-lesional CSPG proteins to enhance and sustain axonal sprouting, (iii) Determine whether axon sprouting is regionally and temporally specific to novel regions of fore-limb evoked functional activation after injury. We will assess whether axonal sprouting provides the anatomical substrate for functional recovery in the same animal, (iv) Determine if attenuating CSPG expression improves functional and neurobehavioural outcome. We will use functional microPET imaging and behavioral tests of fore-limb function to determine if enhancing sprouting improves outcome, (v) Determine if activating cellular growth status by BDNF infusion combined with attenuation of CSPG expression results in further increases in sprouting and improved behavioral outcome.