Axon Plasticity and Recovery of Function after Traumatic Brain Injury

描述（由申请人提供）：创伤性脑损伤（TBI）导致严重的急性神经行为缺陷，尽管有一些自发恢复，但在更长时间内持续存在。目前至少有530万美国人——占美国人口的2%——生活在由创伤性脑损伤导致的残疾中。然而，除了急性干预外，目前还没有普遍接受的医学治疗方法来减少TBI后继发性神经病理和促进功能恢复。提出的研究的中心假设是：(1)TBI后有限的功能恢复是由于，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)减少生长抑制分子（growth- ims）的治疗将改善功能结果；(4)减少生长抑制分子和激活细胞生长的联合治疗将进一步增强发芽和功能结果。我们基于控制性皮质撞击（CCI）损伤后的观察得出这一假设，这是一种与TBI临床相关的模型：1)持续的行为缺陷发生，尽管功能成像数据显示在新的易损区域激活；2)自发轴突发芽仅发生在生长抑制硫酸软骨素蛋白聚糖（CSPGs）减少的区域；3) CSPGs的药理学减少增加了病灶周围的发芽，4)同样的治疗诱导的发芽是脊髓损伤后功能结果增强的解剖学基础，也延长了暗养猫的可塑性关键时期。基于这些观察结果，本提案的重点是CSPGs的生长抑制活性及其对脑外伤后轴突可塑性失效的贡献。具体目的是：(i)确定CCI损伤后CSPG表达与自发轴突发芽的关系。我们将研究自发性轴突发芽是否只发生在CSPG表达低和CSPG神经周围网络组织减少的区域，（ii）确定CSPG蛋白表达减弱是否会增强随后的轴突发芽。我们将使用软骨素酶ABC来减少单发CSPG蛋白，以增强和维持轴突发芽。（iii）确定轴突发芽是否在区域和时间上特异性于损伤后前肢诱发功能激活的新区域。我们将评估轴突发芽是否为同一动物的功能恢复提供了解剖学基础，（iv）确定减弱CSPG表达是否能改善功能和神经行为结果。我们将使用功能性微pet成像和前肢功能行为测试来确定增强发芽是否能改善结果。(v)确定通过BDNF输注激活细胞生长状态并抑制CSPG表达是否能进一步增加发芽和改善行为结果。

DESCRIPTION (provided by applicant): 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.