SYNAPTIC REMODELING OF THE STRIATUM AFTER DEAFFERENTATION

该项目旨在确定调节细胞的细胞机制， 纹状体（ST）神经突生长和突触替代 对损伤的反应以及衰老对这些过程的影响。 研究 在上一个资助期间进行的研究表明， 反应性突触发生的细胞基础包括激活 部分重叠的发育信号的特定集合， 细胞类型，脑区和病变特异性，这些反应可能 受到年龄的不同影响。 然而，虽然以前的解剖学 研究已经很容易地证明了神经元形成新的 突触回路对脑损伤的细胞机制 调节反应性突触发生的机制尚不清楚。 拟议的研究是已完成工作的直接延伸 以前，并将测试四个一般假设：1），不同的集， 的生长相关蛋白调节神经突生长， 皮质纹状体神经元对不同传入神经阻滞病变的反应： 2)碎片清除、终端增殖和 损伤后ST段的突触替代受年龄和 3）突触神经支配的新模式， 在皮层损伤后ST段中形成的是不同的， 黑质或两者，并反映在药理学 纹状体神经元上突触输入的性质;以及4） 慢性饮食限制或多巴胺受体激动剂治疗 培高利特来操纵ST中的老化效应（即，反应性 星形胶质细胞增多症，D2受体丢失）将逆转衰老对 皮层损伤后出现树突重塑和神经突生长。 我们将在年轻人（4个月）和老年人中使用实验性传入神经阻滞病变 (24 mos）大鼠来模拟不同的神经递质组合 可能影响神经突生长和突触替代的缺陷， 脑损伤后ST。 此外，我们将筛选老年大鼠之前， 手术，使用平衡木测试，以确定老年大鼠的子集， 黑质纹状体缺陷可能会改变他们对 病变 我们还将评估功能恢复率， 与我们的形态学和分子数据相关联 形态 ST段传入输入的重塑将使用 超微结构的方法;而突触生理学的解剖学 将通过电生理分析检查重组ST。 在 此外，我们还将采用原位杂交和western blot方法， 以确定mRNA和蛋白质水平变化的时间过程， 我们假设它们与神经突的生长有关 ST中的生长和突触替换（即，SCG-10 GAP-43 BDNF GDNF等）。

This project seeks to identify the cellular mechanisms that regulate neurite outgrowth and synapse replacement in the striatum (ST) in response to injury and the effect of aging on these processes. Studies conducted during the previous funding period support the belief that the cellular basis of reactive synaptogenesis involves the activation of specific sets of partially overlapping developmental signals that are cell type, brain region and lesion specific, and that these responses may be differentially affected by age. However, while previous anatomical studies have readily demonstrated the ability of neurons to form new synaptic circuits in response to brain injury the cellular mechanisms that regulate reactive synaptogenesis remain unclear. The studies proposed are a direct extension of the work completed previously and will test four general hypotheses: 1) that different sets of growth associated proteins regulate neurite outgrowth in corticostriatal neurons in response to different deafferentation lesions: 2) that the time course for debris removal, terminal proliferation and synapse replacement in the ST after injury is influenced by age and the type of lesion involved; 3) that the new pattern of synaptic innervation that is formed in the ST is different after lesions of the cortex, substantia nigra or both, and are reflected in the pharmacological properties of the synaptic input on striatal neurons; and 4) that chronic dietary restriction or treatment with the dopamine agonist pergolide to manipulate the effects of aging in the ST (i.e., reactive astrocytosis, loss of D2 receptors) will reverse the effects of aging on dendrite remodeling and neurite outgrowth found after the cortex lesion. We will use experimental deafferentation lesions in young (4 mos) and old (24 mos) rats to model different combinations of neurotransmitter deficits that may effect neurite outgrowth and synapse replacement in the ST following brain injury. In addition, we will screen aged rats prior to surgery, using the balance beam test, to identify subsets of old rats with nigrostriatal deficits that may alter their ability to respond to the lesion. We will also assess the rate of functional recovery to correlate with our morphological and molecular data. Morphological remodeling of afferent input to the ST will be evaluated using ultrastructural methods; while synaptic physiology of the anatomically reorganized ST will be examined by electrophysiological analysis. In addition, we will use in in situ hybridization and western blot methods to define the time course of changes in the levels of mRNAs and proteins that we hypothesize are associated with the promotion of neurite outgrowth and synapse replacement in the ST (i.e., SCG-10, GAP-43, BDNF, GDNF, etc.).