ACTIVITY DEPENDENT PLASTICITY OF NEUROENDOCRINE AXONS

描述(申请人摘要)：本项目的长期目标 是：1)确定神经元活动与轴突联系的机制 成体中枢神经系统发芽；2)发现成熟性减退的原因 在轴突萌发中；以及3)研究潜在的补偿方法 这些减量。这些目标将使用一个模型来解决 神经内分泌系统表现出异常旺盛的轴突可塑性， 下丘脑大细胞神经分泌系统，简称MNS。未损伤的神经元 幼年(35日龄)大鼠的MNS具有健壮的侧枝轴突 对破坏对侧大脑半球的病变作出反应而发芽 双边制度。这种萌芽反应是依赖于活动的。MNS神经元 在轴突萌发期间过度活跃，分泌更多的神经肽 催产素和加压素，同时萌发新的轴突侧支 在神经垂体内重建神经分泌轴突群。 如果MNS神经元的活动被抑制，则不会发生发芽 建立慢性低磨牙状态，并使MNS神经元更加成熟 (125日龄)大鼠不会因损伤而变得过度活跃，并 不是发芽。该提案的具体目的是：1)确定它是否是 启动和/或维持增长过程，即 活性依赖，并研究谷氨酸能和去甲肾上腺素能的作用 刺激萌发的传入；2)确定是否依赖于活动 轴突萌发是由生长因子IGF-I、CNTF和BDNF介导的， 细胞因子IL-1β，由神经细胞和胶质细胞合成并作用于神经元和胶质细胞 MNS；以及3)确定导致成熟度下降的机制 在侧枝萌发中的作用并确定慢性高渗刺激是否 MNS神经元可以逆转这种下降。这些目标将通过以下方式实现 受体阻断或慢性渗透刺激改变MNS活性 并将表达、细胞定位和活性的变化联系起来 上述因子及其受体与轴突出芽程度的关系 不同年龄的动物。这些目标的实现将提供新的见解 关于轴突重建的细胞机制 受损大脑中的种群以及在这些区域发生的改变 大脑成熟过程中的机制。

DESCRIPTION (applicant's abstract): The long term objectives of this project are: 1) to determine the mechanisms that link neuronal activity to axonal sprouting in the adult CNS; 2) to discover the cause of maturational decrements in axonal sprouting; and 3) to examine potential means of compensating for these decrements. These objectives will be addressed using a model neuroendocrine system that displays unusually vigorous axonal plasticity, the hypothalamic magnocellular neurosecretory system, or MNS. Uninjured neurons in the MNS of young adult (35 day-old) rats undergo robust collateral axonal sprouting in response to a lesion that destroys the contralateral side of this bilateral system. This sprouting response is activity-dependent. MNS neurons are hyperactive during axonal sprouting, secreting more of the neuropeptides oxytocin and vasopressin, while simultaneously sprouting new axon collaterals that reestablish the neurosecretory axon population within the neurohypophysis. Sprouting does not occur if activity of MNS neurons is inhibited by establishment of a chronic hyposmolar state, and MNS neurons in more mature (125 day-old) rats do not become hyperactive in response to the lesion and do not sprout. The specific aims of the proposal are: 1) to determine if it is the initiation and/or the maintenance of the growth process that is activity-dependent, and to examine the role of glutamatergic and noradrenergic afferents in stimulating sprouting; 2) to determine if activity-dependent axonal sprouting is mediated by the growth factors IGF-I, CNTF, and BDNF and the cytokine IL-1beta, synthesized by and acting upon the neurons and glia of the MNS; and 3) to identify mechanisms responsible for the maturational decline in collateral sprouting and to determine if chronic hyperosmotic stimulation of MNS neurons can reverse this decline. These aims will be accomplished by altering MNS activity by receptor blockade or through chronic osmostimulation and correlating changes in the expression, cellular localization, and activity of the above factors and their receptors with the extent of axonal sprouting in animals of different ages. Fulfillment of these aims will provide new insights regarding the cellular mechanisms involved in reestablishment of axon populations in the injured brain and the alterations that occur in these mechanisms during brain maturation.