NEUROTROPHIC FACTORS AND TRIGEMINAL PATTERN FORMATION

神经营养因子和三叉神经模式的形成

• 批准号: 5215132
• 负责人: MARK F JACQUIN
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5215132
• 关键词: apoptosis; brain mapping; brain stem; developmental neurobiology; embryo /fetus; ganglions; gene expression; growth factor receptors; histochemistry /cytochemistry; in situ hybridization; intercellular connection; laboratory rat; neurogenesis; neuronal transport; neurotrophic factors; receptor binding; slow release drug; somesthetic sensory cortex; thalamus; trigeminal nerve

Our long-term goal is to reveal processes responsible for somatotopic pattern formation. Lesion, deprivation and descriptive paradigms have implicated ordered peripheral connections in the development of somatotopy; yet, impulse blockade has no effect on pattern formation. Thus, it is unclear what signalling mechanism is used by the periphery in establishing CNS patterns. We will employ the rodent whisker/barrel model to address the following general hypothesis: Somatotopic patterns result as a consequence of neurotrophically regulated, naturally occurring cell death in the trigeminal (V) ganglion. Preliminary data suggest novel causal relationships between nerve growth factor (NGF) level, V ganglion cell number, and the development of barrels, suggesting that regressive processes produce somatotopic patterns. To assess the validity and implications of these observations, and to begin to explore how neurotrophic factors impact on ganglion cell survival and CNS pattern formation, the following specific hypotheses will be tested in rats: 1: Whisker-related patterns emerge in fetal V brainstem nuclei during a period when large numbers of V ganglion cells die of natural causes. We will use an array of histochemical markers and image analysis to assay the development of whisker-related patterns, as well as stereological methods to determine if ganglion cell number predicts the emergence and relative maturity of somatotopic patterns. 2: V ganglion cells express mRNA message for different neurotrophic receptors during different phases of fetal development. In situ hybridization experiments will be carried out on fetal V ganglia to determine patterns of expression of the protein product of the trk proto-oncogene which has similar properties to the NGF high-affinity receptor, the trk-B gene product that binds brain-derived neurotrophic factor (BDNF), and the trk-C gene product that binds neurotrophin-3 (NT-3). A retrograde tracer will also be used to correlate projection status with receptor gene expression over the period of naturally occurring ganglion cell death and CNS pattern formation. 3: systemic delivery of NGF, BDNF and/or NT-3 will rescue V ganglion cells from naturally occurring cell death. We will determine the ages at which each or all of these neurotrophic factors is most effective in sustaining supernumerary V ganglion cells. A slow-release, chronic delivery procedure will be used for convenient, long-term delivery of NGF, BDNF, and/or NT-3 at varying fetal ages. 4: Central V patterns do not develop when supernumerary V ganglion cells are sustained by neurotrophic augmentation. Histochemical markers, image analysis, and ganglion cell stereology will be used in each animal to reveal relationships between ganglion cell number and whisker-related patterns in the brainstem, thalamus, and barrel cortex. Postnatal cases will also be studied to determine if ganglion cells are permanently rescued and if pattern formation is permanently interrupted. These studied may uncover general principles controlling somatosensory development in humans in light of recent indications that humans have somatotopically parcellated, barrel-like aggregations in V and dorsal column nuclei. Biological actions of neurotrophic factors will also be revealed that may be of clinical value.

我们的长期目标是揭示负责躯体异位性的过程， 图案形成 损伤、剥夺和描述性范例 暗示了有序的外周连接在 然而，冲动阻断对图案形成没有影响。 因此，目前还不清楚外围国家使用的是什么信号机制 建立中枢神经系统模式。 我们将使用啮齿动物的胡须/桶 模型，以解决以下一般假设： 结果是神经营养调节的结果， 在三叉神经（V）神经节中发生细胞死亡。 初步数据 提示神经生长因子（NGF） 水平，V神经节细胞数量，和桶的发展，表明 回归过程会产生躯体位置模式 评估 有效性和这些意见的影响，并开始探索 神经营养因子如何影响神经节细胞存活和CNS模式 形成，将在大鼠中测试以下特定假设：1： 胎儿脑干V核团在发育过程中出现须状突起相关的模式。 大量V神经节细胞自然死亡的时期。 我们 将使用一系列组织化学标记和图像分析来分析 胡须相关模式的发展，以及体视学 确定神经节细胞数量是否预测出现的方法， 体视模式的相对成熟。 2：V节细胞表达 不同神经营养受体在不同时期的mRNA信息 胎儿的发育。 将进行原位杂交实验 在胎儿V神经节上， trk原癌基因的产物，其具有与NGF相似的性质 高亲和力受体，trk-B基因产物，结合脑源性 神经营养因子（BDNF）和trk-C基因产物， 神经营养素-3（NT-3）。 逆行示踪剂也将用于 将投射状态与受体基因表达相关联， 神经节细胞自然死亡和中枢神经系统模式形成。 3：全身递送NGF、BDNF和/或NT-3将拯救V神经节 自然发生的细胞死亡。 我们将确定年龄 每一种或所有这些神经营养因子在 维持多余的V神经节细胞 一种缓释，慢性 交付程序将用于方便，长期交付 NGF、BDNF和/或NT-3。 4：中央V型 当额外的V神经节细胞被维持时， 神经营养增强 组织化学标记，图像分析， 将在每只动物中使用神经节细胞体视学来揭示 神经节细胞数量与须相关模式之间的关系 脑干丘脑和桶状皮层 产后病例也将 进行研究，以确定神经节细胞是否被永久拯救， 图案形成被永久中断。 这些研究可能揭示 控制人类躯体感觉发育的一般原则 根据最近的迹象表明人类已经在躯体位置上被包裹， V核和背柱核内有桶状聚集。 生物 神经营养因子的作用也将被揭示，这可能是 临床价值