NEUROTROPHIC FACTORS AND TRIGEMINAL PATTERN FORMATION

我们的长期目标是揭示躯体过敏的过程 图案的形成。损害、剥夺和描述性范式有 外周有序连接在脑血管疾病发生中的作用 然而，脉冲阻断对图案的形成没有影响。 因此，不清楚外围设备使用的是什么信令机制 在建立中枢神经系统模式方面。我们将使用啮齿动物胡须/桶 解决以下一般假设的模型：体视模式 结果是神经营养调节的结果，自然 在三叉神经节发生细胞死亡。初步数据 提示神经生长因子(NGF)之间存在新的因果关系 水平，V神经节细胞数量，以及桶的发育，提示 倒退的过程产生了躯体过敏的模式。要评估 这些观察的有效性和含义，并开始探索 神经营养因子对神经节细胞存活和中枢神经系统构型的影响 为了形成，将在大鼠身上检验以下具体假设：1： 胚胎V脑干核团中出现与胡须相关的模式 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志物和图像分析来分析 与胡须相关的图案以及体视学的发展 方法确定神经节细胞数量是否预测出现和 体位模式的相对成熟度。2：V神经节细胞表达 不同神经营养受体在不同时相的mRNA信息 对胎儿发育的影响。将进行原位杂交实验 对胎儿V神经节进行检测以确定该蛋白的表达模式 Trk原癌基因产物，具有与NGF相似的特性 高亲和力受体，trk-B基因产物结合脑源性 神经营养因子(BDNF)及其结合的trk-C基因产物 神经营养因子-3(NT-3)。逆行示踪剂也将用于 投射状态与该时期受体基因表达的相关性 自然发生的神经节细胞死亡和中枢神经系统模式的形成。 3：全身应用NGF、BDNF和/或NT-3将挽救V神经节 来自自然发生的细胞死亡的细胞。我们将确定年龄 其中每一种或所有这些神经营养因子在哪些方面最有效 维持多余的V神经节细胞。一种缓释的、慢性的 交付程序将用于方便、长期交付 NGF、BDNF和/或NT-3在不同胎龄的表达。4：中央V形图案起作用 当多余的V神经节细胞由 神经营养增强。组织化学标记物、图像分析和 神经节细胞体视学将用在每只动物身上来揭示 神经节细胞数量与胡须相关模式的关系 在脑干、丘脑和桶状皮质。出生后的病例也会 被研究以确定神经节细胞是否被永久挽救以及是否 图案形成被永久中断。这些研究可能会揭示 人类躯体感觉发育的一般控制原则 鉴于最近有迹象表明，人类在体位上存在分裂， V柱核和背侧柱核内有桶状聚集。生物学 神经营养因子的作用也将被揭示，可能是 临床价值。

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.