Ethanol, neurotrophins, and thalamocortical matching

描述（由申请人提供）：早期接触乙醇会严重影响神经系统的发育。事实上，胎儿接触酒精已被描述为智力迟钝的主要原因。在发育过程中，神经元过度产生，在自然发生的神经元死亡（NQND）期间，一个子集被消除。NOND是用于匹配系统内投射和目标人群的机制，暴露于乙醇会干扰三叉-体感（tri-ss）系统中的数字匹配。乙醇处理大鼠三叉神经主感觉核和体感觉皮层（2级和4级神经元）神经元减少33%。相比之下，神经元的数量；在丘脑腹基底核（VB）（3阶神经元）中，乙醇没有改变。神经元存活源于年轻神经元成功竞争神经营养因子（如神经生长因子）的能力，而神经营养因子的供应有限。这些因子的表达和活性受到乙醇的影响。拟议的项目将测试乙醇诱导的神经营养系统的破坏是tr3 -ss组织变化的基础。将进行两项补充研究。(1)体内实验将检测乙醇对体感觉皮层和VB中神经营养配体和受体表达的影响。我们将结合免疫组织化学原位杂交的方法来探索乙醇靶向自体分泌/旁分泌调节的可能性。(2)体外研究将检验乙醇对神经营养因子受体的表达和激活以及信号通路的激活的影响。研究将使用器官型切片培养来维持丘脑皮质事件，这些事件可以将神经营养物质从皮层逆行运输到丘脑。这些研究将(1)评估乙醇破坏tri-ss发育的机制，(2)提供有关神经营养因子功能的宝贵数据，(3)为未来神经营养因子在发育中的作用机制研究奠定基础。

DESCRIPTION (provided by applicant): Early exposure to ethanol profoundly affects development of the nervous system. Indeed, fetal alcohol exposure has been described as the primary cause of mental retardation. During development, neurons are overproduced and a subset are eliminated during a period of naturally occurring neuronal death (NQND). NOND is the mechanism used to match projection and target populations within a system Exposure to ethanol interferes with numerical matching in the trigeminal-somatosensory (tri-ss) system. There are 33% fewer neurons in the principal sensory nucleus of the trigeminal nerve and somatosensory cortex (2nd and 4th order neurons) in ethanol-treated rats. In contrast, the number of neurons; n the thalamic ventrobasal nucleus (VB) (3rd order neurons) is not altered by ethanol. Neuronal survival results from the ability of young neurons to successfully compete for neurotrophin(s) (e.g., nerve growth factor; that are available in limited supply. Expression and activity of these factors is compromised by ethanol. The proposed project will test the hypothesis that ethanol-induced disruption of neurotrophin systems underlies the changes in the tri-ss organization. Two complementary studies will be performed. (1) In vivo experiments will examine the effect of ethanol on neurotrophin ligand and receptor expression in both the somatosensory cortex and the VB. The possibility that ethanol targets an autrocine/paracrine -regulation will be explored with a combined immunohistochemical-in situ hybridization approach. (2) In vitro studies will examine the effects of ethanol on expression and activation of neurotrophin receptors, and activation of signaling pathways. Studies will use organotypic slice cultures that maintain the thalamocortical afferents that can retrogradely transport neurotrophins from cortex to thalamus. These studies will (1) assess mechanisms by which ethanol disrupts tri-ss development, (2) provide valuable data on neurotrophin function, and (3) be a base for future mechanistic studies of the role of neurotrophins in development.