Ethanol, neurotrophins, and thalamocortical matching

描述(申请人提供)：早期接触乙醇会对神经系统的发育产生深远的影响。事实上，胎儿酒精暴露被描述为智力低下的主要原因。在发育过程中，神经元被过度生产，在自然发生的神经元死亡(NQND)期间，一个亚群被消除。NOND是用于匹配系统内的投影和目标人群的机制，暴露于乙醇会干扰三叉神经-躯体感觉(tri-ss)系统中的数字匹配。酒精处理组大鼠三叉神经感觉主核和体感皮质(2级和4级神经元)神经元减少33%。相反，乙醇对丘脑腹基底核(VB)(三级神经元)的神经元数量没有影响。神经元存活的结果是年轻神经元成功地竞争神经营养因子(S)(例如，神经生长因子；神经营养因子)的能力，而神经营养因子是有限供应的。这些因子的表达和活性受到乙醇的影响。这项拟议的项目将检验这样一种假设，即酒精导致的神经营养素系统的破坏是tri-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躯体感觉皮质和VB中神经营养因子配体和受体表达的影响。乙醇以自体/旁分泌调节为靶点的可能性将通过免疫组织化学-原位杂交相结合的方法来探索。(2)体外实验将研究乙醇对神经营养素受体表达和激活以及信号通路激活的影响。研究将使用器官型切片培养，以维持丘脑皮质传入神经营养因子从皮质到丘脑的逆行运输。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有价值的数据，以及(3)为未来神经营养因子在发育中的作用的机制研究奠定基础。

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.