Development of Sexually Dimorphic Forebrian Pathways

描述（由申请人提供）：这项工作的长期目标是阐明哺乳动物前脑两性二态神经通路发育的细胞机制。该计划将使用两性二态的边缘-下丘脑通路作为模型系统来研究性类固醇激素如何指定前脑连接模式。在出生后的第二周，视前区腹侧脑室周围核（AVPV）接受来自终纹床核（BSTp）主核的两性二态输入，该输入根据定向机制发育。在过去的项目期间，我们开发了一个器官型共培养模型，以证明这条途径的性别分化是由于雌激素受体α (er α)介导的靶标依赖性作用于AVPV。本研究的初步证据表明，雌激素调节的神经营养因子BDNF（脑源性神经营养因子）和3类信号蛋白Sema 3C在AVPV中以两性二态模式表达，似乎在促进BSTp-AVPV投射中发挥重要作用。我们的总体假设是，E2在生命的最初几天作用于AVPV，改变神经营养因子和趋化因子的表达，促进BSTp神经元的神经支配。体外和体内实验模型将用于验证两个特定假设：在出生后发育过程中，erα介导AVPV中BDNF的表达增加，BDNF通过TrkB受体作用于BSTp轴突，促进神经突延伸。具体目标2。依赖erα的信号蛋白在AVPV中的表达影响从BSTp到AVPV的两性二态投射的发展。除了表征这些分子在BSTp- avpv通路发展过程中的表达外，我们还将利用功能丧失/功能获得策略来探索它们在BSTp生长和指导BSTp预测中的作用。这些研究的结果将对我们对调节激素控制大脑发育的分子事件的新兴理解做出重大贡献，并将增加对轴突指导的发育调节的了解。这些研究也可能为神经连接中导致各种激素敏感神经疾病的性别相关畸变的机制提供线索。

DESCRIPTION (provided by applicant): The long-range goal of this work is to clarify cellular mechanisms that underlie development of sexually dimorphic neural pathways in the mammalian forebrain. The proposed project will use a sexually dimorphic limbic-hypothalamic pathway as a model system to study how sex steroid hormones specify patterns of forebrain connections. During the second week of life, the anteroventral periventricular nucleus of the preoptic region (AVPV) receives a sexually dimorphic input from the principal nucleus of the bed nuclei of the stria terminalis (BSTp) that develops according to a directed mechanism. During the past project period we developed an organotypic co-culture model to demonstrate that sexual differentiation of this pathway is due to a target dependent, estrogen receptor alpha (ERalpha)-mediated, action of estrogen on the AVPV. Preliminary evidence presented in the body of this application indicates that the estrogen-regulated neurotrophin BDNF (brain derived neurotrophic factor), and the class 3 semaphorin Sema 3C, are expressed in the AVPV in sexually dimorphic patterns and appear to play important roles in promoting BSTp-AVPV projections. Our Overall Hypothesis is that E2 acts on the AVPV during the first few days of life to alter expression of neurotrophic and chemotropic factors that promote its innervation by BSTp neurons. Both in vitro and in vivo experimental models will be used to test two specific hypotheses: Specific Aim 1. During postnatal development, ERalpha mediates increased expression of BDNF in the AVPV, which acts on BSTp axons via TrkB receptors to promote neurite extension. Specific Aim 2. ERalpha dependent expression of semaphorin in the AVPV influences development of sexually dimorphic projections from the BSTp to the AVPV. In addition to characterizing expression of these molecules during development of the BSTp-AVPV pathway, we will utilize a loss of function/gain of function strategy to explore their role during growth and guidance of BSTp projections. The results of these studies will make a significant contribution to our emerging understanding of molecular events that mediate hormonal control of brain development, and will add to what is known about developmental regulation of axon guidance generally. These studies may also provide clues about mechanisms responsible for sex-linked aberrations in neural connectivity that contribute to a variety of hormone-sensitive neurological disorders.