Development of Sexually Dimorphic Forebrian Pathways

性二态性前体通路的发育

• 批准号: 7561037
• 负责人: RICHARD B SIMERLY
• 金额: $ 31.83万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7561037
• 关键词: Alkaline Phosphatase; Amygdaloid structure; Anatomy; Androgen Receptor; Anteroventral Thalamic Nucleus; Axon; Binding Sites; Biological Assay; Biological Models; Brain-Derived Neurotrophic Factor; Cell Nucleus; Cells; Chimeric Proteins; Coculture Techniques; Development; Estradiol; Estrogen Receptor alpha; Estrogens; Event; Experimental Models; Exposure to; Female; Goals; Gonadal Steroid Hormones; Gonadotropins; Growth; Hormonal; Hormones; Hypothalamic structure; Immunoblotting; Immunohistochemistry; In Situ Hybridization; In Vitro; Knock-in Mouse; Knockout Mice; Label; Life; Link; Location; Mediating; Messenger RNA; Modeling; Molecular; Mus; Mutant Strains Mice; Mutate; Neonatal; Neural Pathways; Neurites; Neurons; Neuropilin-1; Neuropilins; Neurotrophic Tyrosine Kinase Receptor Type 2; Pathway interactions; Pattern; Perinatal Exposure; Play; Preoptic Areas; Prosencephalon; Rattus; Recording of previous events; Regulation; Relative (related person); Research Personnel; Rodent; Role; Safe Sex; Semaphorin-3; Semaphorins; Sensory; Signal Transduction; Specific qualifier value; Structure; Structure of terminal stria nuclei of preoptic region; System; Testing; Testosterone; Time; To specify; Work; axon guidance; base; density; gain of function; in vivo; loss of function; male; member; mind control; nerve supply; nervous system disorder; neuronal cell body; neurotrophic factor; novel; overexpression; postnatal; programs; protein expression; receptor; relating to nervous system; research study; sex

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.

描述(申请人提供)：这项工作的长期目标是阐明哺乳动物前脑中性二态神经通路发展的细胞机制。这项拟议的项目将使用性二态边缘-下丘脑通路作为模型系统，研究性类固醇激素如何指定前脑连接的模式。在生命的第二周，视前区的前腹侧脑室周围核(AVPV)从终纹床核的主核(BSTp)接受到性二型输入，该主核根据定向机制发育。在过去的项目期间，我们开发了一个器官类型的共培养模型来证明这一途径的性别分化是由于雌激素对AVPV的靶向性依赖，即雌激素受体α(ERα)介导的作用。本申请正文中提出的初步证据表明，雌激素调节的神经营养因子BDNF(脑源性神经营养因子)和3类信号素Sema 3C在AVPV中以性二态模式表达，并似乎在促进BSTp-AVPV投射中发挥重要作用。我们的总体假设是，在生命的最初几天，E2作用于AVPV，改变BSTp神经元促进其神经支配的神经营养和趋化因子的表达。体外和体内实验模型将被用来检验两个特定的假说：特定目的1.在出生后发育过程中，ERpha介导AVPV中BDNF的表达增加，后者通过TrkB受体作用于BSTp轴突，促进轴突的延伸。特定目的2.AVPV中信号素的ERpha依赖表达影响从BSTp到AVPV的性二型投射的发展。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投射的生长和指导中的作用。这些研究的结果将对我们正在形成的对调节大脑发育的激素控制的分子事件的理解做出重大贡献，并将增加对轴突引导的发育调控的总体认识。这些研究还可能提供有关神经连接中性相关异常的机制的线索，这些异常导致各种激素敏感型神经疾病。

项目成果

Target-dependent sexual differentiation of a limbic-hypothalamic neural pathway.

边缘-下丘脑神经通路的目标依赖性性别分化。

• DOI: 10.1523/jneurosci.21-15-05652.2001
• 发表时间: 2001
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Ibanez,MA;Gu,G;Simerly,RB
• 通讯作者: Simerly,RB

Estrogen induces caspase-dependent cell death during hypothalamic development.

• DOI: 10.1523/jneurosci.0135-09.2009
• 发表时间: 2009-08-05
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Waters EM;Simerly RB
• 通讯作者: Simerly RB

Sex-specific patterns of galanin, cholecystokinin, and substance P expression in neurons of the principal bed nucleus of the stria terminalis are differentially reflected within three efferent preoptic pathways in the juvenile rat.

幼年大鼠终纹主床核神经元中甘丙肽、胆囊收缩素和 P 物质表达的性别特异性模式在幼年大鼠的三个传出视前通路中有所不同。

• DOI: 10.1002/cne.10841
• 发表时间: 2003
• 期刊: The Journal of comparative neurology.
• 作者: Polston,EvaK;Simerly,RichardB
• 通讯作者: Simerly,RichardB