BDNF Roles in Regulating Cortical Dendrite Structure

BDNF 在调节皮质树突结构中的作用

• 批准号: 6894001
• 负责人: KEVIN Robert JONES
• 金额: $ 33.3万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6894001
• 关键词: autocrine; biological signal transduction; brain derived neurotrophic factor; cerebral cortex; dendrites; developmental neurobiology; electron microscopy; embryogenesis; gene expression; gene mutation; genetically modified animals; hippocampus; laboratory mouse; neural degeneration; neural plasticity; neuroanatomy; neuroeffector; neuronal transport; synaptogenesis; visual deprivation

DESCRIPTION (provided by applicant): To enable effective responses to a complex and changing world, the neocortex has evolved mechanisms of plasticity that couple patterned neural activity to modification of neural circuitry. Neurotrophins, a family of secreted growth factors, participate in the molecular mechanisms that underly the differentiation and survival of specific neural types, the formation of neural circuitry, the maintenance and plasticity of this circuitry, and the etiology of neural disease. In the cortex, the neurotrophin brain-derived neurotrophic factor (BDNF) is particularly abundant and has been implicated in all of these processes, extending from the initial genesis of cortical neurons through their demise in disease. To precisely identify the necessary functions of BDNF, we have pursued a genetic analysis in the mouse. Because BDNF null mutant mice die during their first weeks of life after retarded postnatal development, interpretation of their forebrain phenotype is complicated. Thus, although BDNF is clearly an important molecule, the specific roles of BDNF in development and maintenance of the cortex are still obscure. Accordingly, we have generated conditional mutations of BDNF that result in loss of BDNF in either the embryo or the adult and begun the analysis of their phenotype. Using these mice, we have found that BDNF is essential for the developmental stabilization of visual cortical layer 2/3 pyramidal neuron dendrite form. This proposal describes further studies of these mice directed toward elucidating specific BDNF functions in the visual cortex. The developmental relationship between dendritic spines, synapses, and defects in dendrite structure will be determined. We will extend our study of cortical dendrites to other layers, and to include adult requirements for BDNF. We will test whether BDNF is necessary for experience-dependent anatomical changes in the cortex. To elucidate directionality of BDNF signaling in the cortex, we will test whether BDNF has cell-autonomous functions. The results of these studies will clarify the roles of BDNF in the development, maintenance, and plasticity of cortical circuitry.

描述（由申请人提供）：为了能够对复杂且不断变化的世界做出有效反应，新皮质已经进化出可塑性机制，将模式化的神经活动与神经回路的修改结合起来。神经营养素是一类分泌性生长因子，参与特定神经类型的分化和存活、神经回路的形成、该回路的维持和可塑性以及神经疾病的病因学的分子机制。在皮质中，神经营养蛋白脑源性神经营养因子（BDNF）特别丰富，并且与所有这些过程有关，从皮质神经元的最初起源一直到它们在疾病中的死亡。为了精确确定 BDNF 的必要功能，我们对小鼠进行了遗传分析。由于 BDNF 缺失突变小鼠在出生后发育迟缓后在生命的第一周内死亡，因此对其前脑表型的解释很复杂。因此，尽管 BDNF 显然是一个重要的分子，但 BDNF 在皮质发育和维持中的具体作用仍然不清楚。因此，我们产生了 BDNF 的条件突变，导致胚胎或成人中 BDNF 的丧失，并开始分析其表型。使用这些小鼠，我们发现 BDNF 对于视觉皮层 2/3 锥体神经元树突形式的发育稳定至关重要。该提案描述了对这些小鼠的进一步研究，旨在阐明视觉皮层中特定的 BDNF 功能。树突棘、突触和树突结构缺陷之间的发育关系将被确定。我们将对皮质树突的研究扩展到其他层，并包括成人对 BDNF 的需求。我们将测试 BDNF 是否对于皮质中依赖于经验的解剖学变化是必要的。为了阐明皮质中 BDNF 信号传导的方向性，我们将测试 BDNF 是否具有细胞自主功能。这些研究的结果将阐明 BDNF 在皮质回路的发育、维持和可塑性中的作用。