BDNF Roles in Regulating Cortical Dendrite Structure

BDNF 在调节皮质树突结构中的作用

• 批准号: 7077648
• 负责人: KEVIN Robert JONES
• 金额: $ 32.53万
• 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/7077648
• 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(申请人提供)：为了能够对复杂和不断变化的世界做出有效的反应，新大脑皮层进化出了可塑性机制，将模式神经活动与神经回路的修饰结合在一起。神经营养因子是一类分泌型生长因子家族，参与了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的分子机制。在大脑皮层，神经营养因子脑源性神经营养因子(BDNF)尤其丰富，并参与了所有这些过程，从皮质神经元的最初形成一直延伸到疾病中的死亡。为了准确地确定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的第一周就会死亡，因此对它们的前脑表型的解释是复杂的。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，我们已经产生了BDNF的条件性突变，导致BDNF在胚胎或成人中丢失，并开始分析它们的表型。利用这些小鼠，我们发现BDNF对于视皮层2/3层锥体神经元树突形式的发育稳定是必不可少的。这项建议描述了对这些小鼠的进一步研究，旨在阐明视觉皮质中特定的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。我们将把我们对皮质树突的研究扩展到其他层面，并包括成人对脑源性神经营养因子的需求。我们将测试脑源性神经营养因子是否是经验依赖的皮质解剖变化所必需的。为了阐明脑源性神经营养因子信号在大脑皮层的方向性，我们将测试脑源性神经营养因子是否具有细胞自主功能。这些研究结果将阐明脑源性神经营养因子在皮质回路的发育、维持和可塑性中的作用。