GABAergic Circuits Critical period in Visual Cortex

GABAergic 电路视觉皮层的关键期

• 批准号: 6765959
• 负责人: Z JOSH HUANG
• 金额: $ 41.5万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6765959
• 关键词: artificial chromosomes; brain derived neurotrophic factor; cell type; confocal scanning microscopy; developmental neurobiology; electrophysiology; functional /structural genomics; gamma aminobutyrate; gene targeting; genetically modified animals; imaging /visualization /scanning; immunocytochemistry; immunofluorescence technique; interneurons; laboratory mouse; neural plasticity; neural transmission; northern blottings; polymerase chain reaction; visual cortex; visual deprivation; visual perception; voltage /patch clamp

Early postnatal experience can profoundly influence the structure and function of the mammalian neocortex. The cellular and molecular mechanisms underlying the critical period plasticity in visual cortex will provide insight into the development of other sensory and cognitive functions, learning and memory, rehabilitation, and regeneration. It has been suggested that the development of GABAergic inhibitory mechanisms may initiate and drive the critical period for ocular dominance (OD) plasticity in visual cortex. GABAergic interneurons are morphologically and physiologically diverse and control cortical excitability at precise spatial and temporal domains. We hypothesize that the functional maturation of distinct classes of GABAergic circuits allows enhanced GABAergic synaptic transmission during the critical period and contributes to OD plasticity. We will use cell type-specific promoters and bacterial artificial chromosome transgenics in mice to label specific classes of GABAergic interneurons in living tissue. We will then characterize the functional maturation of such GFP labeled interneurons in cortical slices using electrophysiology and two-photon imaging. Furthermore, we will alter the expression of the GABA synthetic enzyme GAD65 in two classes of GABAergic circuits: the parvalbumin- containing basket interneurons and the somatostatin- containing bitufted interneurons. We will then examine the consequences of such cell type-specific manipulation of GABAergic transmission on the critical period of OD plasticity using single unit recording in visual cortex. Maturation of cortical GABAergic circuitry is in turn strongly influenced by visual experience. We hypothesize that the brain-derived neurotrophic factor (BDNF) is a key molecular signal that promotes the normal maturation of GABAergic interneurons and retards their development during visual deprivation. We will examine whether BDNF overexpression in visual cortex in transgenic mice can rescue the effects of dark rearing on the maturation of GABAergic circuits and on visual function using immunohistochemistry and electrophysiology. A genetic approach to the function and development of specific classes of GABAergic circuits will contribute to our understanding of the microarchitecture and information processing in normal neocortex and its deregulated states such as epilepsy.

早期产后经验可以深刻影响哺乳动物新皮层的结构和功能。 视觉皮层中关键周期可塑性的基础的细胞和分子机制将洞悉其他感觉和认知功能，学习和记忆，康复和再生的发展。已经提出，GABA能抑制机制的发展可能启动并推动视觉皮层中眼部优势（OD）可塑性的关键时期。 GABA能中神经元在形态和生理上是多样的，并在精确的空间和时间域中控制皮质兴奋性。 我们假设不同类别的GABA能电路的功能成熟允许在关键时期增强GABA能突触传播，并有助于OD可塑性。我们将在小鼠中使用细胞类型特异性启动子和细菌人造染色体转基因，以在活组织中标记特定类别的GABA能中间神经元。 然后，我们将使用电生理学和两光子成像来表征这种GFP在皮质切片中标记的中间神经元的功能成熟。 此外，我们将在两类的GABA能回路中改变GABA合成酶GAD65的表达：包含白细胞蛋白的篮子中神经元和含有bituft的中间神经元的生长抑制剂。 然后，我们将使用视觉皮层中的单个单位记录来检查这种细胞类型特异性操纵GABA能传播在OD可塑性的关键时期的后果。皮质GABA能回路的成熟反过来受视觉体验的强烈影响。 我们假设脑衍生的神经营养因子（BDNF）是一个关键的分子信号，可促进GABA能中间神经元的正常成熟，并在视觉剥夺过程中延迟其发育。 我们将检查转基因小鼠视觉皮层中的BDNF过表达是否可以挽救黑暗饲养对GABA能回路成熟以及使用免疫组织化学和电生理学的视觉功能的影响。针对特定类别的GABA能电路功能和开发的遗传方法将有助于我们理解正常新皮层及其失控状态（例如癫痫）的微体系结构和信息处理。