Dynamic Microdomains in Brain Extracellular Space

大脑细胞外空间的动态微域

• 批准号: 8446998
• 负责人: SABINA HRABETOVA
• 金额: $ 33.51万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446998
• 关键词: Adrenergic Agents; Adrenergic Receptor; Affect; Agonist; Anions; Astrocytes; Axosomatic Synapse; Brain; Brain Neoplasms; Calcium; Caliber; Cations; Cells; Characteristics; Charge; Chemicals; Communication; Complex; Corpus striatum structure; Development; Diffuse; Diffusion; Discrimination; Drug Carriers; Drug Delivery Systems; Environment; Enzymes; Extracellular Matrix; Extracellular Space; Goals; Health; Hippocampus (Brain); Hormones; Hypothalamic structure; Ions; Life; Measurement; Measures; Mediating; Methodology; Methods; Modeling; Morphology; Neocortex; Neuroglia; Neurons; Nutrient; Optics; Patients; Pharmaceutical Preparations; Physiological; Polymers; Process; Property; Research; Resolution; Route; Shapes; Signal Transduction; Signaling Molecule; Solutions; Stimulus; Stress; Structure; Synapses; System; Testing; Therapeutic Agents; Time; Tissues; Transport Process; Visual Cortex; Width; adrenergic; aquaporin 4; brain cell; brain tissue; design; flexibility; in vivo; locus ceruleus structure; mathematical model; nervous system disorder; neuronal cell body; pressure; research study; response; spreading depression; theories; three-dimensional modeling; trafficking; water channel

DESCRIPTION (provided by applicant): The long-term goal of our research is to construct and characterize a realistic three-dimensional model of the brain extracellular space (ECS), in order to predict the impact of microstructural changes on the transport of signaling molecules, nutrients and therapeutic agents. ECS comprises the narrow channels that separate brain cells but cannot be directly visualized in the living brain. It is essential for normal brain function and influences many critical processes including intercellular signaling, nutrient delivery and neurotrophic effects. Significantly, the ECS also forms the final route for all drug delivery to brain cells. To develop quantitative understanding of any of these diffusion-mediated processes, essential structural parameters of the complex ECS environment must be identified and characterized. Traditional diffusion measurements, made over relatively large distances, extract two macroscopic parameters, volume fraction and tortuosity. Volume fraction is the proportion of tissue volume occupied by the ECS, and tortuosity quantifies average hindrance imposed on diffusing molecules by the complex ECS environment. The concentration of a diffusing substance is primarily influenced by volume fraction while tortuosity imposes delays in the timing. It has been taken for granted that these parameters remain constant over all diffusion distances. However, we have recently discovered that diffusion in the brain is transiently anomalous over distances of a few tens of micrometers. This means that, over this distance, the rate of diffusion depends on time and generally is faster than currently believed. To explore the phenomenon of a transiently anomalous diffusion, we introduce the concept of a Dynamic Microdomain (DM), defined as the largest volume of the brain tissue in which the anomalous diffusion is observed. The size of the DM will depend on the local structure and can change in response to various stimuli. In Aim 1, we propose to develop a Fast Optical Tracking of Diffusion (FOTOD) method to measure DM size and analyze diffusion within it. FOTOD will be equally applicable when normal diffusion occurs in a dynamically changing ECS, e.g., during spreading depression (Aim 1) or synchronous neuronal activity (Aim 4). Aims 2-4 will explore several physiologically important aspects of the DM structure with this new methodology. Aim 2 determines that structural plasticity of the astrocytic processes induced by beta2- adrenergic neuron-glia signaling represents an, as yet unrecognized, mechanism that modulates cellular communication in the visual cortex. The astrocytic processes act by altering the DM diffusion properties. Aim 3 shows how negatively-charged perineuronal matrix nets attract polyvalent cations (e.g., calcium) but repulse polyvalent anions, thereby acting as charge discriminators within the DMs. In Aim 4, scaling theory applied to the diffusion of flexible polymers estimates the average width of ECS pores. Very few estimates of this basic parameter exist in living brain, yet the characteristic pore width is essential for the development of drug carriers, and for any realistic model of DMs.

描述（由申请人提供）：我们的长期研究目标是构建和表征一个真实的脑细胞外空间（ECS）的三维模型，以预测微观结构变化对信号分子、营养物质和治疗剂运输的影响。ECS由分隔脑细胞的狭窄通道组成，但在活体大脑中无法直接观察到。它对正常的脑功能至关重要，并影响许多关键过程，包括细胞间信号传导、营养传递和神经营养效应。值得注意的是，ECS也形成了所有药物输送到脑细胞的最终途径。为了定量了解这些扩散介导的过程，必须识别和表征复杂ECS环境的基本结构参数。传统的扩散测量，在相对较大的距离上进行，提取两个宏观参数，体积分数和扭曲度。体积分数是ECS占据组织体积的比例，扭曲度量化了复杂ECS环境对扩散分子施加的平均阻力。扩散物质的浓度主要受体积分数的影响，而扭曲则在时间上造成延迟。人们想当然地认为这些参数在所有扩散距离上都保持不变。然而，我们最近发现，在几十微米的距离内，大脑中的扩散是暂时反常的。这意味着，在这段距离上，扩散的速度取决于时间，通常比目前认为的要快。为了探索瞬时异常扩散现象，我们引入了动态微域（DM）的概念，将其定义为观察到异常扩散的脑组织的最大体积。DM的大小取决于局部结构，并可因各种刺激而改变。在目标1中，我们建议开发一种快速光学扩散跟踪（FOTOD）方法来测量DM尺寸并分析其中的扩散。FOTOD同样适用于动态变化的ECS中发生的正常扩散，例如在扩散抑制（Aim 1）或同步神经元活动（Aim 4）期间。目的2-4将用这种新方法探索DM结构的几个生理重要方面。目的2确定β 2-肾上腺素能神经元-胶质细胞信号诱导的星形细胞过程的结构可塑性代表了一种尚未被认识的调节视觉皮层细胞通讯的机制。星形细胞过程通过改变DM扩散特性起作用。目的3显示了带负电荷的神经元周围基质网如何吸引多价阳离子（如钙），但排斥多价阴离子，从而在DMs内充当电荷鉴别器。在Aim 4中，将标度理论应用于柔性聚合物的扩散，估计了ECS孔的平均宽度。在活体大脑中很少有对这一基本参数的估计，然而特征孔径对于药物载体的开发和任何现实的DMs模型都是必不可少的。