Dynamic Microdomains in Brain Extracellular Space

大脑细胞外空间的动态微域

• 批准号: 8643295
• 负责人: SABINA HRABETOVA
• 金额: $ 34.54万
• 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 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8643295
• 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）：我们研究的长期目标是构建和表征脑细胞外空间（ECS）的真实三维模型，以预测微结构变化对信号分子、营养物质和治疗剂转运的影响。ECS包括分离脑细胞的狭窄通道，但不能在活体大脑中直接可视化。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，营养输送和神经营养作用。值得注意的是，ECS也形成了所有药物递送到脑细胞的最终途径。为了定量地了解这些扩散介导的过程中的任何一个，必须确定和表征复杂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，提取两个宏观参数，体积分数和曲折。体积分数是由ECS占据的组织体积的比例，并且弯曲度量化了由复杂ECS环境施加在扩散分子上的平均阻碍。扩散物质的浓度主要受体积分数的影响，而曲折度在时间上施加延迟。它已被认为是理所当然的，这些参数保持不变，在所有的扩散距离。然而，我们最近发现，大脑中的扩散在几十微米的距离上是短暂异常的。这意味着，在这段距离上，扩散速度取决于时间，通常比目前认为的要快。为了探索瞬态异常扩散的现象，我们引入了动态微区（DM）的概念，定义为观察到异常扩散的脑组织的最大体积。DM的大小将取决于局部结构，并且可以响应于各种刺激而改变。在目标1中，我们提出了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将同样适用于动态变化的ECS中发生正常扩散时，例如，在扩散性抑制（Aim 1）或同步神经元活动（Aim 4）期间。目的2-4将探讨DM结构的几个重要生理学方面与这种新的方法。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胶质细胞过程的结构可塑性代表了一种尚未认识到的调节视觉皮层细胞通讯的机制。星形胶质细胞过程通过改变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（例如，钙），但排斥多价阴离子，从而在DM内充当电荷鉴别剂。在目标4中，应用于柔性聚合物扩散的标度理论估计ECS孔的平均宽度。很少有估计这个基本参数存在于活的大脑，但特征孔宽度是必不可少的药物载体的发展，并为任何现实的模型DM。

项目成果

Brain extracellular space, hyaluronan, and the prevention of epileptic seizures.

• DOI: 10.1515/revneuro-2017-0017
• 发表时间: 2017-11-27
• 期刊: Reviews in the neurosciences
• 影响因子: 4.1
• 作者: Perkins KL;Arranz AM;Yamaguchi Y;Hrabetova S
• 通讯作者: Hrabetova S

Diffusion measurements for drug design.

药物设计的扩散测量。

• DOI: 10.1038/nmat1489
• 发表时间: 2005
• 期刊: Nature materials
• 影响因子: 41.2
• 作者: Thorne,RG;Hrabetová,S;Nicholson,C
• 通讯作者: Nicholson,C

Extracellular diffusion in laminar brain structures exemplified by hippocampus.

• DOI: 10.1016/j.jneumeth.2011.12.008
• 发表时间: 2012-03-30
• 期刊: Journal of neuroscience methods
• 影响因子: 3
• 作者: Saghyan A;Lewis DP;Hrabe J;Hrabetova S
• 通讯作者: Hrabetova S

Rapid volume pulsation of the extracellular space coincides with epileptiform activity in mice and depends on the NBCe1 transporter.

• DOI: 10.1113/jp281544
• 发表时间: 2021-06
• 期刊: JOURNAL OF PHYSIOLOGY-LONDON
• 影响因子: 5.5
• 作者: Colbourn, Robert;Hrabe, Jan;Nicholson, Charles;Perkins, Matthew;Goodman, Jeffrey H.;Hrabetova, Sabina
• 通讯作者: Hrabetova, Sabina