skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Non-invasive fluorescent imaging of gliosis in transgenic mice for profiling developmental neurotoxicity

Abstract

Gliosis is a universal response of Brain to almost all types of neural insults, including neurotoxicity, neurodegeneration, viral infection, and stroke. A hallmark of gliotic reaction is the up-regulation of the astrocytic biomarker GFAP (glial fibrillary acidic protein), which often precedes the anatomically apparent damages in Brain. In this study, neonatal transgenic mice at postnatal day (PD) 4 expressing GFP (green fluorescent protein) under the control of a widely used 2.2-kb human GFAP promoter in Brain are treated with two model neurotoxicants, 1-methyl-4(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH{sub 3}-MPTP), and kainic acid (KA), respectively, to induce gliosis. Here we show that the neurotoxicant-induced acute gliosis can be non-invasively imaged and quantified in Brain of conscious (un-anesthetized) mice in real-time, at 0, 2, 4, 6, and 8 h post-toxicant dosing. Therefore the current methodology could be a useful tool for studying the developmental aspects of neuropathies and neurotoxicity.

Authors:
 [1];  [1];  [2]
  1. Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, the Nanos, 04-01, 138669 (Singapore)
  2. Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, the Nanos, 04-01, 138669 (Singapore). E-mail: lzhuo@ibn.a-star.edu.sg
Publication Date:
OSTI Identifier:
20976936
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 221; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2007.01.023; PII: S0041-008X(07)00046-4; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BIOLOGICAL MARKERS; BRAIN; HUMAN POPULATIONS; PROTEINS; SCREENING; TRANSGENIC MICE

Citation Formats

Ho, Gideon, Zhang Chunyan, and Zhuo Lang. Non-invasive fluorescent imaging of gliosis in transgenic mice for profiling developmental neurotoxicity. United States: N. p., 2007. Web. doi:10.1016/j.taap.2007.01.023.
Ho, Gideon, Zhang Chunyan, & Zhuo Lang. Non-invasive fluorescent imaging of gliosis in transgenic mice for profiling developmental neurotoxicity. United States. doi:10.1016/j.taap.2007.01.023.
Ho, Gideon, Zhang Chunyan, and Zhuo Lang. Tue . "Non-invasive fluorescent imaging of gliosis in transgenic mice for profiling developmental neurotoxicity". United States. doi:10.1016/j.taap.2007.01.023.
@article{osti_20976936,
title = {Non-invasive fluorescent imaging of gliosis in transgenic mice for profiling developmental neurotoxicity},
author = {Ho, Gideon and Zhang Chunyan and Zhuo Lang},
abstractNote = {Gliosis is a universal response of Brain to almost all types of neural insults, including neurotoxicity, neurodegeneration, viral infection, and stroke. A hallmark of gliotic reaction is the up-regulation of the astrocytic biomarker GFAP (glial fibrillary acidic protein), which often precedes the anatomically apparent damages in Brain. In this study, neonatal transgenic mice at postnatal day (PD) 4 expressing GFP (green fluorescent protein) under the control of a widely used 2.2-kb human GFAP promoter in Brain are treated with two model neurotoxicants, 1-methyl-4(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH{sub 3}-MPTP), and kainic acid (KA), respectively, to induce gliosis. Here we show that the neurotoxicant-induced acute gliosis can be non-invasively imaged and quantified in Brain of conscious (un-anesthetized) mice in real-time, at 0, 2, 4, 6, and 8 h post-toxicant dosing. Therefore the current methodology could be a useful tool for studying the developmental aspects of neuropathies and neurotoxicity.},
doi = {10.1016/j.taap.2007.01.023},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 221,
place = {United States},
year = {Tue May 15 00:00:00 EDT 2007},
month = {Tue May 15 00:00:00 EDT 2007}
}
  • Loss of dopamine in the nigrostriatal system causes a severe impairment in motor function in patients with Parkinson's disease and in experimental neurotoxic models of the disease. We have used non-invasive imaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (MRI) to investigate in vivo the changes in the dopamine system in neurotoxic models of Parkinson's disease. In addition to classic neurotransmitter studies, in these models, it is also possible to characterize associated and perhaps pathogenic factors, such as the contribution of microglia activation and inflammatory responses to neuronal damage. Functional imaging techniques are instrumental tomore » our understanding and modeling of disease mechanisms, which should in turn lead to development of new therapies for Parkinson's disease and other neurodegenerative disorders.« less
  • Highlights: ► Aga2/+ mice, model for Osteogenesis imperfecta, have type I collagen mutation. ► Aga2/+ mice display both moderate and severe phenotypes lethal 6–11th postnatal. ► Internal hemorrhages studied in Aga2/+ vs. control mice at 6 and 9 days postnatal. ► Anatomical and functional findings in-vivo contrasted to the ex-vivo appearance. -- Abstract: Mutations in type I collagen genes (COL1A1/2) typically lead to Osteogenesis imperfecta, the most common heritable cause of skeletal fractures and bone deformation in humans. Heterozygous Col1a1{sup Aga2/+}, animals with a dominant mutation in the terminal C-propeptide domain of type I collagen develop typical skeletal hallmarks andmore » internal hemorrhages starting from 6 day after birth. The disease progression for Aga2/+ mice, however, is not uniform differing between severe phenotype lethal at the 6–11th day of life, and moderate-to-severe one with survival to adulthood. Herein we investigated whether a new modality that combines X-ray computer tomography with fluorescence tomography in one hybrid system can be employed to study internal bleedings in relation to bone fractures and obtain insights into disease progression. The disease phenotype was characterized on Aga2/+ vs. wild type mice between 6 and 9 days postnatal. Anatomical and functional findings obtained in-vivo were contrasted to the ex-vivo appearance of the same tissues under cryo-slicing.« less
  • No abstract prepared.
  • The mechanisms by which expression of the {beta}-like globin genes are developmentally regulated are under intense investigation. The temporal control of human embryonic ({epsilon}) globin expression was analyzed. A 3.7-kilobase (kb) fragment that contained the entire human {epsilon}-globin gene was linked to a 2.5-kb cassette of the locus control region (LCR), and the developmental time of expression of this construct was studied in transgenic mice. The human {epsilon}-globin transgene was expressed in yolk sac-derived primitive erythroid cells, but not in fetal liver or bone marrow-derived definitive erythroid cells. The absence of {epsilon} gene expression in definitive erythroid cells suggests thatmore » the developmental regulation of the {epsilon}-globin gene depends only on the presence of the LCR and the {epsilon}-globin gene itself (that is, an autonomous negative control mechanism). The autonomy of {epsilon}-globin gene developmental control distinguishes it from the competitive mechanism of regulation of {gamma} and {beta}-globin genes, and therefore, suggests that at least two distinct mechanisms function in human hemoglobin switching.« less
  • Sequential expression of the genes of the human [beta]-globin locus requires the formation of an erythroid-specific chromatin domain spanning > 200 kb. Regulation of this gene family involves both local interactions with proximal cis-acting sequences and long-range interactions with control elements upstream of the locus. To make it possible to analyze the interactions of cis-acting sequences of the human [beta]-globin locus in their normal spatial and sequence context, the authors characterized two yeast artificial chromosomes (YACs) 150 and 230 kb in size, containing the entire [beta]-globin locus. They have now successfully integrated the 150 kb YAC into the germ linemore » of transgenic mice as a single unrearranged fragment that includes the locus control region, structural genes, and 30 kb of 3[prime] flanking sequences present in the native locus. Expression of the transgenic human [beta]-globin locus is tissue- and developmental stage-specific and closely follows the pattern of expression of the endogenous mouse [beta]-globin locus. By using homology-directed recombination in yeast and methods for the purification and transfer of YACs into transgenic mice, it will now be feasible to study the physiological role of cis-acting sequences in specifying an erythroid-specific chromatin domain and directing expression of [beta]-globin genes during ontogeny.« less