Imaging Cerebral Gene Transcripts in Live Animals

Liu, Christina; Kim, Young R.; Ren, Jia Qian; Eichler, Florian; Rosen, Bruce R.; Liu, Philip K.

doi:10.1523/jneurosci.4660-06.2007

Cited by 52 publications

(78 citation statements)

References 55 publications

(72 reference statements)

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“…We have designed modular MR probes capable of reporting specific cells based on gene transcription in living brains of ordinary subjects (8,13,14 …”

Section: Nih Public Accessmentioning

confidence: 99%

“…To evaluate the level of probe retention, we calculated the mean R 2 * values in the cortex, hippocampus, and striatum. The average R 2 * values and SEM from each of these groups were obtained and analyzed statistically (14). To identify ROI with cell expressing elevated GFAP or actin antigen (MR cell typing), we identified regions where SPION retention was significantly above the preinfusion baseline of the same mouse using R 2 * maps.…”

Section: Mri Protocolmentioning

confidence: 99%

“…We induced BBB leakage by one of three methods: by cortical spreading depression, by inflicting a puncture wound and administering an i.c.v. injection of 2 μl saline in a Hamilton syringe with a 26S gauge needle to the left cerebral ventricle (14), or by performing bilateral carotid artery occlusion (BCAO) for 60 min (8,13). Another group of animals underwent a sham operation (the same surgical procedure without the puncture wound or vessel occlusion for cerebral ischemia) at the same time.…”

Section: General Surgical Preparationmentioning

confidence: 99%

“…We have designed modular MR probes capable of reporting specific cells based on gene transcription in living brains of ordinary subjects (8,13,14). In several proof-of-concept studies, we have developed and validated the delivery and neuronal uptake of modular MR probes in the cerebrospinal fluid after intracerebroventricular (i.c.v.)…”

mentioning

confidence: 99%

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Noninvasive delivery of gene targeting probes to live brains for transcription MRI

Liu

You²,

Ren³

et al. 2007

FASEB j.

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We aimed to test the feasibility of detecting gliosis in living brains when the blood-brain barrier (BBB) is disrupted. We designed a novel magnetic resonance (MR) probe that contains superparamagnetic iron oxide nanoparticles (SPION, a T2 susceptibility contrast agent) linked to a short DNA sequence complementary to the cerebral mRNA of glial fibrillary acidic protein (GFAP) found in glia and astrocytes. As a control, we also used a sequence complementary to the mRNA of β-actin. Our objectives are to demonstrate that this new probe, SPION-gfap, could be delivered to the brain when administered by eyedrop solution to the conjunctival sac. We induced BBB leakage by puncture wound, global cerebral ischemia, and cortical spreading depression in C57BL6 mice; 1 day after probe delivery we acquired T2* MR images and R2* (R2*=1/T2*) maps using a transcription MRI technique in live mice. We found that the SPION-gfap probe reported foci with elevated signal in subtraction R2* maps and that these foci matched areas identified as having extensive glial network (gliosis) in postmortem immunohistochemistry. Similarly, animals administered the control probe exhibited foci of R2* elevation that matched β-actin-expressing endothelia in the vascular wall. We conclude that our modular MR probe, delivered in an eyedrop solution, effectively reports gliosis associated with acute neurological disorders in living animals. As BBB leakage is often observed in acute neurological disorders, this study also served to validate noninvasive delivery of MR probes to the brains of live animals after acute neurological disorders. Keywordsangiogenesis; antisense technology; blood-brain barrier; bulbar conjunctiva; gene expression; molecular imaging 1Correspondence: 149 Thirteenth St., Rm. 2410, Charles-town, MA 02129, USA. E-mail: philipl@nmr.mgh.harvard.edu. Note added in proof:We now have performed BBB leakage determination in mice using Evans blue extravasation (n=8) or Gd-MRI at 1 (n=6), 7 (n=10), and 24 (n=2) h after GCI of 60 min. We found BBB leakage in 4 mice, or 22%, within the first day of GCI. All mice that showed hyperintense DWI (with significant ADC drop) 1 day after GCI in the striatum developed striatal BBB leakage. Gliosis, the outgrowth of a fibrous network of glia in the central nervous system (CNS), is a permanent feature of many human neurological disorders and is especially prevalent in glioma, multiple sclerosis, viral encephalitis, traumatic brain injury, stroke, and cardiac arrest (1-5). Detection of gliosis or cells of abnormal growth has traditionally involved immunohistochemistry methods to detect elevated antigen of glial fibrillary acidic protein (GFAP) levels in postmortem tissue samples (6-8). However, brain biopsy to acquire tissue for these conventional assays is by itself invasive, and the procedure often results in the removal of important tissue. NIH Public AccessMRI is a powerful and noninvasive tool for in vivo imaging of soft tissue (9-12) but is somewhat limited by the unavailability of suitable p...

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“…We have designed modular MR probes capable of reporting specific cells based on gene transcription in living brains of ordinary subjects (8,13,14 …”

Section: Nih Public Accessmentioning

confidence: 99%

Section: Mri Protocolmentioning

confidence: 99%

Section: General Surgical Preparationmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Noninvasive delivery of gene targeting probes to live brains for transcription MRI

Liu

You²,

Ren³

et al. 2007

FASEB j.

View full text Add to dashboard Cite

show abstract

“…Initial examples included detection of lacZ marker expression in developing frog embryos using a gadolinium-chelating β-galactosidase substrate [47], and monitoring of a transferrin receptor reporter gene in mice using transferrin-conjugated SPIOs [48]. Semigenetic contrast mechanisms based on a variety of marker proteins and receptors have now been reported (reviewed in [49][50][51]), and design of contrast agents targeting RNA transcripts has also been described [52,53]. Measurement of biological processes in the nervous system…”

Section: Genetically-controlled Contrast Agentsmentioning

confidence: 99%

MRI contrast agents for functional molecular imaging of brain activity

Jasanoff

2007

Current Opinion in Neurobiology

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SummaryFunctional imaging with MRI contrast agents is an emerging experimental approach that can combine the specificity of cellular neural recording techniques with noninvasive whole-brain coverage. A variety of contrast agents sensitive to aspects of brain activity have recently been introduced. These include new probes for calcium and other metal ions that offer high sensitivity and membrane permeability, as well as imaging agents for high resolution pH and metabolic mapping in living animals. Genetically-encoded MRI contrast agents have also been described. Several of the new probes have been validated in the brain; in vivo use of other agents remains a challenge. This review outlines advantages and disadvantages of specific molecular imaging approaches and discusses current or potential applications in neurobiology.

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