In vivo labeling and quantitative imaging of neuronal populations using MRI

Genetic control of MRI contrast using the manganese transporter Zip14

“…11,66 An Oatp1a1-based gene expression reporter system has produced neuron-specific signal, but this required administration of exogenous gadolinium contrast agent directly into the intrathecal space to circumvent the blood brain barrier. 14 In none of these cases was the resolution as high as used here. Zip14 and these other MRI reporters are not mutually exclusive and leave open the possibility of combining the different strategies to image connectivity in subpopulations of cells, analogous to multichannel fluorescence microscopy.…”

“…[1][2][3][4][5][6][7][8][9][10] The most useful approaches have been expression of ferritin, [11][12][13] the use of CEST-MRI agents, 6 the water transporter Aquaporin1, 7 and the Gadolinium-chelate transporter Oatp1a1. 14 However, these methods have not yet been widely applied for research use beyond the proof-of-principle studies used to develop them. Therefore, no MRI-visible gene-expression reporter has yet found routine use in preclinical models, much less translation to clinical application.…”

“…Only recently have proof-of-principle MRI-visible gene-expression reporters been used for neural tracing but have not yet produced sufficiently large contrast required for delineation of connectivity at the resolution of cytoarchitecture. 11,14 Another exciting application for gene-expression MRI would be to quantify cell types, or to enable production of histological quality images in vivo with MRI. 17,18 MEMRI has been used to generate histological images in a number of animal brains, but the mechanism for the detected contrast is not well established and does not allow for control over which cell types enhance.…”

A Dual‐Gene Reporter‐Amplifier Architecture for Enhancing the Sensitivity of Molecular MRI by Water Exchange

“…The methodology utilizes Aqp1 and Oatp1b3, two genes that have proven effective as standalone reporters in various in vivo applications, including monitoring transcriptional activity, [28,51,52] detecting metastases, [38] tracking cell-cell communication, [40] and examining neural activity and connectivity within the mouse brain. [53,54] Compared to Oatp1b3 utilized alone, T 1 -VISA demonstrated a substantial improvement in detection sensitivity, with the ability to detect on the order of 10 3 cells per voxel. Notably, Oatp1b3 has shown success in detecting lesions estimated to comprise a few thousand cells in vivo.…”

“…Furthermore, the ability to generate contrast with reduced gadolinium doses may be particularly beneficial in expanding the use of Oatp1b3 in applications where administering a large amount of contrast agent is difficult, such as for imaging in the intact brain when the reagent needs to cross the blood-brain barrier (BBB). [54] Initial applications of T 1 -VISAs would likely involve the localized delivery of viral vectors encoding Aqp1 expression from a constitutive promoter and Oatp1b3 from an inducible promoter to respectively allow exchange-based amplification and monitoring of transcription factor activity. However, future applications of T 1 -VISAs could greatly benefit from advances in gene delivery techniques and transgenic models, which would enable the homogeneous organ-wide expression of Aqp1 to be seamlessly integrated with the expression of Oatp1b3 from promoters that report on cell fate, signaling pathways, and other biological functions.…”