Calcium-responsive contrast agents for functional magnetic resonance imaging

Abstract

Calcium ions represent one of the key second messengers accompanying neural activity and synaptic signaling. Accordingly, dynamic imaging of calcium fluctuations in living organisms represents a cornerstone technology for discovering neural mechanisms that underlie memory, determine behavior, and modulate emotional states as well as how these mechanisms are perturbed by neurological disease and brain injury. While optical technologies are well established for high resolution imaging of calcium dynamics, physical limits on light penetration hinder their application for whole-brain imaging in intact vertebrates. Unlike optics, magnetic resonance imaging (MRI) enables noninvasive large-scale imaging across vertebrates of all sizes. This has motivated the development of several sensors that leverage innovative physicochemical mechanisms to sensitize MRI contrast to intracellular and extracellular changes in calcium. Here, we review the current state-of-the-art in MRI-based calcium sensors, focusing on fundamental aspects of sensor performance, in vivo applications, and challenges related to sensitivity. We also highlight how innovations at the intersection of reporter gene technology and gene delivery open potential opportunities for mapping calcium activity in genetically targeted cells, complementing the benefits of small molecule probes and nanoparticle sensors.

Designing Protein‐Based Probes for Sensing Biological Analytes with Magnetic Resonance Imaging

“…[54,55] Given that the BOLD signal only indirectly mirrors neural activity, there is tremendous interest in developing noninvasive probes for imaging calcium, an integral molecular signature of electrical activity in all excitable cells. MRI-based calcium sensing has been mostly demonstrated with synthetic labels, [13] which are difficult to deliver intracellularly and cannot be targeted to genetically defined cell-types and neural projections. As a first step towards addressing these limitations, a genetically encodable calcium sensor was recently derived from calprotectin, a dual Mn 2 + and calcium-binding metalloprotein; and applied to monitor calcium changes in Mn 2 + supplemented cell cultures treated with a calcium ionophore.…”

“…Controlling the clustering of such nanoparticles alters the extent of spin-spin relaxation, thereby providing another well-known mechanism to generate analyteresponsive MRI contrast. Both the above mechanisms have been harnessed to develop a rich and growing repertoire of synthetic MRI contrast agents for sensing a wide range of biological analytes, including reactive oxygen species, [1,2] zinc ions, [3,4] copper, [5][6][7] calcium signals, [8][9][10][11][12][13] neurotransmitters, [14,15] nitric oxide, [16] enzyme activity, [17][18][19][20][21] and oligonucleotides. [22] The aforementioned agents however cannot be expressed in cells by genetic encoding.…”

Probing the interstitial calcium compartment

“…An interesting and recent technology is based on calcium‐sensitive nanoparticles as contrast agents for magnetic resonance imaging (MRI). It provides another option for recording interstitial calcium fluctuations in vivo over large areas of tissue over a timescale of seconds to hours, at low spatial resolution (Miller et al., 2021). The magnetic nanoparticles are made calcium‐sensitive by employing the calcium binding properties of synaptotagmins, synaptic proteins that possess a natural low affinity for calcium ranges from 0.1 to 1 m m .…”

Magnetic Resonance Image in Monitor and Diagnosis of Patients with Neuromyelitis Optica

“…By optimizing the control spin operation, in the nonuniform control field, the thin-layer ensemble spin sensor was used to enhance the multichannel MRI to improve the ensemble sensitivity and field of view (FOV) [ 6 ]. Miller et al (2021) used innovative physicochemical mechanisms to improve sensors and make MRI acquisition more sensitive [ 7 ]. Therefore, MRI combined with sensors is applied to NMO diseases.…”