MIT scientists have devised a new way to image calcium activity that is based on magnetic resonance imaging (MRI) and allows them to image activity deep within the brain.
Using this technique, they can track signalling processes inside the neurons of living animals, enabling them to link neural activity with specific behaviours.
"This paper describes the first MRI-based detection of intracellular calcium signaling, which is directly analogous to powerful optical approaches used widely in neuroscience but now enables such measurements to be performed in vivo in deep tissue," said Alan Jasanoff, a professor at Massachusetts Institute of Technology (MIT) in the US.
In their resting state, neurons have very low calcium levels. However, when they fire an electrical impulse, calcium floods into the cell, according to the study published in the journal Nature Communications.
Over the past several decades, scientists have devised ways to image this activity by labelling calcium with fluorescent molecules. This can be done in cells grown in a lab dish, or in the brains of living animals, but this kind of microscopy imaging can only penetrate a few tenths of a millimetre into the tissue, limiting most studies to the surface of the brain.
"There are amazing things being done with these tools, but we wanted something that would allow ourselves and others to look deeper at cellular-level signalling," Jasanoff said.
To achieve that, the MIT team turned to MRI, a noninvasive technique that works by detecting magnetic interactions between an injected contrast agent and water molecules inside cells.
Many scientists have been working on MRI-based calcium sensors, but the major obstacle has been developing a contrast agent that can get inside brain cells.
Last year, Jasanoff's lab developed an MRI sensor that can measure extracellular calcium concentrations, but these were based on nanoparticles that are too large to enter cells.
To create their new intracellular calcium sensors, the researchers used building blocks that can pass through the cell membrane.
The contrast agent contains manganese, a metal that interacts weakly with magnetic fields, bound to an organic compound that can penetrate cell membranes. This complex also contains a calcium-binding arm called a chelator.
Once inside the cell, if calcium levels are low, the calcium chelator binds weakly to the manganese atom, shielding the manganese from MRI detection.
When calcium flows into the cell, the chelator binds to the calcium and releases the manganese, which makes the contrast agent appear brighter in an MRI image.
"When neurons, or other brain cells called glia, become stimulated, they often experience more than tenfold increases in calcium concentration. Our sensor can detect those changes," Jasanoff says.