New MRI-based calcium sensor can image activity deep within the brain

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Researchers have developed an MRI-based calcium sensor that allows them
to peer deep into the brain. Using this technique, they can track
electrical activity inside the neurons of living animals, enabling them
to link neural activity with specific behaviors.

Calcium is a critical signaling molecule for most cells, and it is
especially important in neurons. Imaging calcium in brain cells can
reveal how neurons communicate with each other; however, current imaging
techniques can only penetrate a few millimeters into the brain.

MIT researchers have now devised a new way to image calcium activity
that is based on magnetic resonance imaging (MRI) and allows them to
peer much deeper into the brain.

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 Using this technique, they can track
signaling processes inside the neurons of living animals, enabling them
to link neural activity with specific behaviors.


“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,”

 says Alan Jasanoff, an MIT
professor of biological engineering, brain and cognitive sciences, and
nuclear science and engineering, and an associate member of MIT’s
McGovern Institute for Brain Research.


MIT postdocs Ali Barandov and Benjamin Bartelle are the paper’s lead
authors. MIT senior Catherine Williamson, recent MIT graduate Emily
Loucks, and Arthur Amos Noyes Professor Emeritus of Chemistry Stephen
Lippard are also authors of the study.


Getting into cells


In their resting state, neurons have very low calcium levels.
However, when they fire an electrical impulse, calcium floods into the
cell. Over the past several decades, scientists have devised ways to
image this activity by labeling 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 millimeter 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 signaling,”

 Jasanoff says.


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.

Precise measurements


The researchers tested their sensor in rats by injecting it into the
striatum, a region deep within the brain that is involved in planning
movement and learning new behaviors.

 They then used potassium ions to
stimulate electrical activity in neurons of the striatum, and were able
to measure the calcium response in those cells.


Jasanoff hopes to use this technique to identify small clusters of
neurons that are involved in specific behaviors or actions.

 Because this
method directly measures signaling within cells, it can offer much more
precise information about the location and timing of neuron activity
than traditional functional MRI (fMRI), which measures blood flow in the
brain.


“This could be useful for figuring out how different structures in
the brain work together to process stimuli or coordinate behavior,”

 he
says.


In addition, this technique could be used to image calcium as it
performs many other roles, such as facilitating the activation of immune
cells.

 With further modification, it could also one day be used to
perform diagnostic imaging of the brain or other organs whose functions
rely on calcium, such as the heart.

This research was published at Nature communications

Story source:
Massachusetts Institute of Technology

 

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