New MRI probe can reveal more of the brain's inner workings
Tracing connections between neuron populations could help researchers map brain circuits that underlie behavior and perception.

Date:
March 3, 2022
Source:
Massachusetts Institute of Technology
Summary:
Using a novel probe for functional magnetic resonance imaging
(fMRI), biological engineers have devised a way to monitor
individual populations of neurons and reveal how they interact
with each other.



FULL STORY ========================================================================== Using a novel probe for functional magnetic resonance imaging (fMRI),
MIT biological engineers have devised a way to monitor individual
populations of neurons and reveal how they interact with each other.


========================================================================== Similar to how the gears of a clock interact in specific ways to turn
the clock's hands, different parts of the brain interact to perform a
variety of tasks, such as generating behavior or interpreting the world
around us. The new MRI probe could potentially allow scientists to map
those networks of interactions.

"With regular fMRI, we see the action of all the gears at once. But with
our new technique, we can pick up individual gears that are defined by
their relationship to the other gears, and that's critical for building
up a picture of the mechanism of the brain," says Alan Jasanoff, an
MIT professor of biological engineering, brain and cognitive sciences,
and nuclear science and engineering.

Using this technique, which involves genetically targeting the MRI probe
to specific populations of cells in animal models, the researchers were
able to identify neural populations involved in a circuit that responds
to rewarding stimuli. The new MRI probe could also enable studies of
many other brain circuits, the researchers say.

Jasanoff is the senior author of the study, which appears today in Nature Neuroscience. The lead authors of the paper are recent MIT PhD recipient Souparno Ghosh and former MIT research scientist Nan Li.

Tracing connections Traditional fMRI imaging measures changes to blood
flow in the brain, as a proxy for neural activity. When neurons receive
signals from other neurons, it triggers an influx of calcium, which causes
a diffusible gas called nitric oxide to be released. Nitric oxide acts
in part as a vasodilator that increases blood flow to the area.



========================================================================== Imaging calcium directly can offer a more precise picture of brain
activity, but that type of imaging usually requires fluorescent chemicals
and invasive procedures. The MIT team wanted to develop a method that
could work across the brain without that type of invasiveness.

"If we want to figure out how brain-wide networks of cells and brain-wide mechanisms function, we need something that can be detected deep in tissue
and preferably across the entire brain at once," Jasanoff says. "The
way that we chose to do that in this study was to essentially hijack
the molecular basis of fMRI itself." The researchers created a genetic
probe, delivered by viruses, that codes for a protein that sends out a
signal whenever the neuron is active. This protein, which the researchers called NOSTIC (nitric oxide synthase for targeting image contrast), is
an engineered form of an enzyme called nitric oxide synthase. The NOSTIC protein can detect elevated calcium levels that arise during neural
activity; it then generates nitric oxide, leading to an artificial fMRI
signal that arises only from cells that contain NOSTIC.

The probe is delivered by a virus that is injected into a particular
site, after which it travels along axons of neurons that connect to that
site. That way, the researchers can label every neural population that
feeds into a particular location.

"When we use this virus to deliver our probe in this way, it causes the
probe to be expressed in the cells that provide input to the location
where we put the virus," Jasanoff says. "Then, by performing functional
imaging of those cells, we can start to measure what makes input to
that region take place, or what types of input arrive at that region."
Turning the gears


==========================================================================
In the new study, the researchers used their probe to label populations
of neurons that project to the striatum, a region that is involved in
planning movement and responding to reward. In rats, they were able to determine which neural populations send input to the striatum during or immediately following a rewarding stimulus -- in this case, deep brain stimulation of the lateral hypothalamus, a brain center that is involved
in appetite and motivation, among other functions.

One question that researchers have had about deep brain stimulation of the lateral hypothalamus is how wide-ranging the effects are. In this study,
the MIT team showed that several neural populations, located in regions including the motor cortex and the entorhinal cortex, which is involved
in memory, send input into the striatum following deep brain stimulation.

"It's not simply input from the site of the deep brain stimulation or
from the cells that carry dopamine. There are these other components,
both distally and locally, that shape the response, and we can put our
finger on them because of the use of this probe," Jasanoff says.

During these experiments, neurons also generate regular fMRI signals,
so in order to distinguish the signals that are coming specifically from
the genetically altered neurons, the researchers perform each experiment
twice: once with the probe on, and once following treatment with a drug
that inhibits the probe. By measuring the difference in fMRI activity
between these two conditions, they can determine how much activity is
present in probe-containing cells specifically.

The researchers now hope to use this approach, which they call
hemogenetics, to study other networks in the brain, beginning with
an effort to identify some of the regions that receive input from the
striatum following deep brain stimulation.

"One of the things that's exciting about the approach that we're
introducing is that you can imagine applying the same tool at many sites
in the brain and piecing together a network of interlocking gears, which consist of these input and output relationships," Jasanoff says. "This
can lead to a broad perspective on how the brain works as an integrated
whole, at the level of neural populations." The research was funded
by the National Institutes of Health and the MIT Simons Center for the
Social Brain.


========================================================================== Story Source: Materials provided by
Massachusetts_Institute_of_Technology. Original written by Anne
Trafton. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Souparno Ghosh, Nan Li, Miriam Schwalm, Benjamin B. Bartelle,
Tianshu
Xie, Jade I. Daher, Urvashi D. Singh, Katherine Xie,
Nicholas DiNapoli, Nicholas B. Evans, Kwanghun Chung, Alan
Jasanoff. Functional dissection of neural circuitry using a
genetic reporter for fMRI. Nature Neuroscience, 2022; DOI:
10.1038/s41593-022-01014-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220303112157.htm

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