Researchers may be able to map brain circuits that underpin behavior and perception by tracing connections between cell populations.
MIT biological engineers have discovered a mechanism to monitor particular populations of neurons and expose how they interact with one another using a unique functional magnetic resonance imaging (fMRI) probe.
Different areas of the brain interact in precise ways to accomplish a range of activities, such as creating behavior or understanding the environment around us, similar to how the gears of a clock interact in unique ways to spin the clock’s hands. Scientists may be able to trace such networks of relationships with the new MRI sensor.
“We can watch the activity of all the gears at the same time with frequent fMRI. However, with our new technique, we can pick up individual gears that are defined by their relationship to other gears, which is critical for constructing a picture of the brain’s mechanism “MIT professor of biological engineering, brain and cognitive sciences, and nuclear science and engineering Alan Jasanoff says.
The researchers were able to identify neuronal populations participating in a circuit that reacts to rewarding stimuli using this approach, which includes genetically directing the MRI probe to particular populations of cells in animal models. According to the researchers, the novel MRI probe might be used to study a variety of different brain circuitry.
Jasanoff is the study’s senior author, and it was published in Nature Neuroscience today. Souparno Ghosh, a recent MIT PhD graduate, and Nan Li, a former MIT research scientist, are the paper’s primary authors.
Connecting the dots
Changes in blood flow in the brain are used as a surrogate for neural activity in traditional fMRI imaging. When neurons receive messages from other neurons, an influx of calcium occurs, causing the production of a diffusible gas called nitric oxide. Nitric oxide works as a vasodilator, allowing more blood to flow into the region.
Calcium imaging may provide a more detailed image of brain activity, but it generally necessitates the use of fluorescent substances and invasive procedures. The MIT researchers hoped to create an approach that could function throughout the brain without being so intrusive.
“We need something that can be detected deep in tissue and ideally throughout the whole brain at once if we want to find out how brain-wide networks of cells and brain-wide processes operate,” Jasanoff adds. “In this work, we choose to do so by effectively hijacking the molecular underpinnings of fMRI itself.”
The researchers developed a virus-based genetic probe that codes for a protein that sends out a signal anytime a neuron is activated. This protein, dubbed NOSTIC (nitric oxide synthase for targeting image contrast) by the researchers, is a modified version of the enzyme nitric oxide synthase. The NOSTIC protein detects increased calcium levels during brain activity and produces nitric oxide, resulting in a fake fMRI signal that only cells that have NOSTIC produce.
The probe is supplied by a virus that is injected into a specific location before traveling down the axons of neurons that connect to that location. The researchers will be able to identify every neuronal population that feeds into a certain area this way.
“When we employ this virus to deliver our probe in this manner, the probe is expressed in the cells that supply input to the region where the virus is placed,” Jasanoff explains. “We may then begin to assess what causes input to that area to occur, or what forms of input arrive at that location, by doing functional imaging of those cells.”
Switching gears
The researchers used their probe to mark groups of neurons that project to the striatum, a brain area involved in movement planning and reward response. They were able to figure out which neuronal populations in rats provide information to the striatum during or soon after a pleasurable stimulus — in this instance, deep brain stimulation of the lateral hypothalamus, a brain area involved in food and motivation, among other things.
One issue that researchers have had regarding lateral hypothalamic deep brain stimulation is how broad the effects are. Following deep brain stimulation, various neuronal populations, including those in the motor cortex and the entorhinal cortex, which is involved in memory, transmit information into the striatum, according to the MIT researchers.
“It’s not only information from the deep brain stimulation location or dopamine-carrying cells. There are additional components that impact the reaction, both distally and locally, and we can pinpoint them thanks to the use of this probe “According to Jasanoff.
Because neurons emit standard fMRI signals during these studies, the researchers repeat each experiment twice: once with the probe on and once after treatment with a medication that suppresses the probe to separate the signals that are coming solely from the genetically changed neurons. They can assess how much activity is present in probe-containing cells precisely by analyzing the difference in fMRI activity between these two circumstances.
The researchers intend to apply this method, which they term hemogenetics, to additional brain networks, starting with a search for some of the areas that get information from the striatum after deep brain stimulation.
“One of the fascinating aspects of the technique we’re proposing is that you can envisage using the same tool at several places in the brain and stitching together a network of interlocking gears made up of these input and output links,” says Jasanoff. “At the level of neuronal populations, this may lead to a wide view on how the brain operates as an integrated whole.”
The National Institutes of Health and the MIT Simons Center for the Social Brain supported the study.
