Functional MRI has become a standard tool to peer into the physiologic processes happening within the brain. Though revolutionary for what it can achieve, traditional fMRI only displays the dynamics of hemoglobin molecules. (Hemoglobin is diamagnetic when oxygenated but becomes paramagnetic when deoxygenated. Hence fMRI detects regions of the brain where oxygen transfer from blood to tissues takes place.) This is an indirect approach that doesn’t provide enough functional resolution and which also results in delayed readings that can mask the nature of underlying neural processes. Now researchers at Caltech and MIT have come up with a way to monitor the activity of dopamine within the brain, greatly expanding the ability of fMRI to help understand how brain functions.
From an MIT press statement:
To build the new sensors, the MIT team worked with chemical engineers at Caltech, using an approach called “directed evolution.” They started with a protein called cytochrome P450, an enzyme found in most organisms that is paramagnetic (meaning it can become weakly magnetic when exposed to a magnetic field). Using a technique called error-prone PCR, which is a faulty version of the way cells naturally replicate their genes, they generated a large collection of different mutated forms of the gene.
Each mutated gene was placed into an E. coli bacterium, which produced the mutated protein. The researchers then tested each protein for its ability to bind dopamine. At the end of each round, they took the best candidate and mutated it again for a new round of improvement. At the end of five rounds, they had two sensors that would bind strongly to dopamine but not to other neurotransmitters.
In studies of rats, the researchers showed that the sensor can effectively detect dopamine in the brain. However, in its current form, the dopamine probe must be injected into the brain, and the imaging is limited to the site of injection.
Bruce Jenkins, director of neurochemical imaging at the Martinos Center for Biomedical Imaging at MGH, says the new probe is “very cleverly designed,” but points out that an important challenge is yet to come: getting the molecule to cross the layer of cells that separates the brain from circulating blood. “Trying to get a charged protein across the blood-brain barrier is very tricky,” he says.
The MIT team hopes to overcome that obstacle by applying barrier disruption techniques used historically to deliver chemotherapeutic agents to the brain. They will also try to genetically program brain cells to express the sensor, so it doesn’t have to be injected.
Abstract in Nature Biotechnology: Directed evolution of a magnetic resonance imaging contrast agent for noninvasive imaging of dopamine
MIT press release: New technique offers a more detailed view of brain activity …
Image credit: Wellcome images: MRI scan showing the regions of the brain involved in recognising familiar faces….