November 5, 2002
New Tool for Studying Animal Models of Neurological and Psychiatric Diseases
Will allow non-invasive study of neurochemistry, behavior, and disease progression
UPTON, NY — Scientists at the U.S. Department of Energy’s Brookhaven National Laboratory have demonstrated that a miniature positron emission tomography (PET) scanner, known as microPET, and the chemical markers used in traditional PET scanning are sensitive enough to pick up subtle differences in neurochemistry between known genetic variants of mice.
This “proof-of-principle” experiment, described in the November issue of the Journal of Nuclear Medicine, “opens up a whole new, non-invasive way to study and follow transgenic or genetically engineered strains of mice that serve as animal models for human neurological diseases, such as Parkinson’s and Alzheimer’s disease or psychiatric diseases such as substance abuse, depression, and anxiety disorders,” said Panayotis (Peter) Thanos, lead author of the paper. Studying animal models may help scientists better understand and develop treatments for the human diseases.
Thanos and his team used microPET to measure the level of “D2” receptors for dopamine — a brain chemical associated with feelings of reward and pleasure, which has been found to play a role in drug addiction — in the brains of normal mice and so-called knockout mice, which had been genetically engineered to lack the gene for D2.
The dopamine D2 receptor has been implicated in a wide variety of neuropsychiatric disorders, including, in recent studies by Brookhaven researchers, alcoholism and substance abuse. Thus, these D2-deficient mice are important for studying human diseases.
Before the scans, each mouse was given an injection of a radiotracer molecule designed to bind to D2 receptors. The microPET scanner then picked up the signal from the tracer to show where and how much was bound in various parts of the brain. The level of the tracer indicates the number of receptors.
In the striatum, a region of the brain normally rich in D2 receptors, “deficient” mice had significantly lower levels of tracer binding compared with their normal counterparts. There was no difference in tracer binding between strains in the cerebellum, an area of the brain that normally lacks D2 receptors, which was studied for comparison.
The scientists ruled out anatomical differences as a possible explanation for their results by comparing magnetic resonance imaging (MRI) brain scans of the two strains, which showed no differences. They also confirmed the difference in D2 receptor levels between “deficient” and normal mice with traditional autoradiography, where tissue samples are labeled with a radiotracer to reveal receptor levels.
“The results clearly show that microPET is an excellent technique that can pick up the neurochemical difference between the two strains in a non-invasive way,” Thanos said. “And because this technique can be used in living animals, we can now study how these neurochemical differences between genetic strains of mice affect behavior and/or disease progression over time in the same animals,” he said.
The technique can easily be extended to study other human neurological or psychiatric diseases for which knockout animal models exist, such as Alzheimer’s and Parkinson’s disease, or even depression and anxiety disorders.
This work was funded by the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the U.S. Department of Energy, which supports basic research in a variety of scientific fields.