For Huda Akil, Ph.D., mood disorders represent an emotional executive function that has failed. To discover the underlying biological mechanism of that failure, Akil and colleagues in the Pritzker Psychiatric Research Consortium have studied illness in humans to discern potential genetic and molecular targets in pathophysiology, then worked backward to find those mechanisms in animal models to suggest research that may eventually lead to treatments.
At the Society for Neuroscience meeting in Washington, D.C., last November, she discussed work on bipolar disorder, a good choice for research because it is highly heritable but has a small prevalence—about 1 percent.
Genetic studies have shown that genes alone don’t determine the appearance of the illness, said Akil, a professor, senior research scientist, and co-director of the Mental Health Research Institute in the Department of Psychiatry at the University of Michigan.
“Heterogenic genotypes produce similar phenotypes,” she said. “The brain serves as the intermediary between genes and phenotype, integrating genes and environment at the circuit level. So you have to look at the brain.”
The brain integrates vulnerability genes, early-life trauma, developmental events, and hormones, resulting in a diagnostic signature that describes the disease.
The consortium is pursuing several lines of research, spurred by genome-wide association studies suggesting several possible targets that are altered in depression.
Akil discussed fibroblast growth factor 2 (FGF2) in her presentation.
In general, higher levels of FGF2 in the hippocampus are associated with lower anxiety and depression, she said. “FGF2 acts like an antidepressant, while FGF2 inhibitors induce depression-like behavior.”
The researchers bred two lines of rats to help them pursue this line of reasoning. One line was “high responders,” ready to explore their environment. The other was “low responders,” a much more timid group.
The high responders had significantly higher levels of FGF2 in their brains and exhibited less anxiety-like and depressive-like behaviors than the low responders. The latter had lower brain levels of FGF2 and acted “just like depressed humans,” said Akil.
She set up a test in which a light would go on in the rat’s cage, then go off, after which food would appear in a nearby niche.
The two lines of rats responded differently to this stimulus. The low responders went straight for the food niche. The high-responding rats “fell in love with the light,” even when light and food were later decoupled.
Genetics were not the only factors at work, however. Under stress, low-responder rats more quickly became more anhedonic (as measured by weekly sucrose preference tests) than their high-responding counterparts.
The environment could work in the opposite direction too. Enriching the rats’ surroundings by adding lots of plastic toys to their cages raised the FGF2 levels and decreased anxiety and depression—especially in the low-responding animals. Conversely, chronic administration of FGF2 decreased depression and anxiety, but again, mainly in the low responders.
FGF2 also had an effect on neurogenesis. Doses of FGF2 increased the survival of adult stem cells in the low-responding rats.
Thus, Akil said, FGF2 is both an inborn factor, influencing vulnerability, but also is affected by stressors in the environment, and is involved in neural remodeling.
The next step in this research is to continue research in postmortem human brains to look at genomewide methylation to understand why gene changes are happening. A second line of inquiry will measure RNA sequencing and expression.
Overall, said Akil, “this research has changed my thinking about depression.”
Mood disorders are brain-wiring disorders, affecting many circuits and genes and producing a unique signature in the brain, she said. Several gene families are involved in these disorders, including signaling molecules, structural genes, growth factors, immune genes, and clock genes.
“It’s not just ‘a serotonin imbalance’ anymore,” she said. “There is no false separation between vulnerability genes and environmental factors.”
An abstract of “Novelty-Seeking Behavior Predicts Vulnerability in a Rodent Model of Depression” is posted at www.sciencedirect.com/science/article/pii/S0031938411000515.