Description of dissertation research projects:

According to the American Psychological Association, mood and anxiety disorders can affect up to 1 in 4 people living in the United States over the course of their lifetimes.  Mood and anxiety disorders are a class of mental illnesses which includes major depression, generalized anxiety, social phobias, and many others.  Characterized by sad and worrisome thoughts and feelings, the lack of motivation, and changes in body function, mood and anxiety disorders have a profound impact on the lives of people living with them.  Increasingly, these illnesses are recognized as biological diseases arising from problems in brain function.  Scientific researchers are searching for the underlying causes for this brain function in order to develop more effective treatments.

The Brain Circuitry Underlying Mood and Anxiety

The human brain is divided into many different regions, and each region has specific functions.  Brain regions that have related functions are generally connected.  These connections allow different brain areas to work together to give rise to complicated functions, such as forming memories or feeling emotions.  These brain circuits can be thought of as the organizing center for a city’s complicated electrical grid.  In a city’s electrical system, electricity flows into an organizing center, where it gets sent to interconnected hubs that regulate distribution, and it finally gets directed back out into the city to light up peoples’ homes.  Similarly, information from the outside world is carried through the body to the organizing center of the brain, where it is processed and distributed in interconnected regions in the brain, and ultimately comes out again as feelings, memories, and actions.  Just as city blocks would lose power if a hub in the organizing center went down, disruptions in brain regions or the connections between them change how people feel and interact with the world.  Mood and anxiety disorders are thought to be caused by these types of disruptions in brain circuitry.

Some symptoms that allow doctors to diagnose a patient with a mood or anxiety disorder can be linked to specific brain circuits.  While there are many regions of the brain which work together to give rise to emotions, some areas play more important roles than others.  One such structure, the hippocampus, is critical to forming and recalling memories.  Some theories suggest that patients with a mood or anxiety illness recall bad memories, such as the loss of a loved one, more frequently than other people, and these bad memories may have a greater impact on the patient’s mood.  Another region, the frontal cortex, is involved in controlling behavior, such as when you control your desire for sweet foods in order to avoid gaining weight.  The frontal cortex may exert less control over emotional regions in patients with mood and anxiety illnesses.  This may cause patients with mood and anxiety disorders to have less control over their emotions, and negative emotions may gain more traction.  The hippocampus and frontal cortex are physically and functionally connected.  In patients with mood and anxiety diseases, bad memories recalled by the hippocampus may affect mood more greatly because the control exerted by the frontal cortex over the hippocampus may be reduced.

Growth Factors Regulate Brain Circuits and Are Disrupted in Mood and Anxiety Diseases

If disrupted brain circuits underlie mood and anxiety disorders, can scientists study molecules that regulate brain regions and the connections between them to better understand how brain circuits change in these illnesses?  Growth factors are a class of molecules which guide and regulate the connections between cells during development, infancy, and adulthood.  Over the past few years, scientists have found evidence that specific growth factors are altered in patients with mood and anxiety disorders.  Two such growth factors are called fibroblast growth factor 2 (FGF2) and fibroblast growth factor 9 (FGF9), originally named for the effects it had on skin cells, or fibroblasts, grown in the lab.  FGF2 has important effects in the brain throughout adulthood: it helps to maintain the connections between brain cells, promotes cells to survive, and encourages new cells to grow. The functions of FGF9 are not well understood, but FGF9 is known to play a role in lung development, skin, and hair.

FGF2 is normally present in the hippocampus and the frontal cortex, two important hubs for the regulation of mood in the brain’s organizing center.  These two regions are linked in healthy brains, but they may function differently in mood and anxiety disorders.  Researchers have observed decreases in size and volume for both the hippocampus and the frontal cortex in patients with major depression.  This suggests that patients with this disease may have fewer cells or connections between cells in these regions.  Scientists have also recently shown that patients with major depression have less FGF2 in their frontal cortices and hippocampi.  Since FGF2 helps to maintain connections between brain cells and promotes cell survival, these decreases in hippocampus and frontal cortex volume may be because there is less FGF2 in these regions—and these decreases in volume and FGF2 levels may be related to the symptoms of depression. Conversely, my research group showed that FGF9 is altered in the opposite direction - depressed patients had elevated levels of FGF9.

Other groups of researchers have examined FGF2 and FGF9 in the brains of animals to supplement data from experiments with human patients with mood and anxiety disorders.  Scientists have found that specific genetic backgrounds and stressful events, two phenomena associated with the development of mood and anxiety illnesses, both decrease FGF2 in the hippocampus.  This result parallels the findings with human patients: when circumstances such as genetic vulnerability to psychiatric illnesses combine with stress, FGF2 levels decrease in brain regions that underlie mood.  When this happens, the cells in these structures may become less healthy, and the connections between these cells aren’t maintained as well.  These effects may then feed-forward to negatively affect mood and anxiety. But in contrast, FGF9 increases in the hippocampus after animals are exposed to stress, which is another piece of evidence suggesting that FGF2 and FGF9 may be having opposite effects in the same brain region. And when our lab conducted experiments to artificially increase or decrease the amount of FGF2 or FGF9 in specific cells in the hippocampus, we saw opposite effects on anxiety-like behavior.

Collectively, these results suggest that high levels of FGF2 may be protective in mood and anxiety disorders, while high levels of FGF9 may increase susceptibility to these disorders. However, much research remains to be done to better understand the roles of FGF2 and FGF9 in critical brain structures like the hippocampus before either molecule can be targeted in developing new antidepressant drugs.

The next steps

The end of my PhD research and the main thrust of my postdoctoral research has used "big data" techniques to better understand how FGF2, FGF9, and other molecules are functionally related in the brain. If you're interested in learning more about my current projects, contact me and we can set up a time to discuss your questions.

 

 

 

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