Psychology 130
Research Paper

Mice May Provide Important Clues for OCD Disorder

Great strides have taken place in the research area of obsessive-compulsive disorder over the past three years, and there is hope that better treatments for humans suffering from this disorder may soon be in place, and it is mice that are providing important clues to what may cause OCD.
The key issue behind OCD research is to find treatment and relief for those humans suffering from this debilitating psychiatric condition which affects about two percent of the world’s population. OCD is one of the most common psychiatric disorders in the world. It is marked by persistent intrusive thoughts (the obsession), repetitive actions (the compulsion) and anxiety. Examples include fear of contamination, or that something terrible will happen to a loved one. They also suffer from repetitive rituals (compulsions), which are often designed to neutralise these thoughts. Examples include hand-washing and checking and rechecking things. These symptoms cause distress and can occupy hours during the day, interfering with a person’s quality of life and their ability to work. The severity of OCD varies widely from person to person, and while the neurobiological basis of the disease is unknown, there are indications in past research that genetics plays a role.
One of the key studies conducted in the last three years was done by the Duke University Medicine Center who had been conducting basic research on how individual brain cells communicate. While they were completing this research, they inadvertently discovered that some of the mice they were studying would groom their faces compulsively to the point where they would bleed. The researchers discovered that these mice had a genetic mutation that prevented their brain cells from producing one key protein. These mice were exhibiting OCD- like behaviours such as this compulsive facial grooming.
This discovery is a huge step in discovering what possibly causes OCD in humans. Dr. Guoping Feng, who led the team of international researchers at Duke, is a molecular geneticist and he comments, "The mice that could not produce this protein exhibited behaviours similar to that of humans with OCD, a compulsive action coupled with increased anxiety. The mice clearly did things that looked like OCD" (Duke).
In their further experiments, the Duke team focused on a portion of the brain known as the striatum, an area that controls the planning and execution of movement, as well as other cognitive functions. It is in many ways "the decider." In normal brains, a protein known as SAPAP3 is crucial for nerve signals to travel from one nerve cell to another across the synapse, the gap between the cells. This protein is important for allowing messages to cross synapses, and it is produced at high levels in the cells that make up the striatum. When the Duke scientists looked closely at the brain cells of the mutant mice, they found that there were defects in the synapses.
The Duke scientists then gave injections to the mice that returned the missing protein into the striatum of the brains of the mutant mice. When the synaptic defects were repaired, their OCD-like behaviours subsided. This is the first scientific evidence that a synaptic defect in the striatum causes OCD-like behaviours.
The researchers also found that a class of drugs known as “selective serotonin reuptake inhibitors (SSRI)” reduced the anxiety levels and suppressed the over-grooming in the mutant mice. This further suggested to the researches that what they observed in mice may also be compared to human OCD. Serotonin, like SAPAP3, is one of many neurotransmitters, chemicals involved in nerve cell communication. While SSRIs are the most commonly prescribed drug for humans with OCD, they are only effective for about half the patients, suggesting to these researchers that many pathways involving different neurotransmitters are likely involved. As a result, Dr. Feng and his group of researchers at Duke are currently looking for additional gene variations that may affect how nerve signals cross synapses, and they are also beginning studies to determine if the gene mutant they discovered in mice plays a role in humans with OCD.
In the meantime, Researchers at the Ansary Stem Cell Institute and the Department of Psychiatry at Weill Cornell Medical College discovered that mice missing a single gene developed repetitive obsessive-compulsive-like behaviours also. These researchers were working with genetically altered mice, which behaved much like people with a certain type of obsessive-compulsive disorder (OCD). Again, this was another “accidental discovery”. The researchers were originally examining what the role of a gene called Slitrk5, had to blood stem and vascular cells. They had disabled the Slitrk5 gene in the mice they were studying and observed OCD like behaviours in the genetically modified mice such as self-grooming and extreme anxiety. When they studied the mice closer they discovered that the frontal lobe-to-striatum circuits of the brain of these mice were altered in the same ways that humans diagnosed with OCD had their circuits altered. These researchers also began conducting new research also in hopes of finding new therapies for human suffering from OCD.
The Weill Cornell researcher concluded that there is a link between Slitrk5 and the development of OCD behaviours in humans. "Overall, our data suggest that Slitrk5 may have a central role in the development of the core symptoms of OCD -- self-injurious, repetitive behaviour and increased anxiety," says Dr. Shahin Rafii, director of the Ansary Stem Cell Institute, Professor of genetic medicine at Weill Cornell Medical College and one of the prime researchers. "Very few psychiatric disorders have been linked to a single gene, and it will be important to find out if patients with the disorder have an alteration of Slitrk5" (Weill Cornell).
The scientists gave Prozac, a standard drug used in the treatment for human patients with OCD, to the genetically modified mice who were exhibiting OCD behaviours and found that the excessive grooming stopped completely. The researchers knew that Prozac worked to ameliorate some OCD symptoms in humans, and became excited when it also worked on the mice. However, the effect can be temporary and more detailed research needs to be conducted, before ultimately new therapies may become available for humans.
In a third study, researchers at Cambridge University have discovered that measuring activity in a region of the brain could help to identify people at risk of developing obsessive compulsive disorder (OCD). Currently when human are diagnosed with OCD it is based on interviews with the person suffering from the disorder, and the habitual behaviour and anxiety has already developed and the disorder has progressed.
The Cambridge scientists discovered that people with OCD and their close family members show under-activation of brain areas responsible for stopping habitual behaviour. This is the first time that scientists have associated functional changes in the brain with family risk for the disorder. Although OCD tends to run in families, genetic factors responsible for this hereditary trait are not known. Genes may pose a risk for OCD by influencing how the brain develops.
The University of Cambridge, Department of Psychiatry lead the research, headed by Dr. Samual Chamberlain. They used functional magnetic resonance imaging (fMRI) to measure brain activity in the frontal brain lobes, an area which involves decision making and behaviour in humans. Fourteen families with a history of OCD and their immediate relatives were tested and compared.
Dr. Chamberlain, who led the study, explains, "Impaired function in brain areas controlling flexible behaviour probably predisposes people to developing the compulsive rigid symptoms that are characteristic of OCD. This study shows that these brain changes run in families and represent a candidate vulnerability factor. The current diagnosis of OCD is subjective and improved understanding of the underlying causes of OCD could lead to more accurate diagnosis and improved clinical treatments. However, much work is still needed to identify the genes contributing to abnormal brain function in those at risk of OCD. We also need to investigate not only vulnerability factors, but also protective factors that account for why many people at genetic risk of the condition never go on to develop the symptoms" (Cambridge).
My assessment is that if researchers in the third study are able to provide methods of diagnosing those predisposed to OCD, it could enable earlier more objective detection, and intervention. Further, as for the results of the studies being completed at Duke University and Weill Cornell Medical College come to fruition, these findings may help scientists and doctors better understand both development and treatment for one or more of the several different types of human OCD behaviours. While direct parallels can’t be drawn right now between mice and humans, there is no denying the similarity in the symptoms displayed in the mice (compulsive grooming) and anxiety, and the spectrum of behaviours in humans which include hand-washing and anxiety amongst its obsessive behaviours. The comparison in the same gene deficiencies in both species is invaluable. By discovering the altered brain functioning and how it works in both mice and humans, it is inevitable that at some point there may be relief for those humans diagnosed with and suffering from this debilitating disorder.

WORKS CITED:

Duke University Medical Center. “Mice Provide Important Clues To Obsessive Compulsive Disorder.: " Science Daily 26 August 2007. 21 November 2010. .

New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College. "A Single Gene Is Responsible for OCD-Like Behaviors in Mice." Science Daily, April
2010. Web. 21 November 2010. .

University of Cambridge. "Obsessive Compulsive Disorder Linked To Brain Activity." Science
Daily, 18 July 2008. Web. 21 November 2010. .