Of Mice and Men (and Anxiety)

Two studies were published this week that made the connection between genetic variations and anxiety disorders in both humans and animals.

One study, published in the journal Science, found that mice and humans with the same mutation in an anxiety-related gene behave similarly. The study, titled "A Genetic Variant BDNF Polymorphism Alters Extinction Learning in Both Mouse and Human," sounds almost deliberately obtuse, but the results are interesting. Lab rats (or in this case, lab mice) are often used in research for any number of reasons, which include the fact that they are small and relatively easy to handle, they reproduce quickly, and over a century of intense breeding and research has enabled researchers to know an animal's exact genetic profile. Many studies in behavioral neuroscience use mice and rats for these reasons, and also because it's generally difficult to get humans to participate in many of these experiments (which are often ended by autopsy so the brain can be examined). From a genetic standpoint, there aren't a whole lot of differences between a human and a mouse. Many of the tasks we both have to complete--digesting food, eliminating waste, maintaining homeostasis--are pretty darn similar, so researchers have hypothesized that the neural circuits controlling behavior in mice and people are actually similar.

This most recent study looked at a variation in the gene that makes Brain Derived Neurotropic Factor (BDNF), a protein responsible for brain growth and development. The interesting result was that the mice and humans who had this variation had similar behaviors. From a Science Daily press release:

To make their comparison, the researchers paired a harmless stimulus with an aversive one, which elicits an anxious-like response, known as conditioned fear. Following fear learning, exposure to numerous presentations of the harmless stimulus alone, in the absence of the aversive stimulus, normally leads to subjects extinguishing this fear response. That is, a subject should eventually stop having an anxious response towards the harmless stimulus.

"But both the mice and humans found to have the alternation in the BDNF gene took significantly longer to 'get over' the innocuous stimuli and stop having a conditioned fear response," explains Dr. Fatima Soliman...

...[Researchers] found that a circuit in the brain involving the frontal cortex and amygdala -- responsible for learning about cues that signal safety and danger -- was altered in people with the abnormality, when compared with control participants who did not have the abnormality.

"Testing for this gene may one day help doctors make more informed decisions for treatment of anxiety disorders," explains Dr. Francis S. Lee.

Specifically, it may help therapists tailor approaches to treating anxiety such as exposure therapy, which is an empirically supported treatment for a variety of anxiety disorders, such as phobias and PTSD.

"Exposure therapy may still work for patients with this gene abnormality, but a positive test for the BDNF genetic variant may let doctors know that exposure therapy may take longer, and that the use of newer drugs may be necessary to accelerate extinction learning," explains Dr. Soliman.

BDNF has also been associated with both anorexia nervosa and bulimia nervosa.

In a completely separate study, researchers have identified a genetic mutation that results in compulsive behaviors in a wide variety of animals. From a New York Times article on the study:

Researchers studied Doberman pinschers that curled up into balls, sucking their flanks for hours at a time, and found that the afflicted dogs shared a gene...the findings [have] broad implications for compulsive disorders in people and animals.

Dr. Dodman and his collaborators searched for a genetic source for this behavior by scanning and comparing the genomes of 94 Doberman pinschers that sucked their flanks, sucked on blankets or engaged in both behaviors with those of 73 Dobermans that did neither. They also studied the pedigrees of all the dogs for complex patterns of inheritance. The researchers identified a spot on canine chromosome 7 that contains the gene CDH2 (Cadherin 2), which showed variation in the genetic code when the sucking and nonsucking dogs were compared.

The statistical association led to further investigation to determine for which protein the gene contained instructions. It did for one of the proteins called cadherins, which are found throughout the animal kingdom and are apparently involved in cell alignment, adhesion and signaling.

Cadherins have also been recently associated with autism spectrum disorder, which includes repetitive and compulsive behaviors...

...“Stress and anxiety, as well as physical trauma and illness, can trigger repetitive behavior that then takes on a life of its own,” Dr. Ginns said.

But he believes that in many cases there is an underlying genetic predisposition that responds to environmental stimuli in such a way that once-normal behavior turns into something pathological. Those genetic dispositions may differ markedly between different behaviors.

Considering the links recently postulated between anorexia and autism as well as anorexia and OCD, these results may one day have an effect on our understanding of eating disorders.


Cathy (UK) said...

Interesting articles; thanks for finding these gems Carrie! In terms of my own experiences of longstanding anorexia nervosa (AN), OCD and autistic spectrum disorder (ASD) - I guess I have inherited a combination of unusual genes...

I had OCD and repetitive behaviours (and also the classic autistic traits of retarded social learning and fear of change) right from being a toddler. When my AN started at age 12 it just seemed like an extension of all these childhood behaviours. The 'fear trigger' for my AN was confusion around the physical and social changes of adolescence. Bullying and abuse at school made me feel 'crap' about myself. And so I starved out my anxiety through food restriction and over-exercise - which became compulsive.

The suggested link between AN and ASDs has confused some people who argue that AN is not autism. I totally agree. However, the expression of autistic traits within people with ASDs and AN can vary quite considerably. Some people have particular difficulties with empathy, while others are particularly strong systemisers (i.e. obsessive, compulsive, detail-orientated, perfectionistic and ordered). I am a strong systemiser - which helps to explain the difficulties I had with abandoning anorexic rituals.

Personally, I feel that the links that have been made between AN and ASD are the most promising yet in our understanding of some cases of AN.

Paul Greene, Ph.D. said...

Thanks for your very well written and well informed post! I had actually not heard about these interesting studies. Personally I wonder exactly what the treatment implications would be, were doctors to discover that a patient had the mutation described in the first article. I suspect that the real implications of this advance will not be seen until new classes of drugs are developed specifically for people with certain genetic vulnerabilities. Time will tell. Thanks again --

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I'm a science writer, a jewelry design artist, a bookworm, a complete geek, and mom to a wonderful kitty. I am also recovering from a decade-plus battle with anorexia nervosa. I believe that complete recovery is possible, and that the first step along that path is full nutrition.

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