Scaredy Cats, Warriors and Worriers?

By Claudia Wassmann

Differences in people’s emotionality have an important impact both on how they react to events in their daily lives and how they feel about themselves. In the past ten years, research has illuminated that small variations in our genetic make-up can significantly alter how we see the world. Researchers have focused predominantly on the role of neurotransmitters in the brain (particularly serotonin and dopamine). These neurotransmitters are known to be involved in affective disorders, such as major depression and anxiety disorders, as well as cognitive and affective impairments from schizophrenia.

Neuroimaging techniques, such as functional MRI, along with analyses of an individual’s genetics, reveal that variations in specific genes alter availability of these neurotransmitters in the brain, which affects basic cognitive function in healthy volunteers. Milestone studies such as Lesch et. al. (1996), showed in vitro (in cell cultures) that small differences in the gene that codes for the transporter protein of serotonin lead to differences in the effectiveness of this transporter protein.[1] In particular, a long allele variant of the gene leads to the production of a transporter protein that is almost twice as effective at carrying serotonin back into the brain cell, ending its action (neurotransmission), than the effectiveness of the protein that is coded for by the short allele variant of the same gene. Therefore, in the brains of those who carry the long allele, less serotonin is available at the synapse, compared to individuals who inherited the short allele variant for whom more serotonin is available for a longer period of time. Lesch combined these results with answers from conventional behavioral questionnaire studies. He found that people who carry the genetic variant which codes for the less effective transporter protein were more prone to anxiety disorders and depression.

Imaging genomics began in 2002 when a group of researchers at the NIMH used functional MRI to show this difference in the effectiveness of the serotonin transporter protein led to detectable differences in basic brain function in healthy volunteers.[2] It particularly affected the reactivity of the amygdala, a brain structure centrally involved in affective regulation. Hariri et.al. found that in the brains of people who carry the short allele, the amygdala in the right hemisphere (which deals with negative emotions) was more strongly activated in reaction to stimuli with negative connotations. In this study, two groups of participants looked at pictures of human faces with fearful, angry, and neutral expressions, and pictures of geometric forms (circles and vertical and horizontal ellipses) while undergoing a brain scan. Subjects were asked to look at the pictures for five seconds and decide which of two pictures shown at the bottom of a screen matched the picture on top. The brain scans suggested that unconscious processing of fear and threat-related information gave a different pattern of reactivity in the amygdala.

As well as how information is processed in the brain, activation of the amygdala also changes other physiological features such as heart rate, breathing and sweating, which are regulated by the autonomous nervous system and so beyond our conscious control. These bodily reactions then feed back into our psychological evaluations of a situation, affecting our judgements. The connectivity of the amygdala with other areas of the brain, such as the prefrontal cortex (important for cognitive control), are altered too when the amygdala is strongly activated, which makes it harder to shut down the amygdala activation voluntarily and focus on other things.

A longitudinal study followed in 2003 which demonstrated that people who carry the gene variant that codes for the less effective serotonin transporter are more susceptible to anxiety related behaviors and pathologies. They also tend to be less able to cope with stress. In particular, Caspi et.al. analyzed life histories of a group of 847 Caucasian 26-years-olds, who had been followed from 3 years old, through their childhood, adolescence and early adulthood. The study showed that people who carry the short allele variant were more likely to develop clinical depression in reaction to stressful negative life events, such as abuse or neglect during childhood, divorce, unemployment, and low socioeconomic status during their adult lives.[3]

These findings have great sociological resonance. Interpreting facial expressions is part of nearly every social situation, the visual information being only one aspect of the many kinds of information the brain takes in at an unconscious level of nervous processing. People who carry the short allele variant of the serotonin transporter protein also have a stronger startle response than individuals who carry the long allele, and one might say they tend to react like “scaredy cats.”

As long as the demands on the brain are not excessive, short and long allele carriers perform similarly. But definitions of “excessive” differs between the two groups. What one person perceives as stressful might not be perceived in the same way by someone who carries the long allele variant because their brain is able to shut down the amygdala response more quickly.

But serotonin is not the only neurotransmitter the brain uses. Variations in genes which alter the availability of dopamine also affect complex aspects of our feelings, cognition and behavior. Dopamine has several functions and two mechanisms are implicated in the regulation of dopamine levels in the brain. The action of dopamine can be terminated by the enzyme COMT (the catechol-O-methyltransferase that ends dopamine signaling), and by transporting dopamine back into the cell through the dopamine transporter protein (DAT). Variations in the genes for COMT and for DAT alter the availability of dopamine in the prefrontal cortex and other brain areas involved in emotional processing. These variations directly affect the functions of the prefrontal cortex, such as working memory capacity.

The neurotransmitter dopamine is also involved in feelings of “reward” after the successful completion of a task and necessary for the execution of muscular movements. Its lack is for instance felt in Parkinson’s disease. Dopamine is crucial “for determining neuronal signal-to-noise ratios” in prefrontal cortex.[5] That means it fine-tunes nervous activation. This allows us to keep our attention focused on the task we want to carry out and filter out other kinds of intruding sensory information and interfering thoughts which might hinder our performance.

Differences in availability of dopamine seem to lead to marked differences in intellectual performance. Optimal concentrations of dopamine – not too much or too little – are required for optimal working memory functioning. In particular, Bertolino et al. showed that the effects variants in the genes that code for the enzyme COMT and the transporter protein DAT add up. Individuals who carry two copies of the COMT “Met allele” (that is, who are homozygous for the “Met allele”) and who are also homozygous for the dopamine transporter “DAT 10-repeat” have “the most focused response” in neuronal activity in the prefrontal cortex and working memory circuits.[6] They have a higher concentration of dopamine which is available for a longer period of time, allowing them to stay focused and needing less cognitive resources to perform the same tasks than do individuals who inherited the variant of the COMT gene that codes for the more efficient version of the COMT enzyme that clears dopamine more quickly from the synapse.[7] With more dopamine available in the “Met allele” carriers, the cells in the prefrontal cortex are better able to filter information from meaningless noise.

However, while people who carry the “Met allele” show better performance in working memory tasks and prefrontal cortex function, they also show greater excitability of the amygdala in reaction to emotional threats. Therefore, they are prone to “rumination” and “perseveration.” As more dopamine becomes available in brain areas involved in emotional processing (in the limbic system, including the amygdala), the balance of dopamine in the prefrontal cortex and emotion processing areas of the brain is altered. The inhibitory input on the amygdala from the prefrontal cortex gets inhibited and the excitatory sensory input to the amygdala increases.[8] The individual “gets stuck” and is less able to shift away their attention and focus on other things.

While the popular press labels people “warriors” who seem poised, resistant to anxiety and not easily uprooted by challenges that occur in their daily life, in contrast to “worriers” who are more preoccupied with negative outcomes of their performance and less able to filter out intruding thoughts, this is only part of the picture.[9] The effects of several genetic variations combine and there are many more genes involved than the three examples presented in this article. Genetic variations in serotonin and dopamine represent two important examples of how these differences can play out in different affective behaviors. If some of us are more fearful than others, the effect of serotonin signaling on amygdala reactivity might help to explain part of this behavior. However, I do not support a return to reductionist genetic determinism which declares that genes encode behaviors. They don’t. As the scientists who conducted the first genomic imaging studies pointed out, “Since this genetically driven effect exists in healthy subjects, it does not, in and of itself, predict dimensions of mood or temperament.”[10] As long-term studies show, differences in amygdala reactivity yield overt behavioral differences and lead to increased anxiety and harm avoidance tendencies only in the context of negative life events. Therfore, the implications of small genetic variations, such as a short or long allele of the gene that codes for the serotonin transporter protein, are broad because they play out over the life cycle of a person when they interact with life experiences.

Claudia Wassmann has a Ph.D. in History of Science from the University of Chicago and an MD from the Free University of Berlin. She held a Knight Science Journalism Fellow at the Massachusetts Institute of Technology and conducted post-doctoral research as a Dewitt Stetten, Jr., Memorial Fellow in the History of Biomedical Sciences and Technology at the National Institutes of Health. She is also a science documentary filmmaker who has won numerous awards, and her current research is concerned with the history of the neurosciences, brain imaging and emotion.

Bertolino, Alessandro , Giuseppe Blasi, Valeria Latorre, Valeria Rubino, Antonio Rampino, Lorenzo Sinibaldi, Grazia Caforio, et al. “Additive Effects of Genetic Variation in Dopamine Regulating Genes on Working Memory Cortical Activity in Human Brain.” The Journal of Neuroscience 26, no. 15 (2006): 3918 –22.

Bronson, Po, and Ashley Merryman. “Why Can Some Kids Handle Pressure While Others Fall Apart?”. New York Times Magazine 10/02/2013 (2013).

Caspi, A, K Sugden, TE Moffitt, A Taylor, IW Craig, H Harrington, J McClay, et al. “Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-Htt Gene.” [In English]. Science 301, no. 5631 (JUL 18 2003 2003): 386-89.

Hariri, A. R., E. M. Drabant, K. E. Munoz, B. S. Kolachana, V. S. Mattay, M. F. Egan, and D. R. Weinberger. “A Susceptibility Gene for Affective Disorders and the Response of the Human Amygdala.” [In eng]. Arch Gen Psychiatry 62, no. 2 (Feb 2005): 146-52.

Hariri, A. R., V. S. Mattay, A. Tessitore, B. Kolachana, F. Fera, D. Goldman, M. F. Egan, and D. R. Weinberger. “Serotonin Transporter Genetic Variation and the Response of the Human Amygdala.” [In eng]. Science 297, no. 5580 (Jul 19 2002): 400-3.

Hariri, Ahmad R. “The What, Where, and When of Catechol-O-Methyltransferase.” Biological Psychiatry 70 (2011): 214-15.

Lesch, KP, D Bengel, A Heils, SZ Sabol, BD Greenberg, S Petri, J Benjamin, et al. “Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region.” [In English]. Science 274, no. 5292 (NOV 29 1996 1996): 1527-31.

[1] KP Lesch et al., “Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region,” Science 274, no. 5292 (1996).

[2] A. R. Hariri et al., “Serotonin Transporter Genetic Variation and the Response of the Human Amygdala,” ibid.297, no. 5580 (2002).

[3] A Caspi et al., “Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-Htt Gene,” ibid.301, no. 5631 (2003).

[4] A. R. Hariri et al., “A Susceptibility Gene for Affective Disorders and the Response of the Human Amygdala,” Arch Gen Psychiatry 62, no. 2 (2005)., p. 147.

[5] Alessandro Bertolino et al., “Additive Effects of Genetic Variation in Dopamine Regulating Genes on Working Memory Cortical Activity in Human Brain,” The Journal of Neuroscience 26, no. 15 (2006).

[6] Bertolino et al., “Additive Effects of Genetic Variation in Dopamine Regulating Genes on Working Memory Cortical Activity in Human Brain.”, p. 3921.

[7] The alleles of the gene contain the amino acid Valine rather than Methionine (158Val/Val).

[8] Ahmad R. Hariri, “The What, Where, and When of Catechol-O-Methyltransferase,” Biological Psychiatry 70 (2011).

[9] Po Bronson and Ashley Merryman, “Why Can Some Kids Handle Pressure While Others Fall Apart?,” New York Times Magazine 10/02/2013 (2013).

[10] Hariri et al., “A Susceptibility Gene for Affective Disorders and the Response of the Human Amygdala.”, p. 146.

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