May 09, 2005
Gene Version Prevents Cingulate From Suppressing Amygdala Fear Response

Having one or two copies of the short version of the serotonin transporter gene prevents enough connections from being formed in the brain between the cingulate and amygdala. As a result fearful and stressful situations cause the amygdala to be too active and the neural circuitry in the cingulate lacks the connectivitiy needed to dampen down the amygdala fear response, leading to anxiety and depression.

The gene codes for the serotonin transporter, the protein in brain cells that recycles the chemical messenger after it's been secreted into the synapse, the gulf between cells. Since the most widely prescribed class of antidepressants act by blocking this protein, researchers have focused on possible functional consequences of a slight variation in its DNA sequence across individuals. Everyone inherits two copies of the gene, one from each parent, which comes in two common versions: short and long. The short version makes less protein, resulting in less recycling, increased levels of serotonin in the synapse, and more serotonin-triggered cellular activity. Previous NIMH-supported studies had shown that inheriting the short variant more than doubles risk of depression following life stresses,** boosts amygdala activity while viewing scary faces,*** and has been linked to anxious temperament. Yet, how it works at the level of brain circuitry remained a mystery.

The NIMH research team first scanned 114 healthy subjects using magnetic resonance imaging (MRI). Those with at least one copy of the short variant had less gray matter, neurons and their connections, in the amygdala-cingulate circuit than those with two copies of the long variant.

Next, using functional magnetic resonance imaging (fMRI), the researchers monitored the brain activity of 94 healthy participants while they were looking at scary faces, which activates fear circuitry. Those with the short variant showed less functional connectivity, in the same circuit.

Nearly 30 percent of subjects' scores on a standard scale of "harm avoidance," an inherited temperament trait associated with depression and anxiety, was explained by how well the mood-regulating circuit was connected.

"Until now, it's been hard to relate amygdala activity to temperament and genetic risk for depression," said Dr. Andreas Meyer-Lindenberg, a lead author. "This study suggests that the cingulate's ability to put the brakes on a runaway amygdala fear response depends upon the degree of connectivity in this circuit, which is influenced by the serotonin transporter gene."

Since serotonin activity plays a key role in wiring the brain's emotion processing circuitry during early development, the researchers propose that the short variant leads to stunted coupling in the circuit, a poorly regulated amygdala response and impaired emotional reactivity resulting in increased vulnerability to persistent bad moods and eventually depression as life's stresses take their toll.

One can imagine a couple of ways that future biotechnological advances will provide ways to treat this problem. First off, cell therapies, gene therapies, or nerve growth factor therapies could be used to encourage the growth of neurons between the cingulate and the amygdala. Another more "cyborg-ish" possibility would be to implant electrodes in the brain to deliver artificial signals into the amygdala to suppress the fear response.

Note how these scientists combined genetic test results with brain scan results. Once DNA sequencing and testing costs drop by orders of magnitude brain scan tests will be comparable to all the genetic variations in the genome to find other genetic variations that influence emotions and other aspects of cognition.

Share |      Randall Parker, 2005 May 09 05:24 PM  Brain Emotions

Lei said at May 10, 2005 6:11 AM:

brain scan tests will be comparable to all the genetic variations in the genome

Not sure what you mean by this. Brain scan tests focus on function while genetic variations focus on root cause. I can't see how one will replace the other.

Randall Parker said at May 10, 2005 6:24 AM:


Perhaps the problem is poor wording on my part. The results of brain scan tests will be compared to the results of genetics tests. Patterns found in brain scan tests (e.g. the size of the amygdala) can be compared to genetic sequences to look for correlations. The purpose is to use brain scan in combination with DNA sequencing data to find genetic variations that cause differences in brain function.

Grace said at June 11, 2005 1:26 PM:

I have a small lipoma in the hypothalumus area of the brain. I have been checked several times to see if I am currently
going through Menopause. Every time it shows I am Not. However, I am struggling with depression and my body temperature is up and down.

how much does diet affect this area of the brain????

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