Researchers at the National Institute of Mental Health ( NIMH ), a part of National Institute of Health ( NIH ) found that carriers of the short allele of a polymorphism of the in the serotonin transporter gene promotor region ( 5-HTTLPR ) have increased anxiety-related temperamental traits, increased amygdala reactivity and elevated risk of depression.

The study has been published in Nature Neuroscience.

The serotoninergic system is known to modulate mood, emotion, sleep and appetite and thus is implicated in the control of numerous behavioural and physiological functions. Decreased serotoninergic neurotransmission has been proposed to play a key role in the aetiology of depression.
The concentration of synaptic serotonin is controlled directly by its reuptake into the pre-synaptic terminal and, thus, drugs blocking serotonin transport have been successfully used for the treatment of depression.

Researchers have focused on possible functional consequences of a slight variation in serotonin transporter ( 5-HTT ) gene’s DNA sequence across individuals.

The NIMH research team first scanned 114 healthy subjects using magnetic resonance imaging ( MRI ).
Carriers of the short allele 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 allele 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 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.

Source: National Institute of Mental Health, 2005


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