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5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression.

Carriers of the short allele of a functional 5' promoter polymorphism of the serotonin transporter gene have increased anxiety-related temperamental traits, increased amygdala reactivity and elevated risk of depression. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to elucidate neural mechanisms underlying this complex genetic association. Morphometrical analyses showed reduced gray matter volume in short-allele carriers in limbic regions critical for processing of negative emotion, particularly perigenual cingulate and amygdala. Functional analysis of those regions during perceptual processing of fearful stimuli demonstrated tight coupling as a feedback circuit implicated in the extinction of negative affect. Short-allele carriers showed relative uncoupling of this circuit. Furthermore, the magnitude of coupling inversely predicted almost 30% of variation in temperamental anxiety. These genotype-related alterations in anatomy and function of an amygdala-cingulate feedback circuit critical for emotion regulation implicate a developmental, systems-level mechanism underlying normal emotional reactivity and genetic susceptibility for depression.

Pubmed ID: 15880108


  • Pezawas L
  • Meyer-Lindenberg A
  • Drabant EM
  • Verchinski BA
  • Munoz KE
  • Kolachana BS
  • Egan MF
  • Mattay VS
  • Hariri AR
  • Weinberger DR


Nature neuroscience

Publication Data

June 26, 2005

Associated Grants

  • Agency: Intramural NIH HHS, Id:

Mesh Terms

  • Amygdala
  • Anthropometry
  • Anxiety Disorders
  • Atrophy
  • Brain Chemistry
  • Brain Mapping
  • Depressive Disorder
  • Fear
  • Genetic Predisposition to Disease
  • Gyrus Cinguli
  • Humans
  • Magnetic Resonance Imaging
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Mutation
  • Nerve Tissue Proteins
  • Neural Pathways
  • Neuropsychological Tests
  • Polymorphism, Genetic
  • Questionnaires
  • Serotonin
  • Serotonin Plasma Membrane Transport Proteins