title: Effects of HTR1A C(-1019)G on amygdala reactivity and trait anxiety.
abstract: BACKGROUND
  Serotonin 1A (5-hydroxytryptamine 1A [5-HT(1A)]) autoreceptors mediate negative feedback inhibition of serotonergic neurons and play a critical role in regulating serotonin signaling involved in shaping the functional response of major forebrain targets, such as the amygdala, supporting complex behavioral processes. A common functional variation (C[-1019]G) in the human 5-HT(1A) gene (HTR1A) represents 1 potential source of such interindividual variability. Both in vitro and in vivo, -1019G blocks transcriptional repression, leading to increased autoreceptor expression. Thus, -1019G may contribute to relatively decreased serotonin signaling at postsynaptic forebrain target sites via increased negative feedback.
  
  
  OBJECTIVE
  To evaluate the effects of HTR1A C(-1019)G on amygdala reactivity and to use path analyses to explore the impact of HTR1A-mediated variability in amygdala reactivity on individual differences in trait anxiety. We hypothesized that -1019G, which potentially results in decreased serotonin signaling, would be associated with relatively decreased amygdala reactivity and related trait anxiety.
  
  
  METHODS
  Imaging genetics in participants from an archival database.
  
  
  METHODS
  Eighty-nine healthy adults.
  
  
  RESULTS
  Consistent with prior findings, -1019G was associated with significantly decreased threat-related amygdala reactivity. Importantly, this effect was independent of that associated with another common functional polymorphism that affects serotonin signaling, 5-HTTLPR. While there were no direct genotype effects on trait anxiety, HTR1A C(-1019)G indirectly predicted 9.2% of interindividual variability in trait anxiety through its effects on amygdala reactivity.
  
  
  CONCLUSIONS
  Our findings further implicate relatively increased serotonin signaling, associated with a genetic variation that mediates increased 5-HT(1A) autoreceptors, in driving amygdala reactivity and trait anxiety. Moreover, they provide empirical documentation of the basic premise that genetic variation indirectly affects emergent behavioral processes related to psychiatric disease risk by biasing the response of underlying neural circuitries.
authors.affiliation: Hôpital de laTimone, ServiceHospitalo-Universitaire dePsychiatrie, Hôpital SteMarguerite, Marseille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Fakra
authors.forename: Luke W
authors.initials: LW
authors.lastname: Hyde
authors.forename: Adam
authors.initials: A
authors.lastname: Gorka
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Fisher
authors.forename: Karen E
authors.initials: KE
authors.lastname: Muñoz
authors.forename: Mark
authors.initials: M
authors.lastname: Kimak
authors.forename: Indrani
authors.initials: I
authors.lastname: Halder
authors.forename: Robert E
authors.initials: RE
authors.lastname: Ferrell
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Manuck
authors.forename: Ahmad R
authors.initials: AR
authors.lastname: Hariri
mesh_terms: D000328:Adult; D000483:Alleles; D000679:Amygdala / Q000503:physiopathology*; D000786:Anger / Q000502:physiology; D001008:Anxiety Disorders / Q000235:genetics* / Q000503:physiopathology; D001143:Arousal / Q000235:genetics* / Q000502:physiology; D001288:Attention / Q000502:physiology; D017660:Autoreceptors / Q000235:genetics*; D004292:Dominance, Cerebral / Q000502:physiology; D005149:Facial Expression; D005239:Fear / Q000502:physiology; D005260:Female; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010100:Oxygen / Q000097:blood*; D010364:Pattern Recognition, Visual / Q000502:physiology; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D017660:Autoreceptors; D044282:Receptor, Serotonin, 5-HT1A; D010100:Oxygen