title: Variation in serotonin transporter expression modulates fear-evoked hemodynamic responses and theta-frequency neuronal oscillations in the amygdala.
abstract: BACKGROUND
  Gene association studies detect an influence of natural variation in the 5-hydroxytryptamine transporter (5-HTT) gene on multiple aspects of individuality in brain function, ranging from personality traits through to susceptibility to psychiatric disorders such as anxiety and depression. The neural substrates of these associations are unknown. Human neuroimaging studies suggest modulation of the amygdala by 5-HTT variation, but this hypothesis is controversial and unresolved, and difficult to investigate further in humans.
  
  
  METHODS
  We used a mouse model in which the 5-HTT is overexpressed throughout the brain and recorded hemodynamic responses (using a novel in vivo voltammetric monitoring method, analogous to blood oxygen level-dependent functional magnetic resonance imaging) and local field potentials during Pavlovian fear conditioning.
  
  
  RESULTS
  Increased 5-HTT expression impaired, but did not prevent, fear learning and significantly reduced amygdala hemodynamic responses to aversive cues. Increased 5-HTT expression was also associated with reduced theta oscillations, which were a feature of aversive cue presentation in controls. Moreover, in control mice, but not those with high 5-HTT expression, there was a strong correlation between theta power and the amplitude of the hemodynamic response.
  
  
  CONCLUSIONS
  Direct experimental manipulation of 5-HTT expression levels throughout the brain markedly altered fear learning, amygdala hemodynamic responses, and neuronal oscillations.
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Barkus
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Line
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Huber
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom.
authors.forename: Liliana
authors.initials: L
authors.lastname: Capitao
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom.
authors.forename: Joao
authors.initials: J
authors.lastname: Lima
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Katie
authors.initials: K
authors.lastname: Jennings
authors.affiliation: Department of Chemistry, National University of Ireland, Maynooth, Ireland.
authors.forename: John
authors.initials: J
authors.lastname: Lowry
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: Trevor
authors.initials: T
authors.lastname: Sharp
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom.
authors.forename: David M
authors.initials: DM
authors.lastname: Bannerman
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom. Electronic address: stephen.mchugh@psy.ox.ac.uk.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: McHugh
mesh_terms: D000679:Amygdala / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D005239:Fear / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013826:Theta Rhythm / Q000502:physiology*
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D010100:Oxygen
keywords: amygdala; fMRI; fear; serotonin transporter; theta oscillations; tissue oxygen