title: Interaction of the serotonin transporter-linked polymorphic region and environmental adversity: increased amygdala-hypothalamus connectivity as a potential mechanism linking neural and endocrine hyperreactivity.
abstract: BACKGROUND
  Gene by environment (G×E) interaction between genetic variation in the promoter region of the serotonin transporter gene (serotonin transporter-linked polymorphic region [5-HTTLPR]) and stressful life events (SLEs) has been extensively studied in the context of depression. Recent findings suggest increased neural and endocrine stress sensitivity as a possible mechanism conveying elevated vulnerability to psychopathology. Furthermore, these G×E mediated alterations very likely reflect interrelated biological processes.
  
  
  METHODS
  In the present functional magnetic resonance imaging study, amygdala reactivity to fearful stimuli was assessed in healthy male adults (n = 44), who were previously found to differ with regard to endocrine stress reactivity as a function of 5-HTTLPR × SLEs. Furthermore, functional connectivity between the amygdala and the hypothalamus was measured as a potential mechanism linking elevated neural and endocrine responses during stressful/threatening situations. The study sample was carefully preselected regarding 5-HTTLPR genotype and SLEs.
  
  
  RESULTS
  We report significant G×E interaction on neural response patterns and functional amygdala-hypothalamus connectivity. Specifically, homozygous carriers of the 5-HTTLPR S' allele with a history of SLEs (S'S'/high SLEs group) displayed elevated bilateral amygdala activation in response to fearful faces. Within the same sample, a comparable G×E interaction effect has previously been demonstrated regarding increased cortisol reactivity, indicating a cross-validation of heightened biological stress sensitivity. Furthermore, S'S'/high SLEs subjects were characterized by an increased functional coupling between the right amygdala and the hypothalamus, thus indicating a potential link between neural and endocrine hyperreactivity.
  
  
  CONCLUSIONS
  The present findings contribute to the ongoing debate on 5-HTTLPR × SLEs interaction and are discussed with respect to clinical implications.
authors.affiliation: Department of Biological Psychology, Technische Universität, Dresden, Germany. alexander@biopsych.tu-dresden.de
authors.forename: Nina
authors.initials: N
authors.lastname: Alexander
authors.forename: Tim
authors.initials: T
authors.lastname: Klucken
authors.forename: Georgia
authors.initials: G
authors.lastname: Koppe
authors.forename: Roman
authors.initials: R
authors.lastname: Osinsky
authors.forename: Bertram
authors.initials: B
authors.lastname: Walter
authors.forename: Dieter
authors.initials: D
authors.lastname: Vaitl
authors.forename: Gebhard
authors.initials: G
authors.lastname: Sammer
authors.forename: Rudolf
authors.initials: R
authors.lastname: Stark
authors.forename: Juergen
authors.initials: J
authors.lastname: Hennig
mesh_terms: D000328:Adult; D000679:Amygdala / Q000378:metabolism*; D001931:Brain Mapping / Q000379:methods; D005149:Facial Expression; D005239:Fear; D059647:Gene-Environment Interaction; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism*; D008016:Life Change Events; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009434:Neural Pathways / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D012016:Reference Values; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism
chemical_list: C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D006854:Hydrocortisone