title: Amygdala functional connectivity, HPA axis genetic variation, and life stress in children and relations to anxiety and emotion regulation.
abstract: Internalizing pathology is related to alterations in amygdala resting state functional connectivity, potentially implicating altered emotional reactivity and/or emotion regulation in the etiological pathway. Importantly, there is accumulating evidence that stress exposure and genetic vulnerability impact amygdala structure/function and risk for internalizing pathology. The present study examined whether early life stress and genetic profile scores (10 single nucleotide polymorphisms within 4 hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predicted individual differences in amygdala functional connectivity in school-age children (9- to 14-year-olds; N = 120). Whole-brain regression analyses indicated that increasing genetic "risk" predicted alterations in amygdala connectivity to the caudate and postcentral gyrus. Experience of more stressful and traumatic life events predicted weakened amygdala-anterior cingulate cortex connectivity. Genetic "risk" and stress exposure interacted to predict weakened connectivity between the amygdala and the inferior and middle frontal gyri, caudate, and parahippocampal gyrus in those children with the greatest genetic and environmental risk load. Furthermore, amygdala connectivity longitudinally predicted anxiety symptoms and emotion regulation skills at a later follow-up. Amygdala connectivity mediated effects of life stress on anxiety and of genetic variants on emotion regulation. The current results suggest that considering the unique and interacting effects of biological vulnerability and environmental risk factors may be key to understanding the development of altered amygdala functional connectivity, a potential factor in the risk trajectory for internalizing pathology.
authors.affiliation: The Program in Neuroscience, Washington University in St. Louis.
authors.forename: David
authors.identifier: 0000-0002-1214-1965
authors.initials: D
authors.lastname: Pagliaccio
authors.affiliation: Department of Psychiatry, Washington University in St. Louis.
authors.forename: Joan L
authors.initials: JL
authors.lastname: Luby
authors.affiliation: The Program in Neuroscience, Washington University in St. Louis.
authors.forename: Ryan
authors.initials: R
authors.lastname: Bogdan
authors.affiliation: Department of Psychiatry, Washington University in St. Louis.
authors.forename: Arpana
authors.initials: A
authors.lastname: Agrawal
authors.affiliation: Department of Psychiatry, Washington University in St. Louis.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gaffrey
authors.affiliation: Department of Psychiatry, Washington University in St. Louis.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Belden
authors.affiliation: Department of Psychiatry, Washington University in St. Louis.
authors.forename: Kelly N
authors.initials: KN
authors.lastname: Botteron
authors.affiliation: Department of Psychiatry, Washington University in St. Louis.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Harms
authors.affiliation: The Program in Neuroscience, Washington University in St. Louis.
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Barch
mesh_terms: D000293:Adolescent; D000679:Amygdala / Q000000981:diagnostic imaging / Q000503:physiopathology*; D001007:Anxiety / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology* / Q000523:psychology; D002648:Child; D004644:Emotions / Q000502:physiology*; D005260:Female; D059647:Gene-Environment Interaction; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009415:Nerve Net / Q000000981:diagnostic imaging / Q000503:physiopathology*; D059906:Neuroimaging; D010913:Pituitary-Adrenal System / Q000503:physiopathology*; D020641:Polymorphism, Single Nucleotide; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D013315:Stress, Psychological / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology* / Q000523:psychology; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D000099052:CRF Receptor, Type 1; D000099159:Tacrolimus Binding Protein 5
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D022021:Tacrolimus Binding Proteins; D000099052:CRF Receptor, Type 1; D000099159:Tacrolimus Binding Protein 5; C497713:NR3C1 protein, human; C561839:NR3C2 protein, human