Congcong Liu1, Lei Xu1, Jialin Li1, Feng Zhou1, Xi Yang1, Xiaoxiao Zheng1, Meina Fu1, Keshuang Li1, Cornelia Sindermann2, Christian Montag1,2, Yina Ma3, Dirk Scheele4,5, Richard P Ebstein6,7, Shuxia Yao1, Keith M Kendrick1, Benjamin Becker1. 1. The Clinical Hospital of the Chengdu Brain Science Institute, School of Life Science and Technology, MOE Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, 611731Chengdu, China. 2. Department of Molecular Psychology, Institute of Psychology and Education, Ulm University, 89081Ulm, Germany. 3. State Key Laboratory of Cognitive Neuroscience and Learning, IDG/McGovern Institute of Brain Research, Beijing Normal University, 100875Beijing, China. 4. Division of Medical Psychology, Department of Psychiatry and Psychotherapy, University Hospital Bonn, 53105Bonn, Germany. 5. Department of Psychiatry, School of Medicine & Health Sciences, University of Oldenburg, 26129Oldenburg, Germany. 6. School of Management, Zhejiang University of Technology, 310023Hangzhou, China. 7. China Center for Behavior Economics and Finance, South Western University of Finance and Economics (SWUFE), 611130, Chengdu, China.
Abstract
BACKGROUND: Early life stress has been associated with emotional dysregulations and altered architecture of limbic-prefrontal brain systems engaged in emotional processing. Serotonin regulates both, developmental and experience-dependent neuroplasticity in these circuits. Central serotonergic biosynthesis rates are regulated by Tryptophan hydroxylase 2 (TPH2) and transgenic animal models suggest that TPH2-gene associated differences in serotonergic signaling mediate the impact of aversive early life experiences on a phenotype characterized by anxious avoidance. METHODS: The present study employed an imaging genetics approach that capitalized on individual differences in a TPH2 polymorphism (703G/T; rs4570625) to determine whether differences in serotonergic signaling modulate the effects of early life stress on brain structure and function and punishment sensitivity in humans (n = 252). RESULTS: Higher maltreatment exposure before the age of 16 was associated with increased gray matter volumes in a circuitry spanning thalamic-limbic-prefrontal regions and decreased intrinsic communication in limbic-prefrontal circuits selectively in TT carriers. In an independent replication sample, associations between higher early life stress and increased frontal volumes in TT carriers were confirmed. On the phenotype level, the genotype moderated the association between higher early life stress exposure and higher punishment sensitivity. In TT carriers, the association between higher early life stress exposure and punishment sensitivity was critically mediated by increased thalamic-limbic-prefrontal volumes. CONCLUSIONS: The present findings suggest that early life stress shapes the neural organization of the limbic-prefrontal circuits in interaction with individual variations in the TPH2 gene to promote a phenotype characterized by facilitated threat avoidance, thus promoting early adaptation to an adverse environment.
BACKGROUND: Early life stress has been associated with emotional dysregulations and altered architecture of limbic-prefrontal brain systems engaged in emotional processing. Serotonin regulates both, developmental and experience-dependent neuroplasticity in these circuits. Central serotonergic biosynthesis rates are regulated by Tryptophan hydroxylase 2 (TPH2) and transgenic animal models suggest that TPH2-gene associated differences in serotonergic signaling mediate the impact of aversive early life experiences on a phenotype characterized by anxious avoidance. METHODS: The present study employed an imaging genetics approach that capitalized on individual differences in a TPH2 polymorphism (703G/T; rs4570625) to determine whether differences in serotonergic signaling modulate the effects of early life stress on brain structure and function and punishment sensitivity in humans (n = 252). RESULTS: Higher maltreatment exposure before the age of 16 was associated with increased gray matter volumes in a circuitry spanning thalamic-limbic-prefrontal regions and decreased intrinsic communication in limbic-prefrontal circuits selectively in TT carriers. In an independent replication sample, associations between higher early life stress and increased frontal volumes in TT carriers were confirmed. On the phenotype level, the genotype moderated the association between higher early life stress exposure and higher punishment sensitivity. In TT carriers, the association between higher early life stress exposure and punishment sensitivity was critically mediated by increased thalamic-limbic-prefrontal volumes. CONCLUSIONS: The present findings suggest that early life stress shapes the neural organization of the limbic-prefrontal circuits in interaction with individual variations in the TPH2 gene to promote a phenotype characterized by facilitated threat avoidance, thus promoting early adaptation to an adverse environment.
Entities:
Keywords:
Amygdala; early life stress; frontal cortex; punishment sensitivity; serotonin