Postnatal stressors, producing a dysregulation of the limbic-hypothalamic pituitary adrenal (LHPA) axis, can have a deleterious effect on a child's pubertal and psychosocial development. Importantly, the gonadal release of estradiol (E2) occurring during the pubertal transition likely contributes to the continued maturation of cortico-limbic circuits that regulate emotional behavior but stress-induced delayed puberty could compromise this development. Puberty may, thus, be a time when children, particularly girls, show an increased vulnerability to the emergence of psychosocial problems as a result of incomplete cortico-limbic development resulting from psychosocial stress exposure. In addition, some individuals are genetically predisposed to respond differentially to stress, as individuals with a specific polymorphism in the gene encoding the serotonin (5HT) reuptake transporter (SERT) are more susceptible to stressors. We propose that psychosocial stress interacts with genetic vulnerability to induce dysregulation of the LHPA axis to disrupt puberty and delay exposure to increases in E2, thus placing these females at risk for neurobiological defects and mood disorders. This project will study the behavioral, physiological, and neurobiological consequences of psychosocial stress, imposed by social subordination, during adolescence in female rhesus monkeys.
Specific Aim 1 will test the hypothesis that social subordination, exacerbated by the presence of the short allele in the SERT gene, produces LHPA dysregulation and delays puberty.
Aim 2 will test the hypothesis that exposure to psychosocial stressors during adolescence increases emotional reactivity by prolonging the pubertal transition and reducing exposure to E2, particularly in females with the short allele in the SERT gene.
Aim 3 will use neuroimaging to test the hypothesis that development of cortico-limbic circuits and 5HT systems regulating emotional behavior are adversely affected by exposure to psychosocial stressors and reduced levels of E2.
Aim 4 will test the hypothesis that SSRI therapy to subordinate females may normalize LHPA activity but not growth or puberty, delaying exposure to increasing levels of E2, and attenuating maturation of cortico-limbic circuits and 5HT systems. These studies will elucidate the complex interplay between behavior, genetics, and reproductive maturation, providing a comprehensive understanding of the role of adolescence as a critical period for the emergence of mood disorders in girls.

Public Health Relevance

Using a rhesus monkey model, this project is designed to provide a better understanding of how psychosocial stress, imposed by social subordination, affects brain maturations and emotional development in females and whether this is influenced by polymorphisms in the gene that encodes the serotonin re-uptake transporter (SERT), a protein essential for normal serotonin neurotransmission and emotionality. These studies will elucidate the complex interplay between behavior, genetics, and reproductive maturation, providing a comprehensive understanding of how adolescence represents a critical period for the emergence of psychiatric disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MESH-L (02))
Program Officer
Garriock, Holly A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
Other Domestic Higher Education
United States
Zip Code
Ulrich-Lai, Yvonne M; Fulton, Stephanie; Wilson, Mark et al. (2015) Stress exposure, food intake and emotional state. Stress 18:381-99
Yan, Yumei; Nair, Govind; Li, Longchuan et al. (2014) In vivo evaluation of optic nerve development in non-human primates by using diffusion tensor imaging. Int J Dev Neurosci 32:64-8
Howell, Brittany R; Godfrey, Jodi; Gutman, David A et al. (2014) Social subordination stress and serotonin transporter polymorphisms: associations with brain white matter tract integrity and behavior in juvenile female macaques. Cereb Cortex 24:3334-49
Embree, M; Michopoulos, V; Votaw, J R et al. (2013) The relation of developmental changes in brain serotonin transporter (5HTT) and 5HT1A receptor binding to emotional behavior in female rhesus monkeys: effects of social status and 5HTT genotype. Neuroscience 228:83-100
Wilson, Mark E; Bounar, Shannon; Godfrey, Jodi et al. (2013) Social and emotional predictors of the tempo of puberty in female rhesus monkeys. Psychoneuroendocrinology 38:67-83
Michopoulos, Vasiliki; Checchi, Marta; Sharpe, Desiree et al. (2011) Estradiol effects on behavior and serum oxytocin are modified by social status and polymorphisms in the serotonin transporter gene in female rhesus monkeys. Horm Behav 59:528-35
Shepard, Kathryn N; Michopoulos, Vasiliki; Toufexis, Donna J et al. (2009) Genetic, epigenetic and environmental impact on sex differences in social behavior. Physiol Behav 97:157-70