Stress and Pubertal Timing Affect Amygdala Functional Circuitry in Females

点击翻译按钮获取中文摘要

 DESCRIPTION: Early life exposure to psychosocial stress is one of the strongest predictors of psychopathology, particularly for conditions that are more prevalent in females, such as mood disorders. The incidence of these disorders dramatically increases during adolescence, suggesting that the interaction between psychosocial stress and the neurodevelopmental changes of puberty, such as changing levels of sex hormones, may be a critical mechanism for the emergence of emotional dysregulation during this developmental period. Identifying the neurobehavioral bases of these links is crucial to our understanding of the etiology of mental illness, its emergence during adolescence, and the development of intervention strategies aimed at ameliorating the long- term effects of psychosocial stress. We propose to investigate the neurobiological bases of these links by examining the effects of psychosocial stress and the timing of puberty on intrinsic brain functional organization in a female rhesus macaque model. Socially housed female macaques organize into a dominance hierarchy in which subordinates are subject to frequent harassment in an environment that mimics the unpredictable nature of human social environments, providing an ethologically valid model for studying long-term neurobehavioral effects of psychosocial stress. This model overcomes many challenges inherent to longitudinal studies of chronic stress in humans. More important, the model permits experimental manipulations to disentangle the effects of stress, chronological age, and puberty. Our proposal capitalizes on a unique opportunity to examine pre-existing resting fMRI data collected from dominant (DOM; n=10) and subordinate (SUB; n=16) female macaques 12 months after the onset of puberty (menarche) and from a matched cohort of DOM (n=12) and SUB (n=13) females treated with a drug (Lupron) that experimentally delayed puberty. Using this unique dataset, we will examine the separate and interacting effects of social subordination stress and the timing of puberty (and associated elevations in gonadal steroids) on functional circuitry during adolescence. We focus on amygdala circuitry, particularly connections with ventromedial prefrontal cortex, based on neuroimaging evidence of stress-related alterations in this circuit as well as its sensitivity to gonadal steroids. We will also examine the relationship between amygdala circuitry and socio-emotional phenotypes (e.g., response to threats), thus revealing brain-behavior links that are relevant to human psychopathology. Investigation of these links is timely, given the steep drop in the age of the onset of puberty in the US, the substantial rise in rates of psychological disorders among youth, and the ensuing public health burden. Attainment of our aims will add further scientific value to our translational model of psychosocial stress at minimal additional cost, and will suggest future studies that may reveal causal mechanisms linking psychosocial stress and puberty-related increases in gonadal steroids to emotional dysregulation, as well as targets for interventions aimed at ameliorating the long-term effects of psychosocial stress and reducing women's psychopathological burden.