Although stress is part of life, the incidence of toxic stress is increasing among America's youth. This increased exposure to toxic levels of stress has substantial consequences and can precipitate and augment chronic mental and somatic health conditions throughout adulthood. While both men and women suffer the consequences of early life stress, the precise manifestation of chronic developmental stress varies in a sex-dependent manner. Chronic stress during adolescence is particularly harmful because of interactions of stressor exposure with the maturation the hypothalamic-pituitary-adrenal (HPA) axis and the reproductive axis. Alterations in these endocrine axes exert pervasive effects because many of the receptors for the hormones of these axes are transcription factors. The overarching hypothesis of this line of research is that altered regulation and function of transcription factors underlies the prolonged adverse effects of adolescent stress. The current application focuses on two transcription factors that our preliminary data suggest are altered by chronic adolescent stress: the glucocorticoid receptor (GR), a transcription factor that is the main effector of the HPA axis, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF?B), a transcription factor which mediates activation of inflammatory pathways. It is of interest to consider these transcription factors together because significant bidirectional crosstalk occurs between GR and NF?B. Based on our preliminary data, the central hypothesis of this proposal is that chronic adolescent stress leads to GR-centric modifications in adult females and NF?B-centric modifications in adult males. Completion of Specific Aim 1 will determine the extent to which adolescent stress alters regulation of the GR in adult male and female rats. These data will provide an essential understanding of the prolonged effects of adolescent stress on GR regulation which is necessary to determine whether adult GR dysregulation is a candidate mechanism for adolescent stress-induced chronic conditions.
Specific Aim 2 will examine the influence of adolescent stress on regulation of NF?B in adult male and female rats. These experiments will provide information about the effects of adolescent stress on regulation and translocation of NF?B in adulthood and establish the degree to which NF?B is a candidate regulator of exaggerated inflammation following chronic adolescent stress.
Specific Aim 3 will establish the extent to which adolescent stress alters adult gene expression specifically mediated by GR and NF?B. These data are complementary to the first two aims because in addition to regulation of transcription factors at the level of translocation, transcription factor effects can diverge at the point of gene transcription. Collectively, the data generated by this application will establish the extent to which chronic adolescent stress-induces changes in adult GR and NF?B. The proposed work will establish an understanding of sex differences created by chronic stress at the mechanistic level and provide the basis to develop a scientific foundation for clinical practice allowing for better management and elimination of stress-related disorders.
Adolescent stress causes repercussions in adulthood, but the mechanisms which mediate these physiological and behavioral changes remain unknown, thereby preventing adequate treatment. The proposed research is relevant to public health because determining the extent to which chronic adolescent stress alters regulation and function of transcription factors in both males and females will provide the fundamental knowledge necessary to allow identification of prevention and treatment strategies to ameliorate lifelong adverse consequences of adolescent stress, which will lead to enhanced health and reduced disability.
