It has been well established that early life adversity exposure (prior to puberty) is one of the strongest predictors of adult affective disorders such depression, anxiety, PTSD, and bipolar disorder, especially in women. The most common underlying feature in affective disorders is that of stress dysregulation. The goal of this proposal is to determine how the prepubertal adversity experience reprograms the brain toward stress dysregulation, or stress resilience, and how this is influenced during dynamic hormonal changes across the female life span, including pregnancy and aging. We are proposing to examine similar outcome measures proposed in the human subject studies in Projects I & II in a mouse model. The mouse model allows greater control over manipulations in the environment and dissection of potential mechanisms involved in programming of endpoints than what is possible in humans, and thus is an invaluable model for this SCOR proposal.
Aims for these studies include: 1) To examine the programming effects of prepubertal adversity on adult stress responsivity during the period of dynamic hormonal change, pregnancy, in a mouse model. Behavioral and physiological analyses during this period will include assessment of the HPA stress axis, and anxiety-like behaviors as well as stress responsivity in both male and female offspring; 2) To examine the programming effects of prepubertal adversity on adult stress responsivity during the period of dynamic hormonal change, aging, in a mouse model. Sex differences in behavioral and physiological analyses in aged mice will include assessment of the HPA stress axis, cognitive flexibility and performance, and anxiety- like behaviors; and 3) To examine the potential molecular mechanisms by which prepubertal adversity may program changes in stress pathway maturation and thus altering long-term adult stress responses during dynamic hormonal periods, including examination of the sex-specific brain miRNA environment and epigenetic histone marks in relevant brain regions during the prepubertal window.
Prepubertal trauma is one of the greatest predictors of affective disorder onset in women. The proposed studies in this Project will utilize a mouse model to examine how the brain responds during the stress insult, and which important genes are affected. As affective disorders tend to present during periods of dynamic hormonal shifts, mice will be studied during the important periods life, pregnancy & menopause, when the adult brain may be more sensitive t0 stress.
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