By investigating hypothalamo-pituitary-adrenal (HPA) neuropeptide responses to maternal separation during infancy in the rat, we hope to develop neuroendocrine markers for early identification of children experiencing significant familial stress, and who may be at risk for developing depression. During infancy, the rat HPA axis activity is regulated by the mother. Acute separation from the mother increased serum corticosterone. Subsequent maternal contact quickly reversed this response. Repeated separations from the mother during the first two weeks of life permanently desensitized the HPA axis to stimulation. We have observed that oxytocin (OXT) and corticotropin releasing factor (CRF) stimulated corticosterone secretion during infancy. The magnitude of the stimulation was dependent upon maternal separation. It is hypothesized that acute and repeated separation induced changes in CRF and OXT concentrations. We will measure the levels of CRF and OXT by radioimmunoassay in cell body and terminal areas of infant rat brain following acute or repeated maternal separation (Study 1). To test the hypothesis that the concentration of adrenocorticotropic hormone (ACTH) and alpha-melanocyte stimulating hormone (alpha-MSH) may also flucuate with separation state, we will measure the levels of these hormones by radioimmunoassay in pituitary and serum following acute and repeated maternal separation, and in response to CRF and OXT administration (Study 2). To distinguish the relative contributions of CRF and OXT to the corticosterone-releasing potency of acute maternal separation, we will administer specific CRF or OXT antibodies to pups exposed to acute maternal separation with and without CRF or OXT administration (Study 3). HPA axis desensitization following repeated maternal separation may be dependent upon increased CRF and OXT inhibition by corticosterone negative feedback mechanisms. We will attempt to block the repeated separation effect by administering the corticosterone antagonist, RU-486 (Study 4). Desensitization of the HPA axis to stress as a result of repeated maternal separation persists into adulthood. We hypothesize that adult rats that have been repeatedly separated as infants will exhibit reduced corticosterone responsiveness to OXT and CRF under stressed and non- stressed conditions (Study 5).
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