Conditions such as economic hardship and drug abuse often adversely affect child rearing patterns resulting severely compromised growth and development of the young. The results of epidemiological studies reveal that about one-half of abused children show neurological impairments. Furthermore, these rearing conditions serve as a major risk factor for subsequent patho- and psychphysiologies. Currently, little is known about the neurobiological consequences of altered child rearing patterns and of variations in early experience in general. The studies described in this application are designed to examine the effects of various forms of early experience on the development of neural systems that subserve an animal's response to stress in later life. We feel that this is an important endpoint, since the ability to successfully adapt to stressful stimuli is central to the health of the organism; perhaps increasing so for modern, industrialized societies. We will focus our studies on central corticotropin releasing factor (CRF) systems, as numerous studies implicate these circuits as important mediators of coordinated endocrine, autonomic nervous system and behavioral responses to stressors. The CRF- dense parvicellular paraventricular nucleus of the hypothalamus, which is the origin of the CRF terminal field in the neurohemal zone of the median eminence and the source of some efferents to autonomic centers in the brainstem, is ideally situated to coordinate the diverse adjustments necessary for surviving acute or chronic stressors. Recent evidence from our laboratories suggests that development of at least some central CRF circuits is regulated by early environmental events. While activation of CRF systems and the accompanying endocrine, behavioral, and autonomic responses during times of stress are clearly adaptive, there are conditions in which these same responses might provide a serious health risk. First, in instances where CRF activation is excessive or needlessly prolonged. Second, in instances where CRF activation occurs in response to innocuous stimuli. Indeed, dysregulation of the CRF circuitry would be expected to have wide-ranging consequences for the organism. Interestingly, central administration of CRF is associated with pituitary- adrenal hypertrophy, hyperarousal, anxiety, sleeplessness, anorexia, and reproductive failure in animals; all symptoms which are characteristic of affective disorders. We predict that exposure to certain forms of early experience during the neonatal period permanently alters the CRF neural network resulting in altered sensitivity to stressors as adults. Thus, in certain cases (e.g. maternal deprivation, physical abuse), this effect results in excessive activity within CRF systems and heightened sensitivity to stressors. In other instances, certain early life events (e.g. neonatal handling) appear to result in more efficient CNS regulation of CRF systems and, under appropriate conditions might prove to be protective against the occurrence of pathology in later life.
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