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In a series of studies on the long-term consequences of neonatal rearing, we compared hypothalamic and extrahypothalamic central corticotropin-releasing factor (CRF) systems in male rats reared under conditions of animal facility rearing, nonhandling (HMS0), handling with brief maternal separation for 15 min (HMS15), or handling with moderate maternal separation for 180 min (HMS180) daily from postnatal days 2-14. CRF-like immunoreactivity (CRFir) was elevated in lumbar cerebrospinal fluid of adult HMS180 and HMS0 rats relative to the other groups. In the paraventricular nucleus, central nucleus of the amygdala, bed nucleus of the stria terminalis, and locus coeruleus, CRFir and CRF mRNA levels were significantly elevated in HMS0 and HMS180 rats. Neonatal maternal separation was associated with regionally specific alterations in CRF receptor type 1 (CRF1) mRNA density in HMS180 rats. No rearing-associated differences in CRF2a binding were apparent in either the lateral septum or the ventromedial hypothalamus. These findings indicate that early rearing conditions can permanently alter the developmental set-point of central CRF systems, and potentially influence the expression of behavioral and endocrine responses to stress throughout life, thereby providing a possible neurobiological substrate for the relationship between early life events and increased vulnerability for hypothalamic-pituitary-adrenal axis and coping skill alterations and the frequency of mood disorders in patients with a history of such experiences.

These observations suggest that this maternal separation paradigm is a good model to study the effects of early adverse experience on the development of alcohol preference and anxiety.

Human preterm neonates are subjected to repetitive pain during neonatal intensive care. We hypothesized that exposure to repetitive neonatal pain may cause permanent or long-term changes because of the developmental plasticity of the immature brain. Neonatal rat pups were stimulated one, two, or four times each day from P0 to P7 with either needle prick (noxious groups N 1 , N 2 , N 4 ) or cotton tip rub (tactile groups T 1 , T 2 , T 4 ). In groups N 2 , N 4 , T 2 , T 4 stimuli were applied to separate paws at hourly intervals; each paw was stimulated only once a day. Identical rearing occurred from P7 to P22 days. Pain thresholds were measured on P16, P22, and P65 (hot-plate test), and testing for defensive withdrawal, alcohol preference, air-puff startle, and social discrimination tests occurred during adulthood. Adult rats were exposed to a hot plate at 62°C for 20 s, then sacrificed and perfused at 0 and 30 min after exposure. Fos expression in the somatosensory cortex was measured by immunocytochemistry. Weight gain in the N 2 group was greater than the T 2 group on P16 (p < 0.05) and P22 (p < 0.005); no differences occurred in the other groups. Decreased pain latencies were noted in the N 4 group [5.0 ± 1.0 s vs. 6.2 ± 1.4 s on P16 (p < 0.05); 3.9 ± 0.5 s vs. 5.5 ±1.6 s on P22 (p < 0.005)], indicating effects of repetitive neonatal pain on subsequent development of the pain system. As adults, N 4 group rats showed an increased preference for alcohol (55 ± 18% vs. 32 ± 21%; p < 0.004); increased latency in exploratory and defensive withdrawal behavior (p < 0.05); and a prolonged chemosensory memory in the social discrimination test (p < 0.05). No significant differences occurred in corticosterone and ACTH levels following air-puff startle or in pain thresholds at P65 between N 4 © 1999 Elsevier Science Inc. 1 To whom requests for reprints should be addressed. anandsunny@exchange.uams.edu. and T 4 groups. Fos expression at 30 min after hot-plate exposure was significantly greater in all areas of the somatosensory cortex in the T 4 group compared with the N 4 group (p < 0.05), whereas no differences occurred just after exposure. These data suggest that repetitive pain in neonatal rat pups may lead to an altered development of the pain system associated with decreased pain thresholds during development. Increased plasticity of the neonatal brain may allow these and other changes in brain development to increase their vulnerability to stress disorders and anxietymediated adult behavior. Similar behavioral changes have been observed during the later childhood of expreterm neonates who were exposed to prolonged periods of neonatal intensive care. NIH Public Access KeywordsBehavioral effects; Repetitive pain; Rat pups Premature infants are often exposed to repetitive invasive procedures causing acute pain during the course of neonatal intensive care (4). These experiences occur during a critical window of increased plasticity in the developing brain (32,48 Human infants and neonatal rat pups display a vari...

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This study investigated the effects of acute and chronic restraint stress during the third week of pregnancy on placental 11 -hydroxysteroid dehydrogenase type 2 (11 -HSD2) activity in rats. Acute exposure to stress on gestational day 20 immediately up-regulated placental 11 -HSD2 activity by 160%, while chronic stress from day 14 to day 19 of pregnancy did not significantly alter basal 11 -HSD2 activity. However, the latter reduced the capacity to up-regulate placental 11 -HSD2 activity in the face of an acute stressor by 90%. Thus, immediate up-regulation of 11 -HSD2, the feto-placental barrier to maternal corticosteroids, may protect the fetus against stress-induced high levels of maternal corticosteroids, but exposure to chronic stress greatly diminishes this protection.

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