PubMed · 4288333
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O H Pearson, C N Shealy, B Kaufman, N Samaan. 1965. Anterior pituitary function.. https://pubmed.ncbi.nlm.nih.gov/4288333/
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Self-injurious behavior (SIB) is an untreatable and often life-threatening problem among individuals with developmental disorders, especially those diagnosed with autism. Functioning, relationships and processing of the proopiomelanocortin (POMC) system are "uncoupled" in subgroups of self-injuring individuals resulting in different ratios of ACTH and opioids in the bloodstream, particularly under conditions of stress. In this study, relations between SIB and POMC were evaluated in a multi-year study of the largest prospective sample studied to date. Observations were collected on palmtop computers for 45 treatment-resistant patients who exhibited chronic SIB. Behavior of each subject was observed in natural settings without disruption or intrusion, for continuous, 2.5-h periods, two times a day (morning and afternoon), 4 days a week for two consecutive weeks, for a total of 40 h/subject. Blood was collected in the morning, late afternoon and immediately after an SIB episode on two separate occasions separated by at least 6 months. Levels of beta-endorphin (beta E) and ACTH were assayed by RIA. We discovered that the SIB was the best predictor of subsequent SIB. Moreover, the majority of subjects exhibited this contagious pattern of SIB. Levels of POMC fragments were reliable over a 6- to 9-month period. Subjects exhibiting POMC disregulation characterized by high morning levels of beta E had the highest transitional probabilities of SIB (i.e. contagious patterns; F=8.17, P<0.01). These findings suggest that subjects with "contagious" SIB may represent a behavioral phenotype associated with disregulated expression of the POMC gene.
Neonatal maternal separation of rat pups leads to a stable stress hyper-responsive phenotype characterized by increased basal levels of corticotropin releasing factor (CRF) mRNA in the hypothalamic and extra-hypothalamic nuclei, increased hypothalamic CRF release, and enhanced adrenocorticotrophin hormone (ACTH) and corticosterone (CORT) responses to psychological stressors. Stress and exposure to glucocorticoids either early in life or in adulthood have been associated with hippocampal atrophy and impairments in learning and memory. In this study, male Long Evans rat pups were exposed to daily 3-h (HMS180) or 15-min (HMS15) periods of maternal separation on postnatal days (PND) 2-14 or normal animal facility rearing. Maternal separation and subsequent reunion with the dam resulted in elevated plasma CORT levels versus HMS15 animals at PND7, a time when rat pups are normally hyporesponsive to stressors and show limited pituitary-adrenal responses. As adults, HMS180 rats exhibited elevated indices of anxiety, startle-induced pituitary-adrenal hyper-responsiveness, and slight, but significant impairment on acquisition in the Morris water maze task. In addition, HMS180 rats exhibited decreased mossy fiber density in the stratum oriens region of the hippocampus as measured by Timm's staining, but no change in volume of the dentate gyrus. These changes may be the result of neonatal exposure to elevated glucocorticoids and/or changes in other signaling systems in response to maternal separation. Overall the results suggest that repeated, daily, 3-h maternal separations during critical periods of hippocampal development can disrupt hippocampal cytoarchitecture in a stable manner. The resulting change in morphology may contribute to the subtle, but consistent learning deficit and overall stress hyper-responsive phenotype observed in these animals.
Glucocorticoid activation of two types of adrenocorticosteroid receptors (ACRs), the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR), influences the vulnerability of hippocampal neurons to insult. To examine the potential impact of ACR activation following traumatic brain injury (TBI), the current study assesses regulation of MR and GR expression and glucocorticoid levels following controlled cortical impact (CCI). Male Sprague-Dawley rats were pretreated for 48 h with vehicle, the MR antagonist spironolactone, or the GR antagonist mifepristone (RU486). On day three, subjects were sham-operated or injured by unilateral CCI. In situ hybridization analysis determined that pretreatment with either MR antagonist spironolactone or GR antagonist RU486 increased 24-h hippocampal GR mRNA levels in sham-operated animals only, suggesting that MR and GR regulation of GR mRNA is suppressed following TBI. Injury decreased GR mRNA levels in the ipsilateral dentate gyrus of all pretreatment groups and bilaterally increased MR mRNA levels in CA3 of antagonist-pretreated animals. One day post-injury, plasma corticosterone levels were comparable in sham and injured animals pretreated with vehicle. A separate group of animals that did not receive pretreatment injections prior to sham operation or injury were included for a 24-h time course analysis of plasma ACTH and corticosterone levels. Injury increased hypothalamic-pituitary-adrenal (HPA) activation for approximately 6 h following injury. These results indicate that hippocampal ACR mRNA levels and HPA activation are altered by TBI. Regulation of MR and GR expression following TBI may influence hippocampal neuron viability by modulating glucocorticoid signaling after injury.