Abstract. Alzheimer's disease (AD) is the leading cause of dementia. The etiology of AD remains, in large part, unresolved. In this study, gene expression (microarray) data from postmortem brains in normal aged as well as AD-affected brains in conjunction with transcriptional regulatory networks were explored for etiological insights. The focus was on the hippocampus, a brain region key to memory and learning. The transcriptional regulatory networks were inferred using a trees-based (random forests or extra-trees) as well as a mutual information-based algorithm applied to compendia of adult mouse whole brain and hippocampus microarray data. Network nodes representing human orthologs of the mouse networks were used in the subsequent analysis. Among the potential transcriptional regulators tied to insulin or brain-derived neurotrophic factor (INS1, INS2, BDNF), whose peptide products have been linked to AD, is the Retinoic Acid Receptor-Related Orphan Receptor (RORA). RORA is a nuclear receptor transcription factor whose expression is distinctly upregulated in the AD hippocampus. A notable cross-section of genes differentially expressed in the AD hippocampus was found to be linked to RORA in the networks. Furthermore, several genes associated with RORA in the networks, such as APP, DNM1L, and TIA1 have been implicated in AD. Computationallyderived clusters and modules within the networks indicated strong ties between RORA and genes involved in the AD etiology. In addition, a functional mapping scheme using activity and interaction data affirmed the same network links to RORA. Thus, RORA emerges as a gene with a probable central role in the AD pathology/etiology.
Stress responses during cocaine withdrawal likely contribute to drug relapse and may be intensified as a consequence of prior cocaine use. The present study examined changes in stressor-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis during acute withdrawal from chronic cocaine administration. Adult male Sprague-Dawley rats received daily administration of cocaine (30 mg/kg, i.p.) or saline for 14 days. Twenty-four hours after the last injection, rats in each group were sacrificed under stress-free conditions or following 30 min of immobilization. Plasma corticosterone (CORT) was measured in trunk-blood using radioimmunoassay, corticotropin-releasing hormone (CRH) mRNA levels in the paraventricular nucleus (PVN) of the hypothalamus were measured using in situ hybridization and glucocorticoid receptor (GR) protein expression in the pituitary gland and dissected brain regions was measured using Western blot analysis. Basal CRH mRNA in the PVN was unaltered as a result of prior cocaine administration. However, a significant increase in CRH mRNA was observed 90 min following the termination of restraint in cocaine withdrawn, but not saline-treated, rats. Basal CORT was also unaffected by prior cocaine administration, but the CORT response measured immediately after restraint was significantly augmented in cocaine-withdrawn rats. Differences in GR protein expression in number of regions implicated in negative feedback regulation of HPA function, including the hypothalamus, were not observed. These findings indicate that the HPA response to stressors is intensified during early withdrawal from cocaine administration and may be independent of changes in GR-mediated negative feedback.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.