Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
Endocrinology ; 154(8): 2807-20, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23736296

ABSTRACT

Although glucocorticoids (GCs) are known to exert numerous effects in the hippocampus, their chronic regulatory functions remain poorly understood. Moreover, evidence is inconsistent regarding the long-standing hypothesis that chronic GC exposure promotes brain aging/Alzheimer disease. Here, we adrenalectomized male F344 rats at 15 months of age, maintained them for 3 months with implanted corticosterone (CORT) pellets producing low or intermediate (glucocorticoid receptor-activating) blood levels of CORT, and performed microarray/pathway analyses in hippocampal CA1. We defined the chronic GC-dependent transcriptome as 393 genes that exhibited differential expression between intermediate and low CORT groups. Short-term CORT (4 days) did not recapitulate this transcriptome. Functional processes/pathways overrepresented by chronic CORT-up-regulated genes included learning/plasticity, differentiation, glucose metabolism, and cholesterol biosynthesis, whereas processes overrepresented by CORT-down-regulated genes included inflammatory/immune/glial responses and extracellular structure. These profiles indicate that GCs chronically activate neuronal/metabolic processes while coordinately repressing a glial axis of reactivity/inflammation. We then compared the GC transcriptome with a previously defined hippocampal aging transcriptome, revealing a high proportion of common genes. Although CORT and aging moved expression of some common genes in the same direction, the majority were shifted in opposite directions by CORT and aging (eg, glial inflammatory genes down-regulated by CORT are up-regulated with aging). These results contradict the hypothesis that GCs simply promote brain aging and also suggest that the opposite direction shifts during aging reflect resistance to CORT regulation. Therefore, we propose a new model in which aging-related GC resistance develops in some target pathways, whereas GC overstimulation develops in others, together generating much of the brain aging phenotype.


Subject(s)
CA1 Region, Hippocampal/metabolism , Corticosterone/pharmacology , Glucocorticoids/pharmacology , Transcriptome/drug effects , Adrenalectomy , Aging/genetics , Animals , Body Weight/drug effects , Corticosterone/blood , Drinking/drug effects , Drug Implants , Eating/drug effects , Glial Fibrillary Acidic Protein/genetics , Glial Fibrillary Acidic Protein/metabolism , Immunohistochemistry , Male , Oligonucleotide Array Sequence Analysis , Rats , Rats, Inbred F344 , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/genetics
2.
PLoS One ; 7(7): e40128, 2012.
Article in English | MEDLINE | ID: mdl-22792227

ABSTRACT

BACKGROUND: Many aging changes seem similar to those elicited by sleep-deprivation and psychosocial stress. Further, sleep architecture changes with age suggest an age-related loss of sleep. Here, we hypothesized that sleep deprivation in young subjects would elicit both stress and aging-like transcriptional responses. METHODOLOGY/PRINCIPAL FINDINGS: F344 rats were divided into control and sleep deprivation groups. Body weight, adrenal weight, corticosterone level and hippocampal CA1 transcriptional profiles were measured. A second group of animals was exposed to novel environment stress (NES), and their hippocampal transcriptional profiles measured. A third cohort exposed to control or SD was used to validate transcriptional results with Western blots. Microarray results were statistically contrasted with prior transcriptional studies. Microarray results pointed to sleep pressure signaling and macromolecular synthesis disruptions in the hippocampal CA1 region. Animals exposed to NES recapitulated nearly one third of the SD transcriptional profile. However, the SD-aging relationship was more complex. Compared to aging, SD profiles influenced a significant subset of genes. mRNA associated with neurogenesis and energy pathways showed agreement between aging and SD, while immune, glial, and macromolecular synthesis pathways showed SD profiles that opposed those seen in aging. CONCLUSIONS/SIGNIFICANCE: We conclude that although NES and SD exert similar transcriptional changes, selective presynaptic release machinery and Homer1 expression changes are seen in SD. Among other changes, the marked decrease in Homer1 expression with age may represent an important divergence between young and aged brain response to SD. Based on this, it seems reasonable to conclude that therapeutic strategies designed to promote sleep in young subjects may have off-target effects in the aged. Finally, this work identifies presynaptic vesicular release and intercellular adhesion molecular signatures as novel therapeutic targets to counter effects of SD in young subjects.


Subject(s)
Aging/genetics , CA1 Region, Hippocampal/metabolism , Sleep Deprivation/genetics , Sleep Deprivation/metabolism , Stress, Physiological/genetics , Transcriptome , Animals , Cluster Analysis , Gene Expression Profiling , Gene Expression Regulation , Male , Proteomics , Rats , Signal Transduction
3.
J Neurosci ; 29(19): 6058-67, 2009 May 13.
Article in English | MEDLINE | ID: mdl-19439583

ABSTRACT

An increase in L-type voltage-gated calcium channel (LTCC) current is a prominent biomarker of brain aging and is believed to contribute to cognitive decline and vulnerability to neuropathologies. Studies examining age-related changes in LTCCs have focused primarily on males, although estrogen (17beta-estradiol, E2) affects calcium-dependent activities associated with cognition. Therefore, to better understand brain aging in females, the effects of chronic E2 replacement on LTCC current activity in hippocampal neurons of young and aged ovariectomized rats were determined. The zipper slice preparation was used to expose cornu ammonis 1 (CA1) pyramidal neurons for recording LTCC currents using the cell-attached patch-clamp technique. We found that an age-related increase in LTCC current in neurons from control animals was prevented by E2 treatment. In addition, in situ hybridization revealed that within stratum pyramidale of the CA1 area, mRNA expression of the Ca(v)1.2 LTCC subunit, but not the Ca(v)1.3 subunit, was decreased in aged E2-treated rats. Thus, the reported benefits of E2 on cognition and neuronal health may be attributed, at least in part, to its age-related decrease in LTCC current.


Subject(s)
Aging/physiology , Calcium Channels, L-Type/metabolism , Calcium Channels/metabolism , Estradiol/pharmacology , Estrogen Replacement Therapy , Hippocampus/drug effects , Pyramidal Cells/drug effects , Animals , Calcium/metabolism , Calcium Channels/genetics , Calcium Channels, L-Type/genetics , Female , Gene Expression , Hippocampus/cytology , Hippocampus/physiology , In Vitro Techniques , Membrane Potentials/physiology , Ovariectomy , Patch-Clamp Techniques , Pyramidal Cells/physiology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Inbred F344
4.
Brain Res Gene Expr Patterns ; 1(3-4): 151-7, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12638125

ABSTRACT

Hypothalamic sites wherein P4, through progestin receptor, (Pgr; commonly abbreviated PR), maximizes the expression of female sexual behaviors and gonadotropin surge release have been studied intensively. However, little is known regarding PR expression in brainstem regions likely to regulate changes in autonomic functions observed when P4 levels are elevated (i.e. pregnancy). Using in situ hybridization, we found PR mRNA-containing cells widely distributed throughout the brainstem of ovariectomized, estradiol-treated Sprague-Dawley rats, with high expression in regions including the medial vestibular nucleus, nucleus of the solitary tract, substantia nigra (compact part), ventral tegmental area, hypoglossal nucleus, locus coeruleus, Purkinje cell layer of the cerebellum and inferior olivary complex. We also detected moderate to high levels of PR gene expression in several regions, such as the trapezoid nucleus, facial nucleus, periaqueductal gray regions, and rostral ventrolateral medulla. These results demonstrate that PR expression is widespread in the brainstem and identify nuclei wherein P4 may act to influence a number of physiological functions during pregnancy.


Subject(s)
Brain Stem/metabolism , RNA, Messenger/genetics , Receptors, Progesterone/genetics , Animals , Estradiol/pharmacology , Female , In Situ Hybridization , Organ Specificity , Ovariectomy , RNA Probes , Rats , Transcription, Genetic
SELECTION OF CITATIONS
SEARCH DETAIL
...