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Combinatorial actions of glucocorticoid and mineralocorticoid stress hormone receptors are required for preventing neurodegeneration of the mouse hippocampus.
Oakley, Robert H; Whirledge, Shannon D; Petrillo, Maria G; Riddick, Natallia V; Xu, Xiaojiang; Moy, Sheryl S; Cidlowski, John A.
Afiliación
  • Oakley RH; Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA.
  • Whirledge SD; Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA.
  • Petrillo MG; Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA.
  • Riddick NV; Department of Psychiatry and Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • Xu X; Laboratory of Integrative Bioinformatics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA.
  • Moy SS; Department of Psychiatry and Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • Cidlowski JA; Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA.
Neurobiol Stress ; 15: 100369, 2021 Nov.
Article en En | MEDLINE | ID: mdl-34368410
Chronic stress contributes to numerous human pathologies including cognition impairments and psychiatric disorders. Glucocorticoids are primary stress hormones that activate two closely related nuclear receptors, the glucocorticoid (GR) and mineralocorticoid receptor (MR), that are both highly expressed in the hippocampus. To investigate potential combinatorial actions of hippocampal GR and MR, we developed mice with conditional knockout of both GR and MR in the hippocampus and compared them to their single knockout counterparts. Mice lacking MR alone or both GR and MR in the hippocampus exhibited altered expression of multiple CA2-specific neuronal markers and enhanced cue-dependent learning in a conditioned fear test. Provocatively, in contrast to the single knockouts, mice depleted of both GR and MR showed profound neurodegeneration of the hippocampus. Neuronal death was increased and neurogenesis was reduced in the dentate gyrus of the double knockout mice. Global gene expression assays of the knockout mice revealed a synergistic increase in the number of dysregulated genes in the hippocampus lacking both GR and MR. This large cohort of genes reliant on both GR and MR for expression was strongly associated with cell death and cell proliferation pathways. GR/MR complexes were detected in CA1 and dentate gyrus neurons suggesting receptor heterodimers contribute to the joint actions of GR and MR. These findings reveal an obligate role for MR signaling in regulating the molecular phenotype of CA2 neurons and demonstrate that combinatorial actions of GR and MR are essential for preserving dentate gyrus neurons and maintaining hippocampal health.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Neurobiol Stress Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Neurobiol Stress Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos