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Stress and glucocorticoids promote oligodendrogenesis in the adult hippocampus.

Chetty S, Friedman AR, Taravosh-Lahn K, Kirby ED, Mirescu C, Guo F, Krupik D, Nicholas A, Geraghty AC, Krishnamurthy A, Tsai MK, Covarrubias D, Wong AT, Francis DD, Sapolsky RM, Palmer TD, Pleasure D, Kaufer D - Mol. Psychiatry (2014)

Bottom Line: We found that immobilization stress decreased neurogenesis and increased oligodendrogenesis in the dentate gyrus (DG) of the adult rat hippocampus and that injections of the rat glucocorticoid stress hormone corticosterone (cort) were sufficient to replicate this effect.We used a nestin-CreER/YFP transgenic mouse line for lineage tracing and found that cort induces oligodendrogenesis from nestin-expressing NSCs in vivo.Using hippocampal NSCs cultured in vitro, we further showed that exposure to cort induced a pro-oligodendrogenic transcriptional program and resulted in an increase in oligodendrogenesis and decrease in neurogenesis, which was prevented by genetic blockade of glucocorticoid receptor (GR).

View Article: PubMed Central - PubMed

Affiliation: Helen Wills Neuroscience Institute, University of California,Berkeley, CA, USA.

ABSTRACT
Stress can exert long-lasting changes on the brain that contribute to vulnerability to mental illness, yet mechanisms underlying this long-term vulnerability are not well understood. We hypothesized that stress may alter the production of oligodendrocytes in the adult brain, providing a cellular and structural basis for stress-related disorders. We found that immobilization stress decreased neurogenesis and increased oligodendrogenesis in the dentate gyrus (DG) of the adult rat hippocampus and that injections of the rat glucocorticoid stress hormone corticosterone (cort) were sufficient to replicate this effect. The DG contains a unique population of multipotent neural stem cells (NSCs) that give rise to adult newborn neurons, but oligodendrogenic potential has not been demonstrated in vivo. We used a nestin-CreER/YFP transgenic mouse line for lineage tracing and found that cort induces oligodendrogenesis from nestin-expressing NSCs in vivo. Using hippocampal NSCs cultured in vitro, we further showed that exposure to cort induced a pro-oligodendrogenic transcriptional program and resulted in an increase in oligodendrogenesis and decrease in neurogenesis, which was prevented by genetic blockade of glucocorticoid receptor (GR). Together, these results suggest a novel model in which stress may alter hippocampal function by promoting oligodendrogenesis, thereby altering the cellular composition and white matter structure.

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Cort increases hippocampal oligodendrogenesis from nestin lineage NSCs in vivo. (a) Nestin-Cre ERT2/RosaYFP mice were injected with tamoxifen to induce YFP reporter gene expression, injected with cort or vehicle for 10 days, and perfused 7 days later for IHC analysis. (b) Cort injection increased the percentage of YFP-labeled cells that co-labeled with the oligodendrocytic marker GST-π; n=8. (c) Representative image of an orthogonal slice of a YFP+/GST-π+ co-labeled cell as well as 3D reconstruction of an image stack of the same cell (d-f). *p < 0.05 (mean ± SEM).
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Figure 2: Cort increases hippocampal oligodendrogenesis from nestin lineage NSCs in vivo. (a) Nestin-Cre ERT2/RosaYFP mice were injected with tamoxifen to induce YFP reporter gene expression, injected with cort or vehicle for 10 days, and perfused 7 days later for IHC analysis. (b) Cort injection increased the percentage of YFP-labeled cells that co-labeled with the oligodendrocytic marker GST-π; n=8. (c) Representative image of an orthogonal slice of a YFP+/GST-π+ co-labeled cell as well as 3D reconstruction of an image stack of the same cell (d-f). *p < 0.05 (mean ± SEM).

Mentions: While NSCs produce neurons, astrocytes, and oligodendrocytes in vitro41, a recent study reported that they do not produce oligodendrocytes in vivo29. If true, this would suggest that hippocampal oligodendrogenesis arises exclusively from a distinct population of OPCs. An alternate possibility is that NSCs generate new oligodendrocytes at a level that is low under “baseline” conditions but higher in response to stress. To investigate this, we used a transgenic mouse (nestin-Cre ERT2/RosaYFP)33 expressing an inducible (fused to estrogen receptor variant ERT2) cre recombinase enzyme driven by the promoter for the NSC marker nestin. In this system, induction with the ERT2 agonist tamoxifen causes recombination leading to constitutive expression of the YFP marker in nestin-expressing NSCs, allowing for unambiguous analysis of their cell fate. After tamoxifen induction to initiate nestin-driven NSC labeling, mice were injected with cort (25 mg/kg) or vehicle for 10 days and assessed for oligodendrogenic potential 7 days later (Figure 2A). Quantification of the percent of NSC derived cells (YFP tagged) that co-labeled with the oligodendrocyte marker GST-π showed that NSCs produced a low number of new oligodendrocytes under control conditions, and that stress significantly increased oligodendrogenesis from NSCs (Figure 2B-F, Supplemental Figure 2).


Stress and glucocorticoids promote oligodendrogenesis in the adult hippocampus.

Chetty S, Friedman AR, Taravosh-Lahn K, Kirby ED, Mirescu C, Guo F, Krupik D, Nicholas A, Geraghty AC, Krishnamurthy A, Tsai MK, Covarrubias D, Wong AT, Francis DD, Sapolsky RM, Palmer TD, Pleasure D, Kaufer D - Mol. Psychiatry (2014)

Cort increases hippocampal oligodendrogenesis from nestin lineage NSCs in vivo. (a) Nestin-Cre ERT2/RosaYFP mice were injected with tamoxifen to induce YFP reporter gene expression, injected with cort or vehicle for 10 days, and perfused 7 days later for IHC analysis. (b) Cort injection increased the percentage of YFP-labeled cells that co-labeled with the oligodendrocytic marker GST-π; n=8. (c) Representative image of an orthogonal slice of a YFP+/GST-π+ co-labeled cell as well as 3D reconstruction of an image stack of the same cell (d-f). *p < 0.05 (mean ± SEM).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4128957&req=5

Figure 2: Cort increases hippocampal oligodendrogenesis from nestin lineage NSCs in vivo. (a) Nestin-Cre ERT2/RosaYFP mice were injected with tamoxifen to induce YFP reporter gene expression, injected with cort or vehicle for 10 days, and perfused 7 days later for IHC analysis. (b) Cort injection increased the percentage of YFP-labeled cells that co-labeled with the oligodendrocytic marker GST-π; n=8. (c) Representative image of an orthogonal slice of a YFP+/GST-π+ co-labeled cell as well as 3D reconstruction of an image stack of the same cell (d-f). *p < 0.05 (mean ± SEM).
Mentions: While NSCs produce neurons, astrocytes, and oligodendrocytes in vitro41, a recent study reported that they do not produce oligodendrocytes in vivo29. If true, this would suggest that hippocampal oligodendrogenesis arises exclusively from a distinct population of OPCs. An alternate possibility is that NSCs generate new oligodendrocytes at a level that is low under “baseline” conditions but higher in response to stress. To investigate this, we used a transgenic mouse (nestin-Cre ERT2/RosaYFP)33 expressing an inducible (fused to estrogen receptor variant ERT2) cre recombinase enzyme driven by the promoter for the NSC marker nestin. In this system, induction with the ERT2 agonist tamoxifen causes recombination leading to constitutive expression of the YFP marker in nestin-expressing NSCs, allowing for unambiguous analysis of their cell fate. After tamoxifen induction to initiate nestin-driven NSC labeling, mice were injected with cort (25 mg/kg) or vehicle for 10 days and assessed for oligodendrogenic potential 7 days later (Figure 2A). Quantification of the percent of NSC derived cells (YFP tagged) that co-labeled with the oligodendrocyte marker GST-π showed that NSCs produced a low number of new oligodendrocytes under control conditions, and that stress significantly increased oligodendrogenesis from NSCs (Figure 2B-F, Supplemental Figure 2).

Bottom Line: We found that immobilization stress decreased neurogenesis and increased oligodendrogenesis in the dentate gyrus (DG) of the adult rat hippocampus and that injections of the rat glucocorticoid stress hormone corticosterone (cort) were sufficient to replicate this effect.We used a nestin-CreER/YFP transgenic mouse line for lineage tracing and found that cort induces oligodendrogenesis from nestin-expressing NSCs in vivo.Using hippocampal NSCs cultured in vitro, we further showed that exposure to cort induced a pro-oligodendrogenic transcriptional program and resulted in an increase in oligodendrogenesis and decrease in neurogenesis, which was prevented by genetic blockade of glucocorticoid receptor (GR).

View Article: PubMed Central - PubMed

Affiliation: Helen Wills Neuroscience Institute, University of California,Berkeley, CA, USA.

ABSTRACT
Stress can exert long-lasting changes on the brain that contribute to vulnerability to mental illness, yet mechanisms underlying this long-term vulnerability are not well understood. We hypothesized that stress may alter the production of oligodendrocytes in the adult brain, providing a cellular and structural basis for stress-related disorders. We found that immobilization stress decreased neurogenesis and increased oligodendrogenesis in the dentate gyrus (DG) of the adult rat hippocampus and that injections of the rat glucocorticoid stress hormone corticosterone (cort) were sufficient to replicate this effect. The DG contains a unique population of multipotent neural stem cells (NSCs) that give rise to adult newborn neurons, but oligodendrogenic potential has not been demonstrated in vivo. We used a nestin-CreER/YFP transgenic mouse line for lineage tracing and found that cort induces oligodendrogenesis from nestin-expressing NSCs in vivo. Using hippocampal NSCs cultured in vitro, we further showed that exposure to cort induced a pro-oligodendrogenic transcriptional program and resulted in an increase in oligodendrogenesis and decrease in neurogenesis, which was prevented by genetic blockade of glucocorticoid receptor (GR). Together, these results suggest a novel model in which stress may alter hippocampal function by promoting oligodendrogenesis, thereby altering the cellular composition and white matter structure.

Show MeSH
Related in: MedlinePlus