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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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Immobilization stress or cort injections increase hippocampal oligodendrogenesis. (a) BrdU-injected adult male rats were subjected to either 1 week of daily immobilization stress or no stress (n=5 no stress control, n=6 stress). (b) IHC analysis of cell fate, quantified as the percentage of BrdU positive cells that co-label as neurons (Tuj1) or oligodendrocytes (MBP) shows that stress decreases neurogenesis and increases oligodendrogenesis. (c) Representative images of confocal analysis represents cells identified as positive for co-localization of BrdU and Tuj1 or MBP; scale bar=10 μM. (d) BrdU-injected adult male rats received daily cort or vehicle injections for 1 week and were perfused on day 7 (n=6 vehicle injected, n=6 cort injected) or day 14 (n=7 vehicle injected, n=6 cort injected). (e) IHC analysis of cell fate at day 7 shows that exposure to stress hormones (cort) decreases neurogenesis and increases oligodendrogenesis. (f) IHC analysis of cell fate at day 14 (1 week after recovery from cort treatment) shows that while neurogenesis is restored to control levels, the effects of increased oligodendrogenesis persist in cort injected animals. *p < 0.05 (mean ± SEM).
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Figure 1: Immobilization stress or cort injections increase hippocampal oligodendrogenesis. (a) BrdU-injected adult male rats were subjected to either 1 week of daily immobilization stress or no stress (n=5 no stress control, n=6 stress). (b) IHC analysis of cell fate, quantified as the percentage of BrdU positive cells that co-label as neurons (Tuj1) or oligodendrocytes (MBP) shows that stress decreases neurogenesis and increases oligodendrogenesis. (c) Representative images of confocal analysis represents cells identified as positive for co-localization of BrdU and Tuj1 or MBP; scale bar=10 μM. (d) BrdU-injected adult male rats received daily cort or vehicle injections for 1 week and were perfused on day 7 (n=6 vehicle injected, n=6 cort injected) or day 14 (n=7 vehicle injected, n=6 cort injected). (e) IHC analysis of cell fate at day 7 shows that exposure to stress hormones (cort) decreases neurogenesis and increases oligodendrogenesis. (f) IHC analysis of cell fate at day 14 (1 week after recovery from cort treatment) shows that while neurogenesis is restored to control levels, the effects of increased oligodendrogenesis persist in cort injected animals. *p < 0.05 (mean ± SEM).

Mentions: Studies investigating the effects of stress on NSCs in the adult hippocampus have primarily focused on the extent to which new neurons are generated. However, new glial cells are also generated in the hippocampus and may similarly be susceptible to environmental factors and hormones. Here we investigated whether stress and stress hormones (GCs) alter the oligodendrogenic potential in the adult hippocampus. To assess these effects, we subjected rats to 1 week of immobilization restraint stress and subsequently quantified the percentage of newborn cells (marked by BrdU, Figure 1A) in the hippocampal DG that adopted a neuronal or oligodendrocytic cell fate. In agreement with previous studies37, 38, stress significantly decreased the percentage of BrdU+ cells that co-labeled with the early neuronal marker Tuj1 (Figure 1B and C). Interestingly, stress significantly increased the percentage of BrdU+ cells that co-labeled with the mature oligodendrocyte marker MBP (Figure 1B and C), as well as the oligodendrocyte marker RIP (Supplemental Figure 1), revealing that stress increases oligodendrogenesis in the DG. To determine if an increase in circulating GCs is sufficient to upregulate hippocampal oligodendrogenesis, we next subjected rats to daily injections of cort (40 mg/kg, comparable to elevated serum GC levels induced by immobilization stress34-36) or vehicle for 1 week (Figure 1D) and assessed the neurogenic and oligodendrogenic potential within the DG. Similar to stressed rats, cort-injected rats showed a decrease in the percentage of new neurons, and an increase in the percentage of new oligodendrocytes, relative to controls (Figure 1E). When rats were allowed to recover from cort injections for 1 week, the percentage of new neurons reached control levels and did not differ between cort and vehicle injected rats (Figure 1F), consistent with prior studies on the long-term changes in neurogenesis following recovery from GC exposure39, 40. In contrast, the percentage of newborn oligodendrocytes in cort vs. vehicle injected rats remained significantly higher and persisted even following recovery from cort injections (Figure 1F).


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)

Immobilization stress or cort injections increase hippocampal oligodendrogenesis. (a) BrdU-injected adult male rats were subjected to either 1 week of daily immobilization stress or no stress (n=5 no stress control, n=6 stress). (b) IHC analysis of cell fate, quantified as the percentage of BrdU positive cells that co-label as neurons (Tuj1) or oligodendrocytes (MBP) shows that stress decreases neurogenesis and increases oligodendrogenesis. (c) Representative images of confocal analysis represents cells identified as positive for co-localization of BrdU and Tuj1 or MBP; scale bar=10 μM. (d) BrdU-injected adult male rats received daily cort or vehicle injections for 1 week and were perfused on day 7 (n=6 vehicle injected, n=6 cort injected) or day 14 (n=7 vehicle injected, n=6 cort injected). (e) IHC analysis of cell fate at day 7 shows that exposure to stress hormones (cort) decreases neurogenesis and increases oligodendrogenesis. (f) IHC analysis of cell fate at day 14 (1 week after recovery from cort treatment) shows that while neurogenesis is restored to control levels, the effects of increased oligodendrogenesis persist in cort injected animals. *p < 0.05 (mean ± SEM).
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Figure 1: Immobilization stress or cort injections increase hippocampal oligodendrogenesis. (a) BrdU-injected adult male rats were subjected to either 1 week of daily immobilization stress or no stress (n=5 no stress control, n=6 stress). (b) IHC analysis of cell fate, quantified as the percentage of BrdU positive cells that co-label as neurons (Tuj1) or oligodendrocytes (MBP) shows that stress decreases neurogenesis and increases oligodendrogenesis. (c) Representative images of confocal analysis represents cells identified as positive for co-localization of BrdU and Tuj1 or MBP; scale bar=10 μM. (d) BrdU-injected adult male rats received daily cort or vehicle injections for 1 week and were perfused on day 7 (n=6 vehicle injected, n=6 cort injected) or day 14 (n=7 vehicle injected, n=6 cort injected). (e) IHC analysis of cell fate at day 7 shows that exposure to stress hormones (cort) decreases neurogenesis and increases oligodendrogenesis. (f) IHC analysis of cell fate at day 14 (1 week after recovery from cort treatment) shows that while neurogenesis is restored to control levels, the effects of increased oligodendrogenesis persist in cort injected animals. *p < 0.05 (mean ± SEM).
Mentions: Studies investigating the effects of stress on NSCs in the adult hippocampus have primarily focused on the extent to which new neurons are generated. However, new glial cells are also generated in the hippocampus and may similarly be susceptible to environmental factors and hormones. Here we investigated whether stress and stress hormones (GCs) alter the oligodendrogenic potential in the adult hippocampus. To assess these effects, we subjected rats to 1 week of immobilization restraint stress and subsequently quantified the percentage of newborn cells (marked by BrdU, Figure 1A) in the hippocampal DG that adopted a neuronal or oligodendrocytic cell fate. In agreement with previous studies37, 38, stress significantly decreased the percentage of BrdU+ cells that co-labeled with the early neuronal marker Tuj1 (Figure 1B and C). Interestingly, stress significantly increased the percentage of BrdU+ cells that co-labeled with the mature oligodendrocyte marker MBP (Figure 1B and C), as well as the oligodendrocyte marker RIP (Supplemental Figure 1), revealing that stress increases oligodendrogenesis in the DG. To determine if an increase in circulating GCs is sufficient to upregulate hippocampal oligodendrogenesis, we next subjected rats to daily injections of cort (40 mg/kg, comparable to elevated serum GC levels induced by immobilization stress34-36) or vehicle for 1 week (Figure 1D) and assessed the neurogenic and oligodendrogenic potential within the DG. Similar to stressed rats, cort-injected rats showed a decrease in the percentage of new neurons, and an increase in the percentage of new oligodendrocytes, relative to controls (Figure 1E). When rats were allowed to recover from cort injections for 1 week, the percentage of new neurons reached control levels and did not differ between cort and vehicle injected rats (Figure 1F), consistent with prior studies on the long-term changes in neurogenesis following recovery from GC exposure39, 40. In contrast, the percentage of newborn oligodendrocytes in cort vs. vehicle injected rats remained significantly higher and persisted even following recovery from cort injections (Figure 1F).

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