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Hippocampal gene expression changes underlying stress sensitization and recovery.

Gray JD, Rubin TG, Hunter RG, McEwen BS - Mol. Psychiatry (2013)

Bottom Line: Most genes increased by CRS were decreased after recovery but many remained altered and did not return to baseline.Quantitative reverse transcription-PCR (qRT-PCR) validated changes from the microarrays in known stress-induced genes and confirmed alterations in the NF-κB pathway genes, Nfkbia, RelA and Nfkb1.These findings establish a baseline profile of normal recovery and adaptation to stress.

View Article: PubMed Central - PubMed

Affiliation: Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA.

ABSTRACT
Chronic and acute stressors have been linked to changes in hippocampal function and anxiety-like behaviors. Both produce changes in gene expression, but the extent to which these changes endure beyond the end of stress remains poorly understood. As an essential first step to characterize abnormal patterns of gene expression after stress, this study demonstrates how chronic restraint stress (CRS) modulates gene expression in response to a novel stressor in the hippocampus of wild-type mice and the extent to which these changes last beyond the end of CRS. Male C57/bl6 mice were subjected to (1) a forced swim test (FST), (2) corticosterone (Cort) or vehicle injections, (3) CRS for 21 days and then a FST, or (4) allowed to recover 21 days after CRS and subjected to FST. Hippocampal mRNA was extracted and used to generate cDNA libraries for microarray hybridization. Naive acute stressors (FST and vehicle injection) altered similar sets of genes, but Cort treatment produced a profile that was distinct from both FST and vehicle. Exposure to a novel stress after CRS activated substantially more and different genes than naive exposure. Most genes increased by CRS were decreased after recovery but many remained altered and did not return to baseline. Pathway analysis identified significant clusters of differentially expressed genes across conditions, most notably the nuclear factor kappa-light-chain-enhancer of B cells (NF-κB) pathway. Quantitative reverse transcription-PCR (qRT-PCR) validated changes from the microarrays in known stress-induced genes and confirmed alterations in the NF-κB pathway genes, Nfkbia, RelA and Nfkb1. FST increased anxiety-like behavior in both the naive and recovery from CRS conditions, but not in mice 24h subsequent to their CRS exposure. These findings suggest that the effects of naive stress are distinct from Cort elevation, and that a history of stress exposure can permanently alter gene expression patterns in the hippocampus and the behavioral response to a novel stressor. These findings establish a baseline profile of normal recovery and adaptation to stress. Importantly, they will serve as a conceptual basis to facilitate the future study of the cellular and regional basis of gene expression changes that lead to impaired recovery from stress, such as those that occur in mood and anxiety disorders.

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Chronic stress alters anxiety-related behaviors after novel stress exposure and recoveryLatency to enter the center of the open field increased in naïve FST and FST after recovery from CRS, but not by FST immediately after CRS (A). Latency to enter the open arms of the EPM was significantly increased by a novel stress only after recovery from CRS (B). (*p<0.05, ***p<0.001, n=14 controls; n=10/stress condition)
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Figure 3: Chronic stress alters anxiety-related behaviors after novel stress exposure and recoveryLatency to enter the center of the open field increased in naïve FST and FST after recovery from CRS, but not by FST immediately after CRS (A). Latency to enter the open arms of the EPM was significantly increased by a novel stress only after recovery from CRS (B). (*p<0.05, ***p<0.001, n=14 controls; n=10/stress condition)

Mentions: Open field (OF) and elevated plus maze (EPM) were used to assay anxiety-like behaviors after each stress condition. Exposure of a naïve animal to FST on the preceding day significantly increased the latency to explore the center of the OF suggesting increased anxiety (Fig. 3A, t(31)=3.68, p<0.001). Interestingly, FST on the day after the end of CRS failed to alter the latency to center. Recovery from CRS and then exposure to FST significantly increased the center entry latency (t(31)=2.72, p<0.05). Together, these data suggest that exposure to a naïve acute stress (FST) can increase anxiety-like behavior in OF, but exposure to that same stressor one day after a prolonged stress-exposure (CRS) fails to increase anxiety. However, after recovery from CRS, exposure to a novel stressor is once again able to induce anxiety-like behaviors. Latency to enter the open arms of the EPM was not significantly altered across any conditions except CRS+Recovery+FST, suggesting that a novel stress event after a history of stress can increase anxiety-like behaviors as measured by the EPM (Fig. 3B).


Hippocampal gene expression changes underlying stress sensitization and recovery.

Gray JD, Rubin TG, Hunter RG, McEwen BS - Mol. Psychiatry (2013)

Chronic stress alters anxiety-related behaviors after novel stress exposure and recoveryLatency to enter the center of the open field increased in naïve FST and FST after recovery from CRS, but not by FST immediately after CRS (A). Latency to enter the open arms of the EPM was significantly increased by a novel stress only after recovery from CRS (B). (*p<0.05, ***p<0.001, n=14 controls; n=10/stress condition)
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4061278&req=5

Figure 3: Chronic stress alters anxiety-related behaviors after novel stress exposure and recoveryLatency to enter the center of the open field increased in naïve FST and FST after recovery from CRS, but not by FST immediately after CRS (A). Latency to enter the open arms of the EPM was significantly increased by a novel stress only after recovery from CRS (B). (*p<0.05, ***p<0.001, n=14 controls; n=10/stress condition)
Mentions: Open field (OF) and elevated plus maze (EPM) were used to assay anxiety-like behaviors after each stress condition. Exposure of a naïve animal to FST on the preceding day significantly increased the latency to explore the center of the OF suggesting increased anxiety (Fig. 3A, t(31)=3.68, p<0.001). Interestingly, FST on the day after the end of CRS failed to alter the latency to center. Recovery from CRS and then exposure to FST significantly increased the center entry latency (t(31)=2.72, p<0.05). Together, these data suggest that exposure to a naïve acute stress (FST) can increase anxiety-like behavior in OF, but exposure to that same stressor one day after a prolonged stress-exposure (CRS) fails to increase anxiety. However, after recovery from CRS, exposure to a novel stressor is once again able to induce anxiety-like behaviors. Latency to enter the open arms of the EPM was not significantly altered across any conditions except CRS+Recovery+FST, suggesting that a novel stress event after a history of stress can increase anxiety-like behaviors as measured by the EPM (Fig. 3B).

Bottom Line: Most genes increased by CRS were decreased after recovery but many remained altered and did not return to baseline.Quantitative reverse transcription-PCR (qRT-PCR) validated changes from the microarrays in known stress-induced genes and confirmed alterations in the NF-κB pathway genes, Nfkbia, RelA and Nfkb1.These findings establish a baseline profile of normal recovery and adaptation to stress.

View Article: PubMed Central - PubMed

Affiliation: Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA.

ABSTRACT
Chronic and acute stressors have been linked to changes in hippocampal function and anxiety-like behaviors. Both produce changes in gene expression, but the extent to which these changes endure beyond the end of stress remains poorly understood. As an essential first step to characterize abnormal patterns of gene expression after stress, this study demonstrates how chronic restraint stress (CRS) modulates gene expression in response to a novel stressor in the hippocampus of wild-type mice and the extent to which these changes last beyond the end of CRS. Male C57/bl6 mice were subjected to (1) a forced swim test (FST), (2) corticosterone (Cort) or vehicle injections, (3) CRS for 21 days and then a FST, or (4) allowed to recover 21 days after CRS and subjected to FST. Hippocampal mRNA was extracted and used to generate cDNA libraries for microarray hybridization. Naive acute stressors (FST and vehicle injection) altered similar sets of genes, but Cort treatment produced a profile that was distinct from both FST and vehicle. Exposure to a novel stress after CRS activated substantially more and different genes than naive exposure. Most genes increased by CRS were decreased after recovery but many remained altered and did not return to baseline. Pathway analysis identified significant clusters of differentially expressed genes across conditions, most notably the nuclear factor kappa-light-chain-enhancer of B cells (NF-κB) pathway. Quantitative reverse transcription-PCR (qRT-PCR) validated changes from the microarrays in known stress-induced genes and confirmed alterations in the NF-κB pathway genes, Nfkbia, RelA and Nfkb1. FST increased anxiety-like behavior in both the naive and recovery from CRS conditions, but not in mice 24h subsequent to their CRS exposure. These findings suggest that the effects of naive stress are distinct from Cort elevation, and that a history of stress exposure can permanently alter gene expression patterns in the hippocampus and the behavioral response to a novel stressor. These findings establish a baseline profile of normal recovery and adaptation to stress. Importantly, they will serve as a conceptual basis to facilitate the future study of the cellular and regional basis of gene expression changes that lead to impaired recovery from stress, such as those that occur in mood and anxiety disorders.

Show MeSH
Related in: MedlinePlus