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Conditional Inhibition of Adult Neurogenesis by Inducible and Targeted Deletion of ERK5 MAP Kinase Is Not Associated with Anxiety/Depression-Like Behaviors(1,2).

Zou J, Wang W, Pan YW, Abel GM, Storm DR, Xia Z - eNeuro (2015)

Bottom Line: Although there is evidence that adult neurogenesis contributes to the therapeutic efficacy of chronic antidepressant treatment for anxiety and depression disorders, the role of adult neurogenesis in the onset of depression-related symptoms is still open to question.Here, we report that inhibition of adult neurogenesis by this mechanism is not associated with an increase of the baseline anxiety or depression in non-stressed animals, nor does it increase the animal's susceptibility to depression after chronic unpredictable stress treatment.Our findings indicate that impaired adult neurogenesis does not lead to anxiety or depression.

View Article: PubMed Central - HTML - PubMed

Affiliation: Toxicology Program in the Department of Environmental and Occupational Health Sciences.

ABSTRACT
Although there is evidence that adult neurogenesis contributes to the therapeutic efficacy of chronic antidepressant treatment for anxiety and depression disorders, the role of adult neurogenesis in the onset of depression-related symptoms is still open to question. To address this issue, we utilized a transgenic mouse strain in which adult neurogenesis was specifically and conditionally impaired by Nestin-CreER-driven, inducible knockout (icKO) of erk5 MAP kinase in Nestin-expressing neural progenitors of the adult mouse brain upon tamoxifen administration. Here, we report that inhibition of adult neurogenesis by this mechanism is not associated with an increase of the baseline anxiety or depression in non-stressed animals, nor does it increase the animal's susceptibility to depression after chronic unpredictable stress treatment. Our findings indicate that impaired adult neurogenesis does not lead to anxiety or depression.

No MeSH data available.


Related in: MedlinePlus

Characterization of the specificity of Nestin-CreER-mediated recombination in ERK5 icKO mice. A, ERK5 and YFP immunostaining in the dentate gyrus of Nestin-CreERTM/ERK5loxP/loxP/R26-YFPloxP/loxP animals treated with tamoxifen or vehicle control, demonstrating the specificity and effectiveness of Nestin-Cre-ERTM-mediated erk5 deletion. Scale bar, 100 μm. B, YFP immunostaining in the cortex, striatum, and CA1-3 of the hippocampus of Nestin-CreERTM/ERK5loxP/loxP/R26-YFPloxP/loxP animals treated with tamoxifen, demonstrating that Nestin-Cre-ERTM-mediated recombination does not occur in non-neurogenic regions. Scale bar, 100 μm. C, ERK5 immunostaining in the dentate gyrus of ERK5 icKO and control animals 3 months after behavior testing for learning and memory, demonstrating the sustained deletion of erk5 during the time frames of behavior testing. Scale bar, 25 μm.
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Figure 3: Characterization of the specificity of Nestin-CreER-mediated recombination in ERK5 icKO mice. A, ERK5 and YFP immunostaining in the dentate gyrus of Nestin-CreERTM/ERK5loxP/loxP/R26-YFPloxP/loxP animals treated with tamoxifen or vehicle control, demonstrating the specificity and effectiveness of Nestin-Cre-ERTM-mediated erk5 deletion. Scale bar, 100 μm. B, YFP immunostaining in the cortex, striatum, and CA1-3 of the hippocampus of Nestin-CreERTM/ERK5loxP/loxP/R26-YFPloxP/loxP animals treated with tamoxifen, demonstrating that Nestin-Cre-ERTM-mediated recombination does not occur in non-neurogenic regions. Scale bar, 100 μm. C, ERK5 immunostaining in the dentate gyrus of ERK5 icKO and control animals 3 months after behavior testing for learning and memory, demonstrating the sustained deletion of erk5 during the time frames of behavior testing. Scale bar, 25 μm.

Mentions: We utilized an inducible and conditional ERK5 knock-out (ERK5 icKO) mouse model to determine whether the inhibition of adult neurogenesis by ERK5 deletion alters baseline anxiety. In this model, adult Nestin-CreER™/ERK5loxP/loxP mice were treated with tamoxifen to induce erk5 gene deletion in the Nestin-expressing neural stem cells (ERK5 icKO), while vehicle-treated mice of the same genotype or ERK5loxP/loxP littermates treated with tamoxifen or vehicle were used as controls (see Fig. 1 for details). Previous studies showed that Nestin-CreER™-driven erk5 deletion occurs only upon tamoxifen administration (Pan et al., 2012c; Pan et al., 2012d; Li et al., 2013; Wang et al., 2013). To further examine the specificity of tamoxifen-induced, Nestin-CreERTM-mediated recombination, Nestin-CreERTM/ERK5loxP/loxP mice were crossed with R26-YFP reporter mice where Cre-mediated recombination removes a transcriptional STOP to allow YFP expression (Srinivas et al., 2001). Nestin-CreERTM/ERK5loxP/loxP/R26-YFPloxP/loxP mice were euthanized 10 d after the last dose of tamoxifen or vehicle control. There was ERK5 but no YFP expression in the SGZ of vehicle control treated mouse brain (Fig. 3A). In contrast, there were abundant YFP+ cells but no ERK5+ cells along the SGZ of tamoxifen-treated mouse brains. Furthermore, there were no YFP+ cells in the cortex, stratum, CA1, CA2, or CA3 of the hippocampus after tamoxifen treatment (Fig. 3B). These data indicate that Nestin-Cre-ERTM-mediated deletion of erk5 is specific to adult neurogenic regions and there is no discernible deletion of erk5 without tamoxifen or in non-neurogenic regions after tamoxifen treatment.


Conditional Inhibition of Adult Neurogenesis by Inducible and Targeted Deletion of ERK5 MAP Kinase Is Not Associated with Anxiety/Depression-Like Behaviors(1,2).

Zou J, Wang W, Pan YW, Abel GM, Storm DR, Xia Z - eNeuro (2015)

Characterization of the specificity of Nestin-CreER-mediated recombination in ERK5 icKO mice. A, ERK5 and YFP immunostaining in the dentate gyrus of Nestin-CreERTM/ERK5loxP/loxP/R26-YFPloxP/loxP animals treated with tamoxifen or vehicle control, demonstrating the specificity and effectiveness of Nestin-Cre-ERTM-mediated erk5 deletion. Scale bar, 100 μm. B, YFP immunostaining in the cortex, striatum, and CA1-3 of the hippocampus of Nestin-CreERTM/ERK5loxP/loxP/R26-YFPloxP/loxP animals treated with tamoxifen, demonstrating that Nestin-Cre-ERTM-mediated recombination does not occur in non-neurogenic regions. Scale bar, 100 μm. C, ERK5 immunostaining in the dentate gyrus of ERK5 icKO and control animals 3 months after behavior testing for learning and memory, demonstrating the sustained deletion of erk5 during the time frames of behavior testing. Scale bar, 25 μm.
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Related In: Results  -  Collection

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Figure 3: Characterization of the specificity of Nestin-CreER-mediated recombination in ERK5 icKO mice. A, ERK5 and YFP immunostaining in the dentate gyrus of Nestin-CreERTM/ERK5loxP/loxP/R26-YFPloxP/loxP animals treated with tamoxifen or vehicle control, demonstrating the specificity and effectiveness of Nestin-Cre-ERTM-mediated erk5 deletion. Scale bar, 100 μm. B, YFP immunostaining in the cortex, striatum, and CA1-3 of the hippocampus of Nestin-CreERTM/ERK5loxP/loxP/R26-YFPloxP/loxP animals treated with tamoxifen, demonstrating that Nestin-Cre-ERTM-mediated recombination does not occur in non-neurogenic regions. Scale bar, 100 μm. C, ERK5 immunostaining in the dentate gyrus of ERK5 icKO and control animals 3 months after behavior testing for learning and memory, demonstrating the sustained deletion of erk5 during the time frames of behavior testing. Scale bar, 25 μm.
Mentions: We utilized an inducible and conditional ERK5 knock-out (ERK5 icKO) mouse model to determine whether the inhibition of adult neurogenesis by ERK5 deletion alters baseline anxiety. In this model, adult Nestin-CreER™/ERK5loxP/loxP mice were treated with tamoxifen to induce erk5 gene deletion in the Nestin-expressing neural stem cells (ERK5 icKO), while vehicle-treated mice of the same genotype or ERK5loxP/loxP littermates treated with tamoxifen or vehicle were used as controls (see Fig. 1 for details). Previous studies showed that Nestin-CreER™-driven erk5 deletion occurs only upon tamoxifen administration (Pan et al., 2012c; Pan et al., 2012d; Li et al., 2013; Wang et al., 2013). To further examine the specificity of tamoxifen-induced, Nestin-CreERTM-mediated recombination, Nestin-CreERTM/ERK5loxP/loxP mice were crossed with R26-YFP reporter mice where Cre-mediated recombination removes a transcriptional STOP to allow YFP expression (Srinivas et al., 2001). Nestin-CreERTM/ERK5loxP/loxP/R26-YFPloxP/loxP mice were euthanized 10 d after the last dose of tamoxifen or vehicle control. There was ERK5 but no YFP expression in the SGZ of vehicle control treated mouse brain (Fig. 3A). In contrast, there were abundant YFP+ cells but no ERK5+ cells along the SGZ of tamoxifen-treated mouse brains. Furthermore, there were no YFP+ cells in the cortex, stratum, CA1, CA2, or CA3 of the hippocampus after tamoxifen treatment (Fig. 3B). These data indicate that Nestin-Cre-ERTM-mediated deletion of erk5 is specific to adult neurogenic regions and there is no discernible deletion of erk5 without tamoxifen or in non-neurogenic regions after tamoxifen treatment.

Bottom Line: Although there is evidence that adult neurogenesis contributes to the therapeutic efficacy of chronic antidepressant treatment for anxiety and depression disorders, the role of adult neurogenesis in the onset of depression-related symptoms is still open to question.Here, we report that inhibition of adult neurogenesis by this mechanism is not associated with an increase of the baseline anxiety or depression in non-stressed animals, nor does it increase the animal's susceptibility to depression after chronic unpredictable stress treatment.Our findings indicate that impaired adult neurogenesis does not lead to anxiety or depression.

View Article: PubMed Central - HTML - PubMed

Affiliation: Toxicology Program in the Department of Environmental and Occupational Health Sciences.

ABSTRACT
Although there is evidence that adult neurogenesis contributes to the therapeutic efficacy of chronic antidepressant treatment for anxiety and depression disorders, the role of adult neurogenesis in the onset of depression-related symptoms is still open to question. To address this issue, we utilized a transgenic mouse strain in which adult neurogenesis was specifically and conditionally impaired by Nestin-CreER-driven, inducible knockout (icKO) of erk5 MAP kinase in Nestin-expressing neural progenitors of the adult mouse brain upon tamoxifen administration. Here, we report that inhibition of adult neurogenesis by this mechanism is not associated with an increase of the baseline anxiety or depression in non-stressed animals, nor does it increase the animal's susceptibility to depression after chronic unpredictable stress treatment. Our findings indicate that impaired adult neurogenesis does not lead to anxiety or depression.

No MeSH data available.


Related in: MedlinePlus