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Hippocampal neurogenesis enhancers promote forgetting of remote fear memory after hippocampal reactivation by retrieval

View Article: PubMed Central - PubMed

ABSTRACT

Forgetting of recent fear memory is promoted by treatment with memantine (MEM), which increases hippocampal neurogenesis. The approaches for treatment of post-traumatic stress disorder (PTSD) using rodent models have focused on the extinction and reconsolidation of recent, but not remote, memories. Here we show that, following prolonged re-exposure to the conditioning context, enhancers of hippocampal neurogenesis, including MEM, promote forgetting of remote contextual fear memory. However, these interventions are ineffective following shorter re-exposures. Importantly, we find that long, but not short re-exposures activate gene expression in the hippocampus and induce hippocampus-dependent reconsolidation of remote contextual fear memory. Furthermore, remote memory retrieval becomes hippocampus-dependent after the long-time recall, suggesting that remote fear memory returns to a hippocampus dependent state after the long-time recall, thereby allowing enhanced forgetting by increased hippocampal neurogenesis. Forgetting of traumatic memory may contribute to the development of PTSD treatment.

Doi:: http://dx.doi.org/10.7554/eLife.17464.001

No MeSH data available.


Related in: MedlinePlus

Enhancement of adult hippocampal neurogenesis after long-period recall enhanced forgetting of remote fear memory.(A) Memantine (MEM) treatment enhanced forgetting of remote fear memory after 10 min re-exposure (3 min vehicle treatment group (VEH), n = 10; 3 min MEM-treated group, n = 10; 10 min VEH, n = 12; 10 min MEM, n = 13). (B) Running after 10 min re-exposure enhanced forgetting of remote fear memory [No Run (Con), 0 min, n = 12; Run, 0 min, n = 9; No Run, 3 min, n = 12; Run, 3 min, n = 11; No Run, 10 min, n = 12; Run, 10 min, n = 11]. *p<0.05, compared with other groups in the test. The results of the statistical analyses are presented in Figure 3—source data 1.DOI:http://dx.doi.org/10.7554/eLife.17464.00610.7554/eLife.17464.007Figure 3—source data 1.Summary of statistical analyses with F values.The asterisks indicate a significant difference.DOI:http://dx.doi.org/10.7554/eLife.17464.007
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fig3: Enhancement of adult hippocampal neurogenesis after long-period recall enhanced forgetting of remote fear memory.(A) Memantine (MEM) treatment enhanced forgetting of remote fear memory after 10 min re-exposure (3 min vehicle treatment group (VEH), n = 10; 3 min MEM-treated group, n = 10; 10 min VEH, n = 12; 10 min MEM, n = 13). (B) Running after 10 min re-exposure enhanced forgetting of remote fear memory [No Run (Con), 0 min, n = 12; Run, 0 min, n = 9; No Run, 3 min, n = 12; Run, 3 min, n = 11; No Run, 10 min, n = 12; Run, 10 min, n = 11]. *p<0.05, compared with other groups in the test. The results of the statistical analyses are presented in Figure 3—source data 1.DOI:http://dx.doi.org/10.7554/eLife.17464.00610.7554/eLife.17464.007Figure 3—source data 1.Summary of statistical analyses with F values.The asterisks indicate a significant difference.DOI:http://dx.doi.org/10.7554/eLife.17464.007

Mentions: Our observation that MEM failed to promote forgetting of remote fear memory is perhaps not surprising because increases in neurogenesis should only impact memories that depend on the hippocampus. However, previously we showed that reminders (e.g., context re-exposure) may render memories hippocampus-dependent again and make them vulnerable again to amnestic treatments that block reconsolidation (e.g., protein synthesis blockade) (Suzuki et al., 2004). Using the same logic here we ask whether reminders (i.e., context re-exposure) may make remote contextual fear memories susceptible to MEM-induced forgetting. In our previous reconsolidation experiment we found that long (10 min) but not short (3 min) re-exposures to the context were effective, and so here we used these long and brief reminders. Mice were trained as previously, and then re-exposed to the context for 3 or 10 min eight weeks later (re-exposure). Following re-exposure, MEM treatment was initiated and memory tested four weeks later (Figure 3A). All groups showed comparable levels of freezing during the re-exposure (3 or 10 min). Four weeks later, the MEM group with 3 min re-exposure showed comparable freezing with the VEH group in the test. In contrast, the MEM group with 10 min re-exposure showed significantly less freezing than the other groups (Figure 3A). These results indicated re-exposure to the context for 10 min eight weeks after initial training renders the context memory sensitive to MEM-induced forgetting.10.7554/eLife.17464.006Figure 3.Enhancement of adult hippocampal neurogenesis after long-period recall enhanced forgetting of remote fear memory.


Hippocampal neurogenesis enhancers promote forgetting of remote fear memory after hippocampal reactivation by retrieval
Enhancement of adult hippocampal neurogenesis after long-period recall enhanced forgetting of remote fear memory.(A) Memantine (MEM) treatment enhanced forgetting of remote fear memory after 10 min re-exposure (3 min vehicle treatment group (VEH), n = 10; 3 min MEM-treated group, n = 10; 10 min VEH, n = 12; 10 min MEM, n = 13). (B) Running after 10 min re-exposure enhanced forgetting of remote fear memory [No Run (Con), 0 min, n = 12; Run, 0 min, n = 9; No Run, 3 min, n = 12; Run, 3 min, n = 11; No Run, 10 min, n = 12; Run, 10 min, n = 11]. *p<0.05, compared with other groups in the test. The results of the statistical analyses are presented in Figure 3—source data 1.DOI:http://dx.doi.org/10.7554/eLife.17464.00610.7554/eLife.17464.007Figure 3—source data 1.Summary of statistical analyses with F values.The asterisks indicate a significant difference.DOI:http://dx.doi.org/10.7554/eLife.17464.007
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fig3: Enhancement of adult hippocampal neurogenesis after long-period recall enhanced forgetting of remote fear memory.(A) Memantine (MEM) treatment enhanced forgetting of remote fear memory after 10 min re-exposure (3 min vehicle treatment group (VEH), n = 10; 3 min MEM-treated group, n = 10; 10 min VEH, n = 12; 10 min MEM, n = 13). (B) Running after 10 min re-exposure enhanced forgetting of remote fear memory [No Run (Con), 0 min, n = 12; Run, 0 min, n = 9; No Run, 3 min, n = 12; Run, 3 min, n = 11; No Run, 10 min, n = 12; Run, 10 min, n = 11]. *p<0.05, compared with other groups in the test. The results of the statistical analyses are presented in Figure 3—source data 1.DOI:http://dx.doi.org/10.7554/eLife.17464.00610.7554/eLife.17464.007Figure 3—source data 1.Summary of statistical analyses with F values.The asterisks indicate a significant difference.DOI:http://dx.doi.org/10.7554/eLife.17464.007
Mentions: Our observation that MEM failed to promote forgetting of remote fear memory is perhaps not surprising because increases in neurogenesis should only impact memories that depend on the hippocampus. However, previously we showed that reminders (e.g., context re-exposure) may render memories hippocampus-dependent again and make them vulnerable again to amnestic treatments that block reconsolidation (e.g., protein synthesis blockade) (Suzuki et al., 2004). Using the same logic here we ask whether reminders (i.e., context re-exposure) may make remote contextual fear memories susceptible to MEM-induced forgetting. In our previous reconsolidation experiment we found that long (10 min) but not short (3 min) re-exposures to the context were effective, and so here we used these long and brief reminders. Mice were trained as previously, and then re-exposed to the context for 3 or 10 min eight weeks later (re-exposure). Following re-exposure, MEM treatment was initiated and memory tested four weeks later (Figure 3A). All groups showed comparable levels of freezing during the re-exposure (3 or 10 min). Four weeks later, the MEM group with 3 min re-exposure showed comparable freezing with the VEH group in the test. In contrast, the MEM group with 10 min re-exposure showed significantly less freezing than the other groups (Figure 3A). These results indicated re-exposure to the context for 10 min eight weeks after initial training renders the context memory sensitive to MEM-induced forgetting.10.7554/eLife.17464.006Figure 3.Enhancement of adult hippocampal neurogenesis after long-period recall enhanced forgetting of remote fear memory.

View Article: PubMed Central - PubMed

ABSTRACT

Forgetting of recent fear memory is promoted by treatment with memantine (MEM), which increases hippocampal neurogenesis. The approaches for treatment of post-traumatic stress disorder (PTSD) using rodent models have focused on the extinction and reconsolidation of recent, but not remote, memories. Here we show that, following prolonged re-exposure to the conditioning context, enhancers of hippocampal neurogenesis, including MEM, promote forgetting of remote contextual fear memory. However, these interventions are ineffective following shorter re-exposures. Importantly, we find that long, but not short re-exposures activate gene expression in the hippocampus and induce hippocampus-dependent reconsolidation of remote contextual fear memory. Furthermore, remote memory retrieval becomes hippocampus-dependent after the long-time recall, suggesting that remote fear memory returns to a hippocampus dependent state after the long-time recall, thereby allowing enhanced forgetting by increased hippocampal neurogenesis. Forgetting of traumatic memory may contribute to the development of PTSD treatment.

Doi:: http://dx.doi.org/10.7554/eLife.17464.001

No MeSH data available.


Related in: MedlinePlus