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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.


Memantine (MEM) treatment enhanced forgetting of hippocampus-dependent fear memory.(A) MEM treatment enhanced forgetting of hippocampus-dependent inhibitory avoidance memory [vehicle treated group (VEH), n = 11; MEM group, n = 10]. (B) MEM-treated mice showed normal amygdala-dependent memory (VEH, n = 12; MEM, n = 12). (C) MEM treatment affects strong fear memory (VEH, n = 8; MEM, n = 9). (D) Remote fear memory formed eight weeks after MEM treatment did not enhance forgetting (VEH, n = 10; MEM, n = 10). (A) and (C), *p<0.05, compared with the saline group. i.p. = intraperitoneal. The results of the statistical analyses are presented in Figure 2—source data 1.DOI:http://dx.doi.org/10.7554/eLife.17464.00410.7554/eLife.17464.005Figure 2—source data 1.Summary of statistical analyses with F values.The asterisks indicate a significant difference.DOI:http://dx.doi.org/10.7554/eLife.17464.005
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fig2: Memantine (MEM) treatment enhanced forgetting of hippocampus-dependent fear memory.(A) MEM treatment enhanced forgetting of hippocampus-dependent inhibitory avoidance memory [vehicle treated group (VEH), n = 11; MEM group, n = 10]. (B) MEM-treated mice showed normal amygdala-dependent memory (VEH, n = 12; MEM, n = 12). (C) MEM treatment affects strong fear memory (VEH, n = 8; MEM, n = 9). (D) Remote fear memory formed eight weeks after MEM treatment did not enhance forgetting (VEH, n = 10; MEM, n = 10). (A) and (C), *p<0.05, compared with the saline group. i.p. = intraperitoneal. The results of the statistical analyses are presented in Figure 2—source data 1.DOI:http://dx.doi.org/10.7554/eLife.17464.00410.7554/eLife.17464.005Figure 2—source data 1.Summary of statistical analyses with F values.The asterisks indicate a significant difference.DOI:http://dx.doi.org/10.7554/eLife.17464.005

Mentions: In the adult brain neurogenesis persists in the subgranular zone (SGZ) of the hippocampus and in the subventricular zone (SVZ). Therefore, MEM-induced forgetting should be limited to brain regions like the hippocampus that are remodeled with the addition of new neurons (Frankland et al., 2013). To address this, we next trained mice in aversively-motivated tasks that are hippocampus-dependent and -independent, respectively. First, we used an inhibitory avoidance tasks that depends upon the hippocampus (Lorenzini et al., 1996; Zhang et al., 2011). Twenty-four hours after training with a 0.1 mA foot shock, mice were treated with MEM for four weeks (Figure 2A) and then crossover latency was assessed (Test). The MEM group showed significantly shorter crossover latencies than the VEH group (Figure 2A), indicating that MEM enhanced forgetting of inhibitory avoidance memory. We next used cued fear conditioning tasks that can generate an amygdala-dependent fear memory (Phillips and LeDoux, 1992). Mice were presented a tone that co-terminated with a 0.4 mA foot shock in the training context (Training). Mice were assessed for their freezing responses to the tone in a different chamber at 24 hr (Test 1) and four weeks (Test 2) after the training. As in previous experiments, after Test 1 mice received MEM or VEH for four weeks. In contrast to the results shown in Figure 1 and Figure 2A, the MEM group showed similar levels of freezing to the tone with the VEH group in both Test 1 and Test 2 (Figure 2B), indicating that MEM failed to promote forgetting of cued (amygdala-dependent) fear memory. These results are consistent with previous studies (Akers et al., 2014), and suggested that MEM promotes forgetting of only hippocampus-dependent fear memory.10.7554/eLife.17464.004Figure 2.Memantine (MEM) treatment enhanced forgetting of hippocampus-dependent fear memory.


Hippocampal neurogenesis enhancers promote forgetting of remote fear memory after hippocampal reactivation by retrieval
Memantine (MEM) treatment enhanced forgetting of hippocampus-dependent fear memory.(A) MEM treatment enhanced forgetting of hippocampus-dependent inhibitory avoidance memory [vehicle treated group (VEH), n = 11; MEM group, n = 10]. (B) MEM-treated mice showed normal amygdala-dependent memory (VEH, n = 12; MEM, n = 12). (C) MEM treatment affects strong fear memory (VEH, n = 8; MEM, n = 9). (D) Remote fear memory formed eight weeks after MEM treatment did not enhance forgetting (VEH, n = 10; MEM, n = 10). (A) and (C), *p<0.05, compared with the saline group. i.p. = intraperitoneal. The results of the statistical analyses are presented in Figure 2—source data 1.DOI:http://dx.doi.org/10.7554/eLife.17464.00410.7554/eLife.17464.005Figure 2—source data 1.Summary of statistical analyses with F values.The asterisks indicate a significant difference.DOI:http://dx.doi.org/10.7554/eLife.17464.005
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fig2: Memantine (MEM) treatment enhanced forgetting of hippocampus-dependent fear memory.(A) MEM treatment enhanced forgetting of hippocampus-dependent inhibitory avoidance memory [vehicle treated group (VEH), n = 11; MEM group, n = 10]. (B) MEM-treated mice showed normal amygdala-dependent memory (VEH, n = 12; MEM, n = 12). (C) MEM treatment affects strong fear memory (VEH, n = 8; MEM, n = 9). (D) Remote fear memory formed eight weeks after MEM treatment did not enhance forgetting (VEH, n = 10; MEM, n = 10). (A) and (C), *p<0.05, compared with the saline group. i.p. = intraperitoneal. The results of the statistical analyses are presented in Figure 2—source data 1.DOI:http://dx.doi.org/10.7554/eLife.17464.00410.7554/eLife.17464.005Figure 2—source data 1.Summary of statistical analyses with F values.The asterisks indicate a significant difference.DOI:http://dx.doi.org/10.7554/eLife.17464.005
Mentions: In the adult brain neurogenesis persists in the subgranular zone (SGZ) of the hippocampus and in the subventricular zone (SVZ). Therefore, MEM-induced forgetting should be limited to brain regions like the hippocampus that are remodeled with the addition of new neurons (Frankland et al., 2013). To address this, we next trained mice in aversively-motivated tasks that are hippocampus-dependent and -independent, respectively. First, we used an inhibitory avoidance tasks that depends upon the hippocampus (Lorenzini et al., 1996; Zhang et al., 2011). Twenty-four hours after training with a 0.1 mA foot shock, mice were treated with MEM for four weeks (Figure 2A) and then crossover latency was assessed (Test). The MEM group showed significantly shorter crossover latencies than the VEH group (Figure 2A), indicating that MEM enhanced forgetting of inhibitory avoidance memory. We next used cued fear conditioning tasks that can generate an amygdala-dependent fear memory (Phillips and LeDoux, 1992). Mice were presented a tone that co-terminated with a 0.4 mA foot shock in the training context (Training). Mice were assessed for their freezing responses to the tone in a different chamber at 24 hr (Test 1) and four weeks (Test 2) after the training. As in previous experiments, after Test 1 mice received MEM or VEH for four weeks. In contrast to the results shown in Figure 1 and Figure 2A, the MEM group showed similar levels of freezing to the tone with the VEH group in both Test 1 and Test 2 (Figure 2B), indicating that MEM failed to promote forgetting of cued (amygdala-dependent) fear memory. These results are consistent with previous studies (Akers et al., 2014), and suggested that MEM promotes forgetting of only hippocampus-dependent fear memory.10.7554/eLife.17464.004Figure 2.Memantine (MEM) treatment enhanced forgetting of hippocampus-dependent 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.