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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

Memantine (MEM) treatment enhanced forgetting of contextual fear memory through the increase in adult hippocampal neurogenesis.(A) MEM treatment enhanced forgetting of contextual fear memory in a manner dependent on the number of MEM treatments. [VEH = vehicle-treated group, n = 10; MEM (1), n = 10; MEM (4), n = 10]. (B) MEM treatment enhanced forgetting of contextual fear memory in a dose-dependent manner (VEH group, n = 12; MEM25 group, n = 14; MEM50 group, n = 13). (C) Representative immunohistochemically stained BrdU-positive cells (red) and NeuN-positive cells (green) at 24 hr after Test 2. Scale bar = 100 µm. (D) The number of BrdU-positive cells in the dentate gyrus (DG) (VEH, n = 3; MEM25, n = 14; MEM50, n = 3). (E) Correlation between the number of BrdU-positive cells and the differences of freezing scores before and after the MEM treatments (MEM25 = 25 mg/kg body weight; MEM50 = 50 mg/kg body weight) in contextual fear conditioning tasks (n = 14). i.p. = intraperitoneal injection. *p<0.05. The results of the statistical analyses are presented in Figure 1—source data 1.DOI:http://dx.doi.org/10.7554/eLife.17464.00210.7554/eLife.17464.003Figure 1—source data 1.Summary of statistical analyses with F values.The asterisks indicate a significant difference.DOI:http://dx.doi.org/10.7554/eLife.17464.003
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fig1: Memantine (MEM) treatment enhanced forgetting of contextual fear memory through the increase in adult hippocampal neurogenesis.(A) MEM treatment enhanced forgetting of contextual fear memory in a manner dependent on the number of MEM treatments. [VEH = vehicle-treated group, n = 10; MEM (1), n = 10; MEM (4), n = 10]. (B) MEM treatment enhanced forgetting of contextual fear memory in a dose-dependent manner (VEH group, n = 12; MEM25 group, n = 14; MEM50 group, n = 13). (C) Representative immunohistochemically stained BrdU-positive cells (red) and NeuN-positive cells (green) at 24 hr after Test 2. Scale bar = 100 µm. (D) The number of BrdU-positive cells in the dentate gyrus (DG) (VEH, n = 3; MEM25, n = 14; MEM50, n = 3). (E) Correlation between the number of BrdU-positive cells and the differences of freezing scores before and after the MEM treatments (MEM25 = 25 mg/kg body weight; MEM50 = 50 mg/kg body weight) in contextual fear conditioning tasks (n = 14). i.p. = intraperitoneal injection. *p<0.05. The results of the statistical analyses are presented in Figure 1—source data 1.DOI:http://dx.doi.org/10.7554/eLife.17464.00210.7554/eLife.17464.003Figure 1—source data 1.Summary of statistical analyses with F values.The asterisks indicate a significant difference.DOI:http://dx.doi.org/10.7554/eLife.17464.003

Mentions: Post-training memantine (MEM) treatment was previously shown to enhance forgetting of contextual fear memory (Akers et al., 2014). We first confirmed these results under using our experimental conditions (Figure 1A). Mice were trained with a single foot shock (0.4 mA, Training), and 24 hrs later tested (Test 1). Twenty-four hrs after the Test 1, the mice received systemic injections of MEM (50 mg/kg body weight (bw)) or vehicle (VEH) once a week for four weeks (MEM-4 or VEH group). Another group received an injection of MEM only 24 hr after Test 1 (MEM-1 group). Contextual fear memory was assessed again four weeks after initial training (Test 2). All groups displayed comparable and high freezing response levels during Test 1. In contrast, the MEM-1 and -4 groups showed reduced freezing compared to the VEH group in Test 2 (Figure 1A), although this reduction was only statistically significant in the MEM-4 group. These observations were consistent with previous findings (Akers et al., 2014), and indicated that post-training MEM treatment enhanced forgetting in a dose-dependent manner.10.7554/eLife.17464.002Figure 1.Memantine (MEM) treatment enhanced forgetting of contextual fear memory through the increase in adult hippocampal neurogenesis.


Hippocampal neurogenesis enhancers promote forgetting of remote fear memory after hippocampal reactivation by retrieval
Memantine (MEM) treatment enhanced forgetting of contextual fear memory through the increase in adult hippocampal neurogenesis.(A) MEM treatment enhanced forgetting of contextual fear memory in a manner dependent on the number of MEM treatments. [VEH = vehicle-treated group, n = 10; MEM (1), n = 10; MEM (4), n = 10]. (B) MEM treatment enhanced forgetting of contextual fear memory in a dose-dependent manner (VEH group, n = 12; MEM25 group, n = 14; MEM50 group, n = 13). (C) Representative immunohistochemically stained BrdU-positive cells (red) and NeuN-positive cells (green) at 24 hr after Test 2. Scale bar = 100 µm. (D) The number of BrdU-positive cells in the dentate gyrus (DG) (VEH, n = 3; MEM25, n = 14; MEM50, n = 3). (E) Correlation between the number of BrdU-positive cells and the differences of freezing scores before and after the MEM treatments (MEM25 = 25 mg/kg body weight; MEM50 = 50 mg/kg body weight) in contextual fear conditioning tasks (n = 14). i.p. = intraperitoneal injection. *p<0.05. The results of the statistical analyses are presented in Figure 1—source data 1.DOI:http://dx.doi.org/10.7554/eLife.17464.00210.7554/eLife.17464.003Figure 1—source data 1.Summary of statistical analyses with F values.The asterisks indicate a significant difference.DOI:http://dx.doi.org/10.7554/eLife.17464.003
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fig1: Memantine (MEM) treatment enhanced forgetting of contextual fear memory through the increase in adult hippocampal neurogenesis.(A) MEM treatment enhanced forgetting of contextual fear memory in a manner dependent on the number of MEM treatments. [VEH = vehicle-treated group, n = 10; MEM (1), n = 10; MEM (4), n = 10]. (B) MEM treatment enhanced forgetting of contextual fear memory in a dose-dependent manner (VEH group, n = 12; MEM25 group, n = 14; MEM50 group, n = 13). (C) Representative immunohistochemically stained BrdU-positive cells (red) and NeuN-positive cells (green) at 24 hr after Test 2. Scale bar = 100 µm. (D) The number of BrdU-positive cells in the dentate gyrus (DG) (VEH, n = 3; MEM25, n = 14; MEM50, n = 3). (E) Correlation between the number of BrdU-positive cells and the differences of freezing scores before and after the MEM treatments (MEM25 = 25 mg/kg body weight; MEM50 = 50 mg/kg body weight) in contextual fear conditioning tasks (n = 14). i.p. = intraperitoneal injection. *p<0.05. The results of the statistical analyses are presented in Figure 1—source data 1.DOI:http://dx.doi.org/10.7554/eLife.17464.00210.7554/eLife.17464.003Figure 1—source data 1.Summary of statistical analyses with F values.The asterisks indicate a significant difference.DOI:http://dx.doi.org/10.7554/eLife.17464.003
Mentions: Post-training memantine (MEM) treatment was previously shown to enhance forgetting of contextual fear memory (Akers et al., 2014). We first confirmed these results under using our experimental conditions (Figure 1A). Mice were trained with a single foot shock (0.4 mA, Training), and 24 hrs later tested (Test 1). Twenty-four hrs after the Test 1, the mice received systemic injections of MEM (50 mg/kg body weight (bw)) or vehicle (VEH) once a week for four weeks (MEM-4 or VEH group). Another group received an injection of MEM only 24 hr after Test 1 (MEM-1 group). Contextual fear memory was assessed again four weeks after initial training (Test 2). All groups displayed comparable and high freezing response levels during Test 1. In contrast, the MEM-1 and -4 groups showed reduced freezing compared to the VEH group in Test 2 (Figure 1A), although this reduction was only statistically significant in the MEM-4 group. These observations were consistent with previous findings (Akers et al., 2014), and indicated that post-training MEM treatment enhanced forgetting in a dose-dependent manner.10.7554/eLife.17464.002Figure 1.Memantine (MEM) treatment enhanced forgetting of contextual fear memory through the increase in adult hippocampal neurogenesis.

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