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Ongoing neurogenesis in the adult dentate gyrus mediates behavioral responses to ambiguous threat cues

View Article: PubMed Central - PubMed

ABSTRACT

Fear learning is highly adaptive if utilized in appropriate situations but can lead to generalized anxiety if applied too widely. A role of predictive cues in inhibiting fear generalization has been suggested by stress and fear learning studies, but the effects of partially predictive cues (ambiguous cues) and the neuronal populations responsible for linking the predictive ability of cues and generalization of fear responses are unknown. Here, we show that inhibition of adult neurogenesis in the mouse dentate gyrus decreases hippocampal network activation and reduces defensive behavior to ambiguous threat cues but has neither of these effects if the same negative experience is reliably predicted. Additionally, we find that this ambiguity related to negative events determines their effect on fear generalization, that is, how the events affect future behavior under novel conditions. Both new neurons and glucocorticoid hormones are required for the enhancement of fear generalization following an unpredictably cued threat. Thus, adult neurogenesis plays a central role in the adaptive changes resulting from experience involving unpredictable or ambiguous threat cues, optimizing behavior in novel and uncertain situations.

No MeSH data available.


Related in: MedlinePlus

Behavioral response to ambiguous conditioned fear cues is decreased in adult neurogenesis-deficient mice.(A) Examples of conditioned fear training and testing protocols. (B) In a cued fear conditioning task, a perfectly predictive tone cue (Reliable) elicited similar freezing in transgenic (TK) mice (n = 8), which lack adult neurogenesis, and wild-type (WT) controls (n = 6) (*, main effect of tone versus baseline F1,12 = 48.6, p < 0.0001; no other significant effects). (C) A tone that coterminated with a shock only 50% of the time (ambiguous) increased freezing in both WT (n = 7) and TK mice (n = 9; main effect of tone, F1,14 = 55.9, p < 0.0001; post hoc tests show tone greater than baseline, p < 0.005, in both genotypes). However, the tone increased freezing more in WT mice relative to TK mice (tone x genotype interaction, F1,14 = 5.0, p = 0.04; †, post hoc testing indicates p < 0.05 for TK versus WT freezing during the tone). (D) Freezing responses to the reliably predictive tone cue (averaged across six trials for each session) were virtually identical in WT (n = 7) and TK (n = 8) mice during all extinction days. (E) After reliable cue training with a weak shock (0.3 mA compared to 0.5 mA in earlier experiments), WT (n = 11) and TK (n = 13) mice showed increased freezing to the tone (main effect of tone F1,22 = 13.7, p = .001) but equivalent freezing across genotype (main effect of genotype F1,22 = 0.007, p = .93), suggesting equivalent learning with reliable cues even with a weaker shock training protocol. (F) After fear conditioning, a reliable tone cue increased the startle response similarly in mice of both genotypes (*, main effect of tone F1,20 = 4.7, p = 0.04, main effect of genotype F1,20 = 0.016, p = .94; n = 11 for both groups). (G) An ambiguous cue increased startle in WT mice (n = 11) but not TK mice (n = 10) (tone x genotype interaction F1,19 = 4.5, p = 0.047; †, post hoc testing indicates p < 0.05 versus WT at the same time point). Data are represented as mean ± standard error of the mean (SEM). The numerical data used in all figures can be found in S1 Data.
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pbio.2001154.g001: Behavioral response to ambiguous conditioned fear cues is decreased in adult neurogenesis-deficient mice.(A) Examples of conditioned fear training and testing protocols. (B) In a cued fear conditioning task, a perfectly predictive tone cue (Reliable) elicited similar freezing in transgenic (TK) mice (n = 8), which lack adult neurogenesis, and wild-type (WT) controls (n = 6) (*, main effect of tone versus baseline F1,12 = 48.6, p < 0.0001; no other significant effects). (C) A tone that coterminated with a shock only 50% of the time (ambiguous) increased freezing in both WT (n = 7) and TK mice (n = 9; main effect of tone, F1,14 = 55.9, p < 0.0001; post hoc tests show tone greater than baseline, p < 0.005, in both genotypes). However, the tone increased freezing more in WT mice relative to TK mice (tone x genotype interaction, F1,14 = 5.0, p = 0.04; †, post hoc testing indicates p < 0.05 for TK versus WT freezing during the tone). (D) Freezing responses to the reliably predictive tone cue (averaged across six trials for each session) were virtually identical in WT (n = 7) and TK (n = 8) mice during all extinction days. (E) After reliable cue training with a weak shock (0.3 mA compared to 0.5 mA in earlier experiments), WT (n = 11) and TK (n = 13) mice showed increased freezing to the tone (main effect of tone F1,22 = 13.7, p = .001) but equivalent freezing across genotype (main effect of genotype F1,22 = 0.007, p = .93), suggesting equivalent learning with reliable cues even with a weaker shock training protocol. (F) After fear conditioning, a reliable tone cue increased the startle response similarly in mice of both genotypes (*, main effect of tone F1,20 = 4.7, p = 0.04, main effect of genotype F1,20 = 0.016, p = .94; n = 11 for both groups). (G) An ambiguous cue increased startle in WT mice (n = 11) but not TK mice (n = 10) (tone x genotype interaction F1,19 = 4.5, p = 0.047; †, post hoc testing indicates p < 0.05 versus WT at the same time point). Data are represented as mean ± standard error of the mean (SEM). The numerical data used in all figures can be found in S1 Data.

Mentions: To specifically eliminate adult neurogenesis, we treated 8-wk-old mice expressing herpes thymidine kinase in neuronal precursors with the antiviral drug valganciclovir, which inhibits adult neurogenesis without affecting mature neurons or astrocytes [9]. As expected, adult neurogenesis was virtually eliminated in the dentate gyrus (S1 Fig). Mice lacking adult neurogenesis (TK mice) and WT littermate controls (WT mice) were trained in a 3-day cued fear conditioning paradigm (Fig 1A). In a between-subjects design, half of the mice of each genotype were exposed to a tone cue that always coterminated with a shock (reliable fear conditioning), while the other half were exposed to a tone cue that coterminated with a shock only 50% of the time (ambiguous fear conditioning). Different groups of mice were used for the two cue conditions in order to avoid potential overshadowing or interference between the cues [24,25]. TK mice were indistinguishable from WT controls in response to the reliable cue (Figs 1B and S2), consistent with previous studies [7,20,21,26,27]. However, the TK mice trained with the ambiguous cue showed significantly less cue-induced freezing than their WT counterparts (Figs 1C and S2).


Ongoing neurogenesis in the adult dentate gyrus mediates behavioral responses to ambiguous threat cues
Behavioral response to ambiguous conditioned fear cues is decreased in adult neurogenesis-deficient mice.(A) Examples of conditioned fear training and testing protocols. (B) In a cued fear conditioning task, a perfectly predictive tone cue (Reliable) elicited similar freezing in transgenic (TK) mice (n = 8), which lack adult neurogenesis, and wild-type (WT) controls (n = 6) (*, main effect of tone versus baseline F1,12 = 48.6, p < 0.0001; no other significant effects). (C) A tone that coterminated with a shock only 50% of the time (ambiguous) increased freezing in both WT (n = 7) and TK mice (n = 9; main effect of tone, F1,14 = 55.9, p < 0.0001; post hoc tests show tone greater than baseline, p < 0.005, in both genotypes). However, the tone increased freezing more in WT mice relative to TK mice (tone x genotype interaction, F1,14 = 5.0, p = 0.04; †, post hoc testing indicates p < 0.05 for TK versus WT freezing during the tone). (D) Freezing responses to the reliably predictive tone cue (averaged across six trials for each session) were virtually identical in WT (n = 7) and TK (n = 8) mice during all extinction days. (E) After reliable cue training with a weak shock (0.3 mA compared to 0.5 mA in earlier experiments), WT (n = 11) and TK (n = 13) mice showed increased freezing to the tone (main effect of tone F1,22 = 13.7, p = .001) but equivalent freezing across genotype (main effect of genotype F1,22 = 0.007, p = .93), suggesting equivalent learning with reliable cues even with a weaker shock training protocol. (F) After fear conditioning, a reliable tone cue increased the startle response similarly in mice of both genotypes (*, main effect of tone F1,20 = 4.7, p = 0.04, main effect of genotype F1,20 = 0.016, p = .94; n = 11 for both groups). (G) An ambiguous cue increased startle in WT mice (n = 11) but not TK mice (n = 10) (tone x genotype interaction F1,19 = 4.5, p = 0.047; †, post hoc testing indicates p < 0.05 versus WT at the same time point). Data are represented as mean ± standard error of the mean (SEM). The numerical data used in all figures can be found in S1 Data.
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Related In: Results  -  Collection

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pbio.2001154.g001: Behavioral response to ambiguous conditioned fear cues is decreased in adult neurogenesis-deficient mice.(A) Examples of conditioned fear training and testing protocols. (B) In a cued fear conditioning task, a perfectly predictive tone cue (Reliable) elicited similar freezing in transgenic (TK) mice (n = 8), which lack adult neurogenesis, and wild-type (WT) controls (n = 6) (*, main effect of tone versus baseline F1,12 = 48.6, p < 0.0001; no other significant effects). (C) A tone that coterminated with a shock only 50% of the time (ambiguous) increased freezing in both WT (n = 7) and TK mice (n = 9; main effect of tone, F1,14 = 55.9, p < 0.0001; post hoc tests show tone greater than baseline, p < 0.005, in both genotypes). However, the tone increased freezing more in WT mice relative to TK mice (tone x genotype interaction, F1,14 = 5.0, p = 0.04; †, post hoc testing indicates p < 0.05 for TK versus WT freezing during the tone). (D) Freezing responses to the reliably predictive tone cue (averaged across six trials for each session) were virtually identical in WT (n = 7) and TK (n = 8) mice during all extinction days. (E) After reliable cue training with a weak shock (0.3 mA compared to 0.5 mA in earlier experiments), WT (n = 11) and TK (n = 13) mice showed increased freezing to the tone (main effect of tone F1,22 = 13.7, p = .001) but equivalent freezing across genotype (main effect of genotype F1,22 = 0.007, p = .93), suggesting equivalent learning with reliable cues even with a weaker shock training protocol. (F) After fear conditioning, a reliable tone cue increased the startle response similarly in mice of both genotypes (*, main effect of tone F1,20 = 4.7, p = 0.04, main effect of genotype F1,20 = 0.016, p = .94; n = 11 for both groups). (G) An ambiguous cue increased startle in WT mice (n = 11) but not TK mice (n = 10) (tone x genotype interaction F1,19 = 4.5, p = 0.047; †, post hoc testing indicates p < 0.05 versus WT at the same time point). Data are represented as mean ± standard error of the mean (SEM). The numerical data used in all figures can be found in S1 Data.
Mentions: To specifically eliminate adult neurogenesis, we treated 8-wk-old mice expressing herpes thymidine kinase in neuronal precursors with the antiviral drug valganciclovir, which inhibits adult neurogenesis without affecting mature neurons or astrocytes [9]. As expected, adult neurogenesis was virtually eliminated in the dentate gyrus (S1 Fig). Mice lacking adult neurogenesis (TK mice) and WT littermate controls (WT mice) were trained in a 3-day cued fear conditioning paradigm (Fig 1A). In a between-subjects design, half of the mice of each genotype were exposed to a tone cue that always coterminated with a shock (reliable fear conditioning), while the other half were exposed to a tone cue that coterminated with a shock only 50% of the time (ambiguous fear conditioning). Different groups of mice were used for the two cue conditions in order to avoid potential overshadowing or interference between the cues [24,25]. TK mice were indistinguishable from WT controls in response to the reliable cue (Figs 1B and S2), consistent with previous studies [7,20,21,26,27]. However, the TK mice trained with the ambiguous cue showed significantly less cue-induced freezing than their WT counterparts (Figs 1C and S2).

View Article: PubMed Central - PubMed

ABSTRACT

Fear learning is highly adaptive if utilized in appropriate situations but can lead to generalized anxiety if applied too widely. A role of predictive cues in inhibiting fear generalization has been suggested by stress and fear learning studies, but the effects of partially predictive cues (ambiguous cues) and the neuronal populations responsible for linking the predictive ability of cues and generalization of fear responses are unknown. Here, we show that inhibition of adult neurogenesis in the mouse dentate gyrus decreases hippocampal network activation and reduces defensive behavior to ambiguous threat cues but has neither of these effects if the same negative experience is reliably predicted. Additionally, we find that this ambiguity related to negative events determines their effect on fear generalization, that is, how the events affect future behavior under novel conditions. Both new neurons and glucocorticoid hormones are required for the enhancement of fear generalization following an unpredictably cued threat. Thus, adult neurogenesis plays a central role in the adaptive changes resulting from experience involving unpredictable or ambiguous threat cues, optimizing behavior in novel and uncertain situations.

No MeSH data available.


Related in: MedlinePlus