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HDAC I inhibition in the dorsal and ventral hippocampus differentially modulates predator-odor fear learning and generalization.

Yuan RK, Hebert JC, Thomas AS, Wann EG, Muzzio IA - Front Neurosci (2015)

Bottom Line: Inhibition of histone deacetylases (HDACs) in the dorsal hippocampus has been shown to enhance shock-induced contextual fear learning, but it is unknown if HDACs have differential effects along the dorso-ventral hippocampal axis during predator odor fear learning.Conversely, ventrally injected animals did not display enhanced learning in the training context but generalized the fear response to a neutral context.These results may elucidate distinct functions of the dorsal and ventral hippocampus in predator odor-induced fear conditioning as well as some of the molecular mechanisms underlying fear generalization.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of Pennsylvania Philadelphia, PA, USA.

ABSTRACT
Although predator odors are ethologically relevant stimuli for rodents, the molecular pathways and contribution of some brain regions involved in predator odor conditioning remain elusive. Inhibition of histone deacetylases (HDACs) in the dorsal hippocampus has been shown to enhance shock-induced contextual fear learning, but it is unknown if HDACs have differential effects along the dorso-ventral hippocampal axis during predator odor fear learning. We injected MS-275, a class I HDAC inhibitor, bilaterally in the dorsal or ventral hippocampus of mice and found that it had no effects on innate anxiety in either region. We then assessed the effects of MS-275 at different stages of fear learning along the longitudinal hippocampal axis. Animals were injected with MS-275 or vehicle after context pre-exposure (pre-conditioning injections), when a representation of the context is first formed, or after exposure to coyote urine (post-conditioning injections), when the context becomes associated with predator odor. When MS-275 was administered after context pre-exposure, dorsally injected animals showed enhanced fear in the training context but were able to discriminate it from a neutral environment. Conversely, ventrally injected animals did not display enhanced learning in the training context but generalized the fear response to a neutral context. However, when MS-275 was administered after conditioning, there were no differences between the MS-275 and vehicle control groups in either the dorsal or ventral hippocampus. Surprisingly, all groups displayed generalization to a neutral context, suggesting that predator odor exposure followed by a mild stressor such as restraint leads to fear generalization. These results may elucidate distinct functions of the dorsal and ventral hippocampus in predator odor-induced fear conditioning as well as some of the molecular mechanisms underlying fear generalization.

No MeSH data available.


Related in: MedlinePlus

(A) Schematic representation of behavioral paradigm and timing of injections. Animals were injected with MS-275 or vehicle immediately following fear conditioning in context A. Animals injected in the dorsal (B; MS-275: N = 11, vehicle: N = 11) or ventral (C; MS-275: N = 13, vehicle: N = 14) hippocampus after the conditioning session exhibited fear generalization 24 h after conditioning. Means ± SEM are shown, *p < 0.05.
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Figure 3: (A) Schematic representation of behavioral paradigm and timing of injections. Animals were injected with MS-275 or vehicle immediately following fear conditioning in context A. Animals injected in the dorsal (B; MS-275: N = 11, vehicle: N = 11) or ventral (C; MS-275: N = 13, vehicle: N = 14) hippocampus after the conditioning session exhibited fear generalization 24 h after conditioning. Means ± SEM are shown, *p < 0.05.

Mentions: To determine the role of histone acetylation along the longitudinal hippocampal axis after coyote exposure, we then examined groups of mice injected with MS-275 or vehicle (DMSO, 4%) after conditioning (see Figure 3A). The amygdala has been identified as a critical brain region for the associative phase of predator odor fear learning (for review, see Takahashi et al., 2008). In particular, it has been demonstrated that the medial amygdala plays a role during acquisition (Blanchard et al., 2005; Takahashi et al., 2007) and the basolateral amygdala during consolidation (Takahashi et al., 2007). Since the dorsal hippocampus receives very few projections from the basolateral amygdala and no projections from the medial amygdala, the area where olfactory information converges (Pikkarainen et al., 1999), we hypothesized that dorsal injections of MS-275 would not affect predator odor fear learning. Conversely, the ventral hippocampus receives strong projections from the posterior, medial, and basolateral amygdala (Pitkanen et al., 2000; Kemppainen et al., 2002) as well as structures associated with the hypothalamic-pituitary adrenal axis (Witter, 1986), which suggests that the ventral hippocampus may also be involved in processing anxiety and fear. However, since we did not observe any effects of MS-275 on anxiety measures in the ventral region, we hypothesized that HDAC I inhibition after conditioning would not have an effect on the conditioning phase in the ventral hippocampus.


HDAC I inhibition in the dorsal and ventral hippocampus differentially modulates predator-odor fear learning and generalization.

Yuan RK, Hebert JC, Thomas AS, Wann EG, Muzzio IA - Front Neurosci (2015)

(A) Schematic representation of behavioral paradigm and timing of injections. Animals were injected with MS-275 or vehicle immediately following fear conditioning in context A. Animals injected in the dorsal (B; MS-275: N = 11, vehicle: N = 11) or ventral (C; MS-275: N = 13, vehicle: N = 14) hippocampus after the conditioning session exhibited fear generalization 24 h after conditioning. Means ± SEM are shown, *p < 0.05.
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Figure 3: (A) Schematic representation of behavioral paradigm and timing of injections. Animals were injected with MS-275 or vehicle immediately following fear conditioning in context A. Animals injected in the dorsal (B; MS-275: N = 11, vehicle: N = 11) or ventral (C; MS-275: N = 13, vehicle: N = 14) hippocampus after the conditioning session exhibited fear generalization 24 h after conditioning. Means ± SEM are shown, *p < 0.05.
Mentions: To determine the role of histone acetylation along the longitudinal hippocampal axis after coyote exposure, we then examined groups of mice injected with MS-275 or vehicle (DMSO, 4%) after conditioning (see Figure 3A). The amygdala has been identified as a critical brain region for the associative phase of predator odor fear learning (for review, see Takahashi et al., 2008). In particular, it has been demonstrated that the medial amygdala plays a role during acquisition (Blanchard et al., 2005; Takahashi et al., 2007) and the basolateral amygdala during consolidation (Takahashi et al., 2007). Since the dorsal hippocampus receives very few projections from the basolateral amygdala and no projections from the medial amygdala, the area where olfactory information converges (Pikkarainen et al., 1999), we hypothesized that dorsal injections of MS-275 would not affect predator odor fear learning. Conversely, the ventral hippocampus receives strong projections from the posterior, medial, and basolateral amygdala (Pitkanen et al., 2000; Kemppainen et al., 2002) as well as structures associated with the hypothalamic-pituitary adrenal axis (Witter, 1986), which suggests that the ventral hippocampus may also be involved in processing anxiety and fear. However, since we did not observe any effects of MS-275 on anxiety measures in the ventral region, we hypothesized that HDAC I inhibition after conditioning would not have an effect on the conditioning phase in the ventral hippocampus.

Bottom Line: Inhibition of histone deacetylases (HDACs) in the dorsal hippocampus has been shown to enhance shock-induced contextual fear learning, but it is unknown if HDACs have differential effects along the dorso-ventral hippocampal axis during predator odor fear learning.Conversely, ventrally injected animals did not display enhanced learning in the training context but generalized the fear response to a neutral context.These results may elucidate distinct functions of the dorsal and ventral hippocampus in predator odor-induced fear conditioning as well as some of the molecular mechanisms underlying fear generalization.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of Pennsylvania Philadelphia, PA, USA.

ABSTRACT
Although predator odors are ethologically relevant stimuli for rodents, the molecular pathways and contribution of some brain regions involved in predator odor conditioning remain elusive. Inhibition of histone deacetylases (HDACs) in the dorsal hippocampus has been shown to enhance shock-induced contextual fear learning, but it is unknown if HDACs have differential effects along the dorso-ventral hippocampal axis during predator odor fear learning. We injected MS-275, a class I HDAC inhibitor, bilaterally in the dorsal or ventral hippocampus of mice and found that it had no effects on innate anxiety in either region. We then assessed the effects of MS-275 at different stages of fear learning along the longitudinal hippocampal axis. Animals were injected with MS-275 or vehicle after context pre-exposure (pre-conditioning injections), when a representation of the context is first formed, or after exposure to coyote urine (post-conditioning injections), when the context becomes associated with predator odor. When MS-275 was administered after context pre-exposure, dorsally injected animals showed enhanced fear in the training context but were able to discriminate it from a neutral environment. Conversely, ventrally injected animals did not display enhanced learning in the training context but generalized the fear response to a neutral context. However, when MS-275 was administered after conditioning, there were no differences between the MS-275 and vehicle control groups in either the dorsal or ventral hippocampus. Surprisingly, all groups displayed generalization to a neutral context, suggesting that predator odor exposure followed by a mild stressor such as restraint leads to fear generalization. These results may elucidate distinct functions of the dorsal and ventral hippocampus in predator odor-induced fear conditioning as well as some of the molecular mechanisms underlying fear generalization.

No MeSH data available.


Related in: MedlinePlus