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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 exposure to contexts A and B, 24 h prior to fear conditioning. (B) Animals injected with MS-275 (N = 13) in the dorsal hippocampus after contextual pre-exposure (bl A, bl B) exhibited enhanced fear learning in context A and elevated freezing in context B 24 h after conditioning in comparison to the vehicle-injected controls (N = 16). However, freezing was significantly higher in context A, the conditioning context, than in the neutral context B, indicating that these animals still discriminated between the environments. (C) Animals injected with MS-275 in the dorsal hippocampus exhibited a significantly greater percent change in freezing 24 h post-conditioning in context A and a trend toward enhanced freezing in context B relative to baseline freezing in each of these contexts in comparison to controls. (D) Animals injected with MS-275 (N = 17) in the ventral hippocampus after contextual pre-exposure exhibited fear generalization without showing enhanced fear learning 24 h after conditioning; This generalization effect was not observed in control animals injected with vehicle (N = 15). (E) Animals injected with MS-275 in the ventral hippocampus exhibit significantly greater percent change in freezing 24 h post-conditioning in context B relative to baseline in that context in comparison to vehicle-injected controls. No difference in percent change in freezing was observed in the training context A between the MS-275 and vehicle control animals. Means ± SEM are shown, *p < 0.05, #p < 0.09.
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Figure 2: (A) Schematic representation of behavioral paradigm and timing of injections. Animals were injected with MS-275 or vehicle immediately following exposure to contexts A and B, 24 h prior to fear conditioning. (B) Animals injected with MS-275 (N = 13) in the dorsal hippocampus after contextual pre-exposure (bl A, bl B) exhibited enhanced fear learning in context A and elevated freezing in context B 24 h after conditioning in comparison to the vehicle-injected controls (N = 16). However, freezing was significantly higher in context A, the conditioning context, than in the neutral context B, indicating that these animals still discriminated between the environments. (C) Animals injected with MS-275 in the dorsal hippocampus exhibited a significantly greater percent change in freezing 24 h post-conditioning in context A and a trend toward enhanced freezing in context B relative to baseline freezing in each of these contexts in comparison to controls. (D) Animals injected with MS-275 (N = 17) in the ventral hippocampus after contextual pre-exposure exhibited fear generalization without showing enhanced fear learning 24 h after conditioning; This generalization effect was not observed in control animals injected with vehicle (N = 15). (E) Animals injected with MS-275 in the ventral hippocampus exhibit significantly greater percent change in freezing 24 h post-conditioning in context B relative to baseline in that context in comparison to vehicle-injected controls. No difference in percent change in freezing was observed in the training context A between the MS-275 and vehicle control animals. Means ± SEM are shown, *p < 0.05, #p < 0.09.

Mentions: To determine the role of histone acetylation during the formation of a representation of context, MS-275 or vehicle (DMSO, 4%) was injected in either the dorsal or ventral hippocampus after exposure to the training context (baseline context A) and a neutral context (baseline context B) on Day 1 (pre-conditioning injections). Twenty-four hours after the injections (Day 2), these groups were conditioned and tested 1 h after conditioning in the training context A. On day 3, the four groups were retested in the training (A) and neutral (B) context 24 h after conditioning (long-term retrieval test; see Figure 2A). The order of exposure to context A and B during baseline and the 24 h retrieval tests was counterbalanced across animals.


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 exposure to contexts A and B, 24 h prior to fear conditioning. (B) Animals injected with MS-275 (N = 13) in the dorsal hippocampus after contextual pre-exposure (bl A, bl B) exhibited enhanced fear learning in context A and elevated freezing in context B 24 h after conditioning in comparison to the vehicle-injected controls (N = 16). However, freezing was significantly higher in context A, the conditioning context, than in the neutral context B, indicating that these animals still discriminated between the environments. (C) Animals injected with MS-275 in the dorsal hippocampus exhibited a significantly greater percent change in freezing 24 h post-conditioning in context A and a trend toward enhanced freezing in context B relative to baseline freezing in each of these contexts in comparison to controls. (D) Animals injected with MS-275 (N = 17) in the ventral hippocampus after contextual pre-exposure exhibited fear generalization without showing enhanced fear learning 24 h after conditioning; This generalization effect was not observed in control animals injected with vehicle (N = 15). (E) Animals injected with MS-275 in the ventral hippocampus exhibit significantly greater percent change in freezing 24 h post-conditioning in context B relative to baseline in that context in comparison to vehicle-injected controls. No difference in percent change in freezing was observed in the training context A between the MS-275 and vehicle control animals. Means ± SEM are shown, *p < 0.05, #p < 0.09.
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Figure 2: (A) Schematic representation of behavioral paradigm and timing of injections. Animals were injected with MS-275 or vehicle immediately following exposure to contexts A and B, 24 h prior to fear conditioning. (B) Animals injected with MS-275 (N = 13) in the dorsal hippocampus after contextual pre-exposure (bl A, bl B) exhibited enhanced fear learning in context A and elevated freezing in context B 24 h after conditioning in comparison to the vehicle-injected controls (N = 16). However, freezing was significantly higher in context A, the conditioning context, than in the neutral context B, indicating that these animals still discriminated between the environments. (C) Animals injected with MS-275 in the dorsal hippocampus exhibited a significantly greater percent change in freezing 24 h post-conditioning in context A and a trend toward enhanced freezing in context B relative to baseline freezing in each of these contexts in comparison to controls. (D) Animals injected with MS-275 (N = 17) in the ventral hippocampus after contextual pre-exposure exhibited fear generalization without showing enhanced fear learning 24 h after conditioning; This generalization effect was not observed in control animals injected with vehicle (N = 15). (E) Animals injected with MS-275 in the ventral hippocampus exhibit significantly greater percent change in freezing 24 h post-conditioning in context B relative to baseline in that context in comparison to vehicle-injected controls. No difference in percent change in freezing was observed in the training context A between the MS-275 and vehicle control animals. Means ± SEM are shown, *p < 0.05, #p < 0.09.
Mentions: To determine the role of histone acetylation during the formation of a representation of context, MS-275 or vehicle (DMSO, 4%) was injected in either the dorsal or ventral hippocampus after exposure to the training context (baseline context A) and a neutral context (baseline context B) on Day 1 (pre-conditioning injections). Twenty-four hours after the injections (Day 2), these groups were conditioned and tested 1 h after conditioning in the training context A. On day 3, the four groups were retested in the training (A) and neutral (B) context 24 h after conditioning (long-term retrieval test; see Figure 2A). The order of exposure to context A and B during baseline and the 24 h retrieval tests was counterbalanced across animals.

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