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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,B) Photomicrograph of Nissl-stained coronal section showing position of dorsal (A) and ventral (B) guide cannulas. Note that internal cannulas for dorsal injections project an additional 0.7 mm beyond guide cannulas, and internal cannulas for ventral injections project an additional 1.5 mm beyond guide cannulas. Blue arrows indicate estimated injection depth. (C–H) Animals injected with MS-275 or vehicle in either the dorsal or ventral hippocampus showed no significant differences in tests of anxiety. (C–F) Animals injected with MS-275 (dorsal: N = 20; ventral: N = 14) or vehicle (dorsal: N = 21; ventral: N = 20) showed no significant differences in behavior in the open field test. This was evident in the percentage of time spent in the center, inner ring, and outer ring of an open field in the dorsal (C) and ventral (D) groups, as well as the level of freezing observed in the open field in the dorsal (E) and ventral (F) groups. (G,H) Animals injected with MS-275 (dorsal: N = 12; ventral: N = 11) or vehicle (dorsal: N = 12; ventral: N = 11) in the dorsal (G) or ventral (H) hippocampus showed no significant difference in the percentage of time they spent in the white compartment of the black/white box. Means ± SEM are shown.
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Figure 1: (A,B) Photomicrograph of Nissl-stained coronal section showing position of dorsal (A) and ventral (B) guide cannulas. Note that internal cannulas for dorsal injections project an additional 0.7 mm beyond guide cannulas, and internal cannulas for ventral injections project an additional 1.5 mm beyond guide cannulas. Blue arrows indicate estimated injection depth. (C–H) Animals injected with MS-275 or vehicle in either the dorsal or ventral hippocampus showed no significant differences in tests of anxiety. (C–F) Animals injected with MS-275 (dorsal: N = 20; ventral: N = 14) or vehicle (dorsal: N = 21; ventral: N = 20) showed no significant differences in behavior in the open field test. This was evident in the percentage of time spent in the center, inner ring, and outer ring of an open field in the dorsal (C) and ventral (D) groups, as well as the level of freezing observed in the open field in the dorsal (E) and ventral (F) groups. (G,H) Animals injected with MS-275 (dorsal: N = 12; ventral: N = 11) or vehicle (dorsal: N = 12; ventral: N = 11) in the dorsal (G) or ventral (H) hippocampus showed no significant difference in the percentage of time they spent in the white compartment of the black/white box. Means ± SEM are shown.

Mentions: Since we wanted to establish the effects of HDAC inhibition on fear learning, we first investigated whether MS-275 had any effects on innate anxiety. We performed bilateral injections of MS-275 or vehicle into the dorsal or ventral hippocampus of animals 2–3 h prior to behavioral testing in the open field and the black/white box (Figures 1A,B). The open field test, which consists of free exploration in a large arena, evaluates the anxiety that rodents exhibit in open spaces. It is well established that rodents find the inner areas of the open field more anxiogenic than the outer areas (Hall, 1934; Prut and Belzung, 2003). Thus, differences in the amount of time spent in these areas normally reflect distinct levels of anxiety. Thirty-four animals were injected with MS-275 (dorsal: N = 20; ventral: N = 14), and 41 animals were injected with vehicle (dorsal: N = 21; ventral: N = 20). We divided the open field in three concentric areas and calculated the time spent in each of these zones. We did not find any differences between the groups in the percentage of time spent in the three concentric regions comprising the open field (Figures 1C,D; dorsal: center: p = 0.80, inner: p = 0.36, outer: p = 0.62; ventral: center: p = 0.57, inner: p = 0.30, outer: p = 0.46). Additionally, we did not find differences in the levels of freezing in the open field (Figures 1E,F; dorsal: p = 0.45; ventral: p = 0.66).


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,B) Photomicrograph of Nissl-stained coronal section showing position of dorsal (A) and ventral (B) guide cannulas. Note that internal cannulas for dorsal injections project an additional 0.7 mm beyond guide cannulas, and internal cannulas for ventral injections project an additional 1.5 mm beyond guide cannulas. Blue arrows indicate estimated injection depth. (C–H) Animals injected with MS-275 or vehicle in either the dorsal or ventral hippocampus showed no significant differences in tests of anxiety. (C–F) Animals injected with MS-275 (dorsal: N = 20; ventral: N = 14) or vehicle (dorsal: N = 21; ventral: N = 20) showed no significant differences in behavior in the open field test. This was evident in the percentage of time spent in the center, inner ring, and outer ring of an open field in the dorsal (C) and ventral (D) groups, as well as the level of freezing observed in the open field in the dorsal (E) and ventral (F) groups. (G,H) Animals injected with MS-275 (dorsal: N = 12; ventral: N = 11) or vehicle (dorsal: N = 12; ventral: N = 11) in the dorsal (G) or ventral (H) hippocampus showed no significant difference in the percentage of time they spent in the white compartment of the black/white box. Means ± SEM are shown.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4585269&req=5

Figure 1: (A,B) Photomicrograph of Nissl-stained coronal section showing position of dorsal (A) and ventral (B) guide cannulas. Note that internal cannulas for dorsal injections project an additional 0.7 mm beyond guide cannulas, and internal cannulas for ventral injections project an additional 1.5 mm beyond guide cannulas. Blue arrows indicate estimated injection depth. (C–H) Animals injected with MS-275 or vehicle in either the dorsal or ventral hippocampus showed no significant differences in tests of anxiety. (C–F) Animals injected with MS-275 (dorsal: N = 20; ventral: N = 14) or vehicle (dorsal: N = 21; ventral: N = 20) showed no significant differences in behavior in the open field test. This was evident in the percentage of time spent in the center, inner ring, and outer ring of an open field in the dorsal (C) and ventral (D) groups, as well as the level of freezing observed in the open field in the dorsal (E) and ventral (F) groups. (G,H) Animals injected with MS-275 (dorsal: N = 12; ventral: N = 11) or vehicle (dorsal: N = 12; ventral: N = 11) in the dorsal (G) or ventral (H) hippocampus showed no significant difference in the percentage of time they spent in the white compartment of the black/white box. Means ± SEM are shown.
Mentions: Since we wanted to establish the effects of HDAC inhibition on fear learning, we first investigated whether MS-275 had any effects on innate anxiety. We performed bilateral injections of MS-275 or vehicle into the dorsal or ventral hippocampus of animals 2–3 h prior to behavioral testing in the open field and the black/white box (Figures 1A,B). The open field test, which consists of free exploration in a large arena, evaluates the anxiety that rodents exhibit in open spaces. It is well established that rodents find the inner areas of the open field more anxiogenic than the outer areas (Hall, 1934; Prut and Belzung, 2003). Thus, differences in the amount of time spent in these areas normally reflect distinct levels of anxiety. Thirty-four animals were injected with MS-275 (dorsal: N = 20; ventral: N = 14), and 41 animals were injected with vehicle (dorsal: N = 21; ventral: N = 20). We divided the open field in three concentric areas and calculated the time spent in each of these zones. We did not find any differences between the groups in the percentage of time spent in the three concentric regions comprising the open field (Figures 1C,D; dorsal: center: p = 0.80, inner: p = 0.36, outer: p = 0.62; ventral: center: p = 0.57, inner: p = 0.30, outer: p = 0.46). Additionally, we did not find differences in the levels of freezing in the open field (Figures 1E,F; dorsal: p = 0.45; ventral: p = 0.66).

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