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.
Highlights
We recently found that spatial representations formed in the dorsal hippocampus after predator odor fear conditioning are stable in the long term (Wang et al, 2012) but become unstable again during extinction (Wang et al, 2015), suggesting that predator odor learning alters the stability of the dorsal hippocampal representation of context
MS-275 has No Effect on Innate Anxiety Since we wanted to establish the effects of histone deacetylases (HDACs) inhibition on fear learning, we first investigated whether MS-275 had any effects on innate anxiety
While vehicle control animals clearly discriminated between the contexts (t16 = 2.36, p = 0.03), MS-275 animals showed no difference in freezing in context A and B (t19 = 0.08, p = 0.94). These results suggest that HDAC I inhibition in the dorsal and ventral hippocampus plays different roles in predator odor fear memory
Summary
Predator odors are ethologically relevant stimuli that have been shown to elicit a variety of defensive responses in rodents (Blanchard and Blanchard, 1990; Zangrossi and File, 1992; Wallace and Rosen, 2000; Dielenberg and McGregor, 2001; Wang et al, 2013a), and, under some conditions, can produce conditioning (Blanchard et al, 2001; Dielenberg et al, 2001; Takahashi et al, 2008). We have recently developed and characterized a predator odor fear conditioning paradigm using coyote urine that is effective with mice. We showed that this paradigm produces moderate but consistent freezing, a stereotypic response to fear observed in rodents, during long-term retrieval tests. This response is not observed when animals are exposed to water (no odor) or an aversive non-fearful odor (2-methyl butyric acid), indicating that the freezing is a result of associative learning (Wang et al, 2013a, 2015). The conditioned fear response is context specific since freezing is observed only in the training context, and it requires both the dorsal and ventral hippocampus (Wang et al, 2013a)
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