Enhanced fear expression in a psychopathological mouse model of trait anxiety: pharmacological interventions.

Simone B Sartori,Markus Hauschild,Mirjam Bunck,Stefano Gaburro,Nicolas Singewald,Rainer Landgraf,Abraham Palmer

doi:10.1371/journal.pone.0016849

Simone B Sartori, Markus Hauschild + Show 5 more

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https://doi.org/10.1371/journal.pone.0016849

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Abstract

The propensity to develop an anxiety disorder is thought to be determined by genetic and environmental factors. Here we investigated the relationship between a genetic predisposition to trait anxiety and experience-based learned fear in a psychopathological mouse model. Male CD-1 mice selectively bred for either high (HAB), or normal (NAB) anxiety-related behaviour on the elevated plus maze were subjected to classical fear conditioning. During conditioning both mouse lines showed increased fear responses as assessed by freezing behaviour. However, 24 h later, HAB mice displayed more pronounced conditioned responses to both a contextual or cued stimulus when compared with NAB mice. Interestingly, 6 h and already 1 h after fear conditioning, freezing levels were high in HAB mice but not in NAB mice. These results suggest that trait anxiety determines stronger fear memory and/or a weaker ability to inhibit fear responses in the HAB line. The enhanced fear response of HAB mice was attenuated by treatment with either the α2,3,5-subunit selective benzodiazepine partial agonist L-838,417, corticosterone or the selective neurokinin-1 receptor antagonist L-822,429. Overall, the HAB mouse line may represent an interesting model (i) for identifying biological factors underlying misguided conditioned fear responses and (ii) for studying novel anxiolytic pharmacotherapies for patients with fear-associated disorders, including post-traumatic stress disorder and phobias.

Highlights

Fear is a phasic, apprehensive arousal to an explicit threat of an aversive stimulus dissociable from a long-term state of anxiety [1]
Fear conditioning When animals were placed into the conditioning chamber for fear conditioning (Figures 1A and 2A) or into an empty mouse cage for cued fear expression (Figures 2B and D), the freezing behaviour was negligible in both high innate anxiety-related behaviour (HAB) and NAB lines (,3%) indicating that there was no contextual fear component in cued auditory fear expression
Upon repeated unconditioned stimulus (US) presentations conditioned responses as indicated by freezing behaviour increased to the same extent in both the HAB and NAB lines, reaching a maximum of approximately 54% freezing (Figure 1A). 24 h later, when animals were re-exposed to the conditioning context for 3 min, freezing levels were elevated in HAB mice compared with NAB mice (t = 3.793, df = 17, p = 0.002; Figure 1B)

Summary

Introduction

Apprehensive arousal to an explicit threat of an aversive stimulus dissociable from a long-term state of anxiety [1]. Though not all, the experience of an aversive situation that elicits extreme fear may cause a prolonged and/or inappropriate response which even persists after withdrawal of the stimulus. Such subjects develop a pathological form of anxiety including post-traumatic stress disorder (PTSD) or phobia [3,4,5]. What it is that determines either resilience or the propensity to developing an anxiety disorder is thought to result from a combination of biological factors that are heritable and diverse learning experiences gained in early life [6,7]. Trait anxiety is considered to be a major risk factor for anxiety disorders [8] as well as depression [9]

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