Social fear conditioning: a novel and specific animal model to study social anxiety disorder

Abstract

Social anxiety disorder (SAD) is a major health concern with high lifetime prevalence. The current medication is rather unspecific and, despite considerable efforts, its efficacy is still unsatisfactory. However, there are no appropriate and specific animal models available to study the underlying etiology of the disorder. Therefore, we aimed to establish a model of specific social fear in mice and use this social fear conditioning (SFC) model to assess the therapeutic efficacy of the benzodiazepine diazepam and of the antidepressant paroxetine; treatments currently used for SAD patients. We show that by administering electric foot shocks (2-5, 1 s, 0.7 mA) during the investigation of a con-specific, the investigation of unfamiliar con-specifics was reduced for both the short- and long-term, indicating lasting social fear. The induced fear was specific to social stimuli and did not lead to other behavioral alterations, such as fear of novelty, general anxiety, depression, and impaired locomotion. We show that social fear was dose-dependently reversed by acute diazepam, at doses that were not anxiolytic in a non-social context, such as the elevated plus maze. Finally, we show that chronic paroxetine treatment reversed social fear. All in all, we demonstrated robust social fear after exposure to SFC in mice, which was reversed with both acute benzodiazepine and chronic antidepressant treatment. We propose the SFC model as an appropriate animal model to identify the underlying etiology of SAD and possible novel treatment approaches.

Figure 1

Social fear conditioning (SFC) induces short-term social fear in mice. (a) Pre-conditioning investigation of the non-social stimulus (empty cage) by unconditioned (uc) and conditioned (c) mice during SFC (day 1; n=13 per group). (b) Investigation of non-social (ns1–ns3) and social (cages with mice; s1–s6) stimuli during extinction on day 2 (3-min exposure to stimulus, 3-min inter-exposure interval). (c) Investigation of social stimuli (s1–s6) during extinction recall on day 3. Data represent mean percentage of investigation time±SEM. ^*p<0.05 vs uc mice.

Figure 2

Social fear conditioning (SFC) induces long-term social fear in mice. (a) Pre-conditioning investigation of the non-social stimulus (empty cage) by unconditioned (uc) and conditioned (c) mice during SFC (day 1; n=9 per group). (b) Investigation of non-social (ns1–ns3) and social (cages with mice; s1–s6) stimuli during extinction on day 15 (3-min exposure to stimulus, 3-min inter-exposure interval). (c) Investigation of social stimuli (s1–s6) during extinction recall on day 16. Data represent mean percentage of investigation time±SEM. ^*p<0.05 vs uc mice.

Figure 3

No effect of social fear conditioning (SFC) on general anxiety on the elevated plus maze (EPM) (a), depressive-like behavior in the forced swim test (b), and locomotor activity on the EPM (c) and in the home cage (d). Data represent means±SEM for n=7 to 8 mice (separate groups). c, conditioned; uc, unconditioned.

Figure 4

Social fear conditioning (SFC) does not induce fear of novelty. (a) Pre-conditioning investigation of the non-social stimulus (empty cage) by unconditioned (uc) and conditioned (c) mice during SFC (day 1; n=8 per group). (b) Investigation of non-social stimuli (ns1–ns3), novel object stimuli (cages with objects; no1–no3), and social stimuli (cages with mice; s1–s6) during novel object investigation on day 2 (3-min exposure to stimulus, 3-min inter-exposure interval). Data represent mean percentage of investigation time±SEM. ^*p<0.05 vs uc mice.

Figure 5

Exposure to five electric foot shocks in the absence of a social stimulus does not induce social fear. Investigation of non-social (empty cages; ns1–ns3) and social (cages with mice; s1–s6) stimuli by non-shocked and shocked mice (n=8 per group) during extinction 1 day after foot-shock exposure (3-min exposure to stimulus, 3-min inter-exposure interval). Data represent mean percentage of investigation time±SEM.

Figure 6

Acute diazepam treatment reverses short-term social fear. (a) Pre-conditioning investigation of the non-social stimulus (empty cage) during social fear conditioning (day 1; n=10 per group). (b) Investigation of non-social (ns1–ns3) and social (cages with mice; s1–s6) stimuli during extinction on day 2 (3-min exposure to stimulus, 3-min inter-exposure interval). Unconditioned (uc) and conditioned (c) mice were injected intraperitoneally either with vehicle (Veh; 5 ml/kg saline) or with diazepam (Dia; 0.5 mg/kg) 30 min before extinction. (c) Investigation of social stimuli (s1–s6) during extinction recall on day 3. Data represent mean percentage of investigation time±SEM. ^*p<0.05 vs the other three groups.

Figure 7

Chronic paroxetine treatment reverses long-term social fear. (a) Pre-conditioning investigation of the non-social stimulus (empty cage) during social fear conditioning (SFC; day 1; n=8 per group). Paroxetine (Par) was administered over 14 days in the drinking water (Veh) of unconditioned (uc) and conditioned (c) mice starting 1 day after SFC. (b) Investigation of non-social (ns1–ns3) and social (cages with mice; s1–s6) stimuli during extinction on day 15 (3-min exposure to stimulus, 3-min inter-exposure interval). (c) Investigation of social stimuli (s1–s6) during extinction recall on day 16. Data represent mean percentage of investigation time±SEM. ^*p<0.05 vs the other three groups.