Social buffering during fear extinction rescues long-term trauma-induced memory and emotional behavioral alterations in rats

Abstract

Post-Traumatic Stress Disorder (PTSD) is a psychiatric disease that may develop after experiencing a traumatic event and it is characterized by resistance to extinction of the traumatic memory. Psychotherapy, which mainly focuses on favoring fear memory extinction, represents the first-line treatment for PTSD. However, this approach is not always successful. Emerging evidence suggests the importance of a social support in alleviating PTSD symptomatology; however, the efficacy of group therapy for PTSD remains controversial. Here, we evaluated the impact of social support on the efficacy of fear extinction sessions in a chronic PTSD-like rat model. We tested the hypothesis that the presence of a social partner during temporally spaced extinction sessions (to mimic the presence of a social support during therapy) or after the extinction sessions in a neutral environment (to mimic the presence of a social support outside of the therapy setting) would ameliorate long-term PTSD-like symptomatology. Extinction sessions were carried out under different conditions: (i) alone; (ii) with a social partner never exposed to the trauma; (iii) with a trauma-exposed partner. In a separate set of experiments, rats were exposed to the extinction sessions alone and, immediately thereafter, paired with a social partner, as indicated above, in a different context. Extinction sessions carried out in the presence of a social partner never exposed to the traumatic experience rescued long-term trauma-induced PTSD-like symptomatology. We provide evidence of beneficial effects of a "healthy" social support during extinction sessions in ameliorating both immediate and persistent over time cognitive and emotional PTSD-like symptoms.

Fig. 1. Experimental study design of the Extinction pairing experimental protocol.

a Schematic representation of the Extinction pairing experimental design for the Trauma Exposed unpaired (T-Exp unpaired) experimental group. b Schematic representation of the Extinction pairing experimental design for the Trauma Exposed paired with No Trauma Exposed (T-Exp paired with NT-Exp) experimental group and of the No Trauma Exposed paired with Trauma Exposed (NT-Exp paired with T-Exp) experimental group. c Schematic representation of the Extinction pairing experimental design for the Trauma Exposed paired with Trauma Exposed (T-Exp paired with T-Exp) experimental group.

Fig. 2. Experimental study design of the Post-extinction pairing experimental protocol.

a Schematic representation of the Post-extinction pairing experimental design for the Trauma Exposed unpaired (T-Exp unpaired) experimental group. b Schematic representation of the Post-extinction pairing experimental design for the Trauma Exposed paired with No Trauma Exposed (T-Exp paired with NT-Exp) experimental group and of the No Trauma Exposed paired with Trauma Exposed (NT-Exp paired with T-Exp) experimental group. c Schematic representation of the Post-extinction pairing experimental design for the Trauma Exposed paired with Trauma Exposed (T-Exp paired with T-Exp) experimental group.

Fig. 3. Effects of social buffering, during the extinction sessions, on fear memory dynamics and sociability, in the Extinction pairing protocol.

a Freezing behavior during the three extinction sessions at 7, 10 and 13 days after trauma. T-Exp paired with NT-Exp rats showed less levels of freezing as compared to both the T-Exp unpaired and T-Exp paired with T-Exp groups. The NT-Exp paired with T-Exp group showed lower levels of freezing than both the T-Exp unpaired and T-Exp paired with T-Exp groups, and comparable levels of freezing with the T-Exp paired with NT-Exp group. b Magnitude of total time spent in freezing across the three extinction sessions (AUC, area under the curve). Overall, T-Exp paired with NT-Exp rats showed less levels of freezing as compared to both the T-Exp unpaired and the T-Exp paired with T-Exp rats. The NT-Exp paired with T-Exp group showed lower levels of freezing than both the T-Exp unpaired and T-Exp paired with T-Exp groups, and comparable levels of freezing with the T-Exp paired with NT-Exp group. c Social interaction time during the extinction pairing protocol at days 7, 10 and 13 post-trauma. Animals never exposed to the trauma experience (NT-Exp paired with T-Exp) presented significantly higher social interaction time (expressed in seconds) compared to the T-Exp paired with T-Exp group in the last two extinction sessions (days 10 and 13 post-trauma) and compared to the T-Exp paired with NT-Exp group (day 13 post-trauma). d Magnitude of total social interaction time (SI) during the extinction pairing protocol across the three extinction sessions (area under the curve, AUC). Animals never exposed to the trauma experience (NT-Exp paired with T-Exp) presented significantly higher levels of social interaction time as compared to the T-Exp paired with T-Exp group. e Freezing behavior during the extinction retention session 26 days after trauma; for this session all rats were exposed alone to the experimental context. Only social pairing during the three extinction sessions with rats never exposed to a traumatic event reduced levels of freezing in trauma-exposed rats as compared to trauma-exposed rats never paired with a social partner (T-Exp paired with NT-Exp vs T-Exp unpaired). Rats never exposed to the trauma (NT-Exp paired with T-Exp) presented lower levels of freezing as compared to all the remaining experimental groups. f Total time spent in social interaction with rats belonging to the same experimental group 28 days after trauma. Rats exposed to a traumatic event paired with rats never exposed to a trauma (T-Exp paired with NT-Exp) during the three extinction sessions presented higher levels of social interaction 28 days after trauma as compared to trauma-exposed rats never paired with a conspecific (T-Exp unpaired) during the extinction sessions. *, p < 0.05; ***, p < 0.001 vs. T-Exp unpaired rats; #, p < 0.05, ##, p < 0.01; ###, p < 0.001 vs. NT-Exp paired with T- Exp; ♦♦ p < 0.01; ♦♦♦, p < 0.001 vs. T-Exp paired with T-Exp. Data represent mean ± SEM. NT-Exp paired with T-Exp group, n = 10; T-Exp paired with NT-Exp group, n = 10; T-Exp unpaired group, n = 12; T-Exp paired with T-Exp group, n = 12.

Fig. 4. Effects of social buffering, immediately after the extinction sessions, on fear memory dynamics and sociability in the Post-extinction pairing protocol.

a Freezing behavior during the three extinction sessions at 7, 10 and 13 days after trauma. All trauma exposed rats (T-Exp unpaired, T-Exp paired with T-Exp, T-Exp paired with NT-Exp), regardless of the social pairing condition, presented higher levels of freezing compared to rats never exposed to the trauma (NT-Exp paired with T-Exp). b Magnitude of total time spent in freezing across the three extinction sessions (AUC, area under the curve). Overall, all trauma exposed rats (T-Exp unpaired, T-Exp paired with T-Exp, T-Exp paired with NT-Exp), regardless of the social pairing condition, presented higher levels of freezing compared to rats never exposed to the trauma (NT-Exp paired with T-Exp). c Social interaction time during social buffering in the Post-extinction pairing protocol at days 7, 10 and 13 after trauma. There were no significant differences among experimental groups. d Magnitude of total social interaction time (SI) during social buffering in the post-extinction pairing protocol across the three extinction sessions (AUC). There were no significant differences among the experimental groups. e Freezing behavior during the extinction retention session 26 days after trauma, for this session all rats were exposed alone to the experimental context. Social pairing after the three extinction sessions did not ameliorate long-term trauma-induced memory alterations. All trauma exposed rats (T-Exp unpaired, T-Exp paired with T-Exp, T-Exp paired with NT-Exp), regardless of the social pairing condition, presented higher levels of freezing compared to rats never exposed to the trauma (NT-Exp paired with T-Exp). f Total time spent in social interaction with rats belonging to the same experimental group 28 days after trauma. Rats exposed to a traumatic event never paired with a conspecific after the three extinction sessions (T-Exp unpaired group) presented lower levels of social interaction 28 days after trauma as compared to rats never exposed to the traumatic experience (NT-Exp paired with T-Exp). #, p < 0.05, ##, p < 0.01; ###, p < 0.001 vs. NT-Exp paired with T-Exp. Data represent mean ± SEM. n = 12 per group.