Table 1.
Species (strain, sex) | Dyads | Experimental design | Nociceptive stimulus | Time for testing | Observer’s empathic responses | Mechanisms | Sources | |
---|---|---|---|---|---|---|---|---|
Empathy for pain | Rat (SD, M) | Cagemate/Cagemate Non-cagemate/Non-cagemate | Social interaction for 30 min and only partner in pain | s.c. bee venom (0.2 mg in 50 μL) | 30 min after social interaction | Familiarity-selective: PWMT: ↓ PWTL: - Increase in paw flinching |
Increased c-Fos expression in spinal cord Blocked by chemical lesion of bilateral mPFC |
[11] |
Mouse (CD-1, M/F) | Cagemate/Cagemate Non-cagemate/Non-cagemate | Social interaction for 30 min and both animals in pain | i.p. acetic acid (0.9%) or s.c. formalin (1% or 5%) | During social interaction | Familiarity-selective: PWMT: n.a. PWTL: ↓ Increase in writhing or paw flinching |
Blocked only by visual blockade Inducible by suppressing glucocorticoid synthesis in strangers |
[26] [95] |
|
Empathy for fear | Rat (Wistar, M) | Cagemate/cagemate Cagemate/cagemate Non-cagemate/non-cagemate |
Social interaction for 10 min with recent fear conditioning cagemate in home cage | FC by foot-shocks (9×1 s, 55 s ITI, 1.3 mA, 50 Hz) | During social interaction | Increased acoustic startle response to 20×110 dB white-noise (20 ms pulse with 2 ms rise-time) and increased exploration; Increased sniffing and allogrooming; Enhanced acquisition of avoidance response and conditioned freezing (memory) in familiar and unfamiliar dyads; Unchanged thermal pain sensitivity. |
Increased c-Fos expression in lateral and central amygdala | [77] [78] |
Rat (Long-Evans, M/F) | Cagemate/cagemate M/M OF/OF EF/EF |
Social interaction for 10 min with recent fear conditioning cagemate in the home cage | As above | During social interaction | Similar social exploratory behaviors among M, OF and EF; Enhanced acquisition of avoidance response in M and OF but not in EF. |
Increased c-Fos expression in lateral and central amygdala and mPFC (PrLC and ILC) only in male and not female of either OF or EF. | [82] | |
Rat (SD, M) Rat (SD, F) Rat (SD, M/F) |
Cagemate/cagemate Co-housed sisters for 180 days/co-housed non-sisters for 7 days Cagemate/cagemate Dominance/subordinate |
On day 1, a demonstrator was fear conditioned (FC), on day 2, an observer was paired with FC+CS followed by social interaction with each other in home cage for 24 h | FC produced by 3×20 s 80 dB tones co-terminating with foot-shock (3×0.5 s, 180 s ITI, 0.7 mA, 5 Hz) | On day 3, long-term memory test performed with CS | Increased freezing in response to mild CS in 50% in observer Long-term co-housed sisters showed more social contact and freezing than briefly co-housed non-sisters Subordinate showed more freezing when socially interacting with FC dominant conspecific |
n.a. n.a. Increased c-Fos activity in ACC, lateral amygdala, and ventral hippocampus |
[83] [84] [85] |
|
Rat (SD, M) | Cagemate/cagemate | Social interaction between naïve-receiver and FC-sender or between fear-experienced receiver (3 unsignaled foot-shocks: 1 s, 60 s ITI, 1 mA) and FC-sender or between fear-experienced receiver and naïve-sender | FC produced by 10×20 s tones (82 dB, 2.9 kHz) co-terminating with foot-shock (10×1 s, 120 s ITI, 2 mA) | 24 h after social interaction in the home cage | Increased freezing in fear-experienced receiver (observer) but not naïve-receiver in response to FC-sender’s 22kHz ultrasonic vocalization induced by 8 min tone CS | Blocked by electrical lesion or lidocaine infusion at bilateral MGN of fear-experienced receiver | [86] | |
Rat (Long-Evans, F) | Cagemate/cagemate | Social interaction for 40 min between naïve-witness and a distressed demonstrator or between fear experienced witness (foot-shocks: 4×1 s, 240–360 s ITI, 0.8 mA and 1 s, 0,8 mA, every 24 h) and a distressed demonstrator | Produced by foot-shocks (5×5-s, 120–180-s ITI, 0.8 mA) | During witnessing a distressed demonstrator 24 h after consolidation of fear memory following 2-day foot-shock training | Increased freezing and decreased locomotor activity in fear experienced witness but not naïve observer | n.a. | [87] | |
Rat (SD, M) | Cagemate/cagemate Post-weaning social isolated/ post-weaning social isolated |
Social interaction with an FC distressed demonstrator | FC produced by 8 tones (2000 Hz, 20 s) co-terminating with foot-shocks (8×1 s, 80 s ITI, 0.5 mA or 0.8 mA,) | During social interaction with an FC demonstrator and 24 h after acquisition of observational fear learning | Cagemates showed more freezing time than post-weaning socially-isolated conspecific | Impaired observational fear learning in post-weaning socially-isolated observer | [88] | |
Rat (Wistar, M) | Cagemate/cagemate | Two naïve subjects co-housed with two chronic stress-experienced cagemates for 15 days | Stress produced by exposure to 8×4 h white noise (100 dB) during 15 days | 15 days after social interaction with chronic stress-experienced cagemates | Increased level of plasma cortisol and anxiety | n.a. | [89] | |
Rat (Wistar, M) | Cagemate/cagemate Non-cagemate/non-cagemate |
FC subject was allowed to communicate with familiar or unfamiliar odorized neighboring chamber for 1 h on day 1 and 30 min on day 2 | FC produced by 7×3 s tone (65 dB, 8 kHz) co-terminating with foot-shocks (7×0.5 s, 50–270 s ITI, 0.65 mA) | Fear expression test performed on fear-experienced subject by 5×3s CS after odorization | Social buffering of conditioned fear learning obtained in subject odorized by familiar conspecific, resulting in less freezing and more sniffing and walking | Suppression of FC-induced c-Fos expression in PVN and amygdala | [90] | |
Mouse (C57BL/6 vs BALB/cJ, M/F) | Non-cagemates Demonstrator was F1 offspring of C57BL/6×BALB/cJ |
On day 1, two observers from both C57BL/6 and BALB/cJ were exposed to two distressed demonstrators with CS-UCS contingency; on day 2, the same FC procedure was repeated | FC produced by 10×120 s trials randomly sequenced by (1) 30 s CS (85 dB, 1 kHz) co-terminating with UCS foot-shock (2 s, 120 s ITI, 0.5 mA), (2) 30 s tone followed by 2 s UCS, (3) only 2 s UCS, and (4) only 30 s CS. | Immediately after day 2 FC procedure, observer received 5×120s CS followed by 5×120s CS-UCS contingency | C57BL/6 strain showed more freezing and social approach than BALB/cJ strain | n.a. | [79] | |
Mouse (C57BL/6, M/F) Mouse (11 inbred strains: C57BL/6J, C57BL/6NTac, 129S1/SvImJ, 129S4/SvJae, BTBR T(+) Itpr3(tf) /J, AKR/J, BALB/cByJ, C3H/HeJ, DBA/2J, FVB/NJ and NOD/ShiLtJ) |
Siblings/nonsiblings Male/female mating partner |
On day 1, social interaction between a naïve observer and a distressed demonstrator with foot-shock; 24 h after FC, the observer was placed back to the same chamber to acquire observational fear learning | FC produced by 240 s foot-shock (24×2 s, 10 s ITI, 1 mA) | (1) During social interaction with distressing conspecific; (2) 24 h after being placed back to same chamber (contextual cue) |
When sibling and female mating partner (co-housed >10 weeks) served as distressed demonstrator, observer showed more freezing in both testing sessions | (1) Partially blocked by visual blockade; (2) Significantly blocked by unilateral lesion of medial pain system (PF/MD-ACC) and lateral amygdala, but not lateral pain system (VPL/VPM-S1) (3) Cav1.2 VGCC subunit involved Variability in empathy for fear and C57BL/6J, C57BL/6NTac, 129S1/SvImJ, 129S4/SvJae and BTBR T(+) Itpr3(tf) /J showed more observational fear responses, however, AKR/J, BALB/cByJ, C3H/HeJ, DBA/2J, FVB/NJ and NOD/ShiLtJ mice showed low empathic fear response |
[80] [81] |
|
Mouse (C57BL/6, M) | Cagemate/cagemate | On day 1, subjects acquired FC with 5×CS-UCS in context A (cleaned by 1% acid) and extinguished with 6×10 CS in context B (cleaned by 1% ammonium hydroxide); on day 2, tested with 10×CS | FC produced by 5×20 s CS tones (85 dB, 5 kHz) co-terminating with foot-shocks (5×1 s, 0.6 mA) | During extinction test on day 1 and during renewal CS test on day 2 in the presence or absence of a distressed cagemate | In the presence of a distressed cagemate, extinguished fear rekindled by 10×20s CS tones | n.a. | [91] | |
Mouse (C57BL/6, M) | Cagemate/cagemate Co-housed for >8 weeks |
Three-chambered test: (1) Social approach choice: restrained mate vs empty or free-moving mate vs empty or restrained vs free-moving mate; (2) Social approach choice after alternate social interaction with restrained or free-moving mate for 7 days (3) Social approach choice after alternate social interaction with mate in pain or mate without pain for 7 days |
Restrained Restrained s.c. injection of 4% formalin |
30 min observation after training | Subject mouse spent more time in restrained or free-moving cagemate relative to empty chamber, however, it spent almost the same time with restrained and free-moving mates More cagemates (60%) spent more time with restrained relative to free-moving mate Subject mouse spent more time with mate in pain relative to mate without pain |
n.a. | [92] | |
Mouse (C57BL/6J, M) | Cagemate/cagemate Non-cagemate/non-cagemate |
Social interaction between an observer and a distressed demonstrator during FC | FC produced by 240 s foot-shock (1 s, 10 s ITI, 0.5 mA) | Baseline (0–5 min), during foot-shock test (6–9 min) and recovery (10 min) recorded. | Familiar observer showed more freezing than unfamiliar | n.a. | [93] |
↓, decrease; -, no change; cagemate, co-housed for ≥2 weeks; non-cagemate, housed in different cages; isolated, housed singly
ACC, anterior cingulate cortex; CS, conditioning stimulus; EF, estral female; F, female; i.p., intraperitoneal; ILC, infralimbic cortex; ITI, intertrial interval, M, male; MD, mediodorsal nucleus of the thalamus; MGN, medial geniculate nucleus of the thalamus; mPFC, medial prefrontal cortex; n.a., not available; OF, ovariectomized female; FC, Pavlovian contextual fear condition; PF, parafasciculus nucleus of the thalamus; PrLC, prelimbic cortex; PVN, paraventricular nucleus of hypothalamus; PWMT, paw withdrawal mechanical threshold; PWTL, paw withdrawal thermal latency; s.c., subcutaneous; SD, Sprague-Dawley; UCS, unconditioned stimulus; VPL, ventral posterolateral nucleus of the thalamus; VPM, ventral posteromedial nucleus of the thalamus