Table 1.

Familiarity-based empathy for pain or distress in rodents.

	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