Title: Neural Basis of Observational Fear Learning: A Potential Model of Affective Empathy
Abstract: Observational fear learning in rodents is a type of context-dependent fear conditioning in which an unconditioned stimulus (US) is provided vicariously by observing conspecific others receiving foot shocks. This suggests the involvement of affective empathy, with several recent studies showing many similarities between this behavior and human empathy. Neurobiologically, it is important to understand the neural mechanisms by which the vicarious US activates the fear circuit via the affective pain system, obviating the sensory pain pathway and eventually leading to fear memory formation. This paper reviews current studies on the neural mechanisms underlying observational fear learning and provides a perspective on future research on this subject. Observational fear learning in rodents is a type of context-dependent fear conditioning in which an unconditioned stimulus (US) is provided vicariously by observing conspecific others receiving foot shocks. This suggests the involvement of affective empathy, with several recent studies showing many similarities between this behavior and human empathy. Neurobiologically, it is important to understand the neural mechanisms by which the vicarious US activates the fear circuit via the affective pain system, obviating the sensory pain pathway and eventually leading to fear memory formation. This paper reviews current studies on the neural mechanisms underlying observational fear learning and provides a perspective on future research on this subject. Human social interactions are greatly influenced by understanding the emotional states of others. Empathy is the ability to identify another person’s feelings, thoughts, and intentions and to respond appropriately to these emotions (Bernhardt and Singer, 2012Bernhardt B.C. Singer T. The neural basis of empathy.Annu. Rev. Neurosci. 2012; 35: 1-23Crossref PubMed Scopus (355) Google Scholar, de Waal, 2008de Waal F.B. Putting the altruism back into altruism: the evolution of empathy.Annu. Rev. Psychol. 2008; 59: 279-300Crossref PubMed Scopus (936) Google Scholar). Empathy occurs when humans vicariously feel the emotions of others (emotional resonance), explicitly understand the target’s states and their sources, and evoke affective communications that motivate these individuals to remove the sources of the target’s distress and/or provide comfort, such as empathic concern, sympathy, or compassion (de Waal and Preston, 2017de Waal F.B.M. Preston S.D. Mammalian empathy: behavioural manifestations and neural basis.Nat. Rev. Neurosci. 2017; 18: 498-509Crossref PubMed Scopus (21) Google Scholar, Decety, 2011Decety J. Dissecting the Neural Mechanisms Mediating Empathy.Emot. Rev. 2011; 3: 92-108Crossref Scopus (232) Google Scholar, Zaki and Ochsner, 2012Zaki J. Ochsner K.N. The neuroscience of empathy: progress, pitfalls and promise.Nat. Neurosci. 2012; 15: 675-680Crossref PubMed Scopus (374) Google Scholar). Empathy is not unique to humans, as many of its biological mechanisms are shared with other mammalian species. The capacity to share, appreciate, and respond to another’s emotions has evolved over time and ranges from primitive forms, such as mimicry and emotional contagion, to high-level forms, such as perspective taking, sympathy, altruism, and targeted helping (de Waal and Preston, 2017de Waal F.B.M. Preston S.D. Mammalian empathy: behavioural manifestations and neural basis.Nat. Rev. Neurosci. 2017; 18: 498-509Crossref PubMed Scopus (21) Google Scholar, Panksepp and Panksepp, 2013Panksepp J. Panksepp J.B. Toward a cross-species understanding of empathy.Trends Neurosci. 2013; 36: 489-496Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). Recent evidence shows that rodents possess a remarkable affective sensitivity to the emotional state of others and show various forms of empathy-like behaviors, such as observational fear, emotional contagion of pain, consolation, and prosocial helping (Ben-Ami Bartal et al., 2011Ben-Ami Bartal I. Decety J. Mason P. Empathy and pro-social behavior in rats.Science. 2011; 334: 1427-1430Crossref PubMed Scopus (317) Google Scholar, Burkett et al., 2016Burkett J.P. Andari E. Johnson Z.V. Curry D.C. de Waal F.B. Young L.J. Oxytocin-dependent consolation behavior in rodents.Science. 2016; 351: 375-378Crossref PubMed Scopus (164) Google Scholar, Jeon et al., 2010Jeon D. Kim S. Chetana M. Jo D. Ruley H.E. Lin S.Y. Rabah D. Kinet J.P. Shin H.S. Observational fear learning involves affective pain system and Cav1.2 Ca2+ channels in ACC.Nat. Neurosci. 2010; 13: 482-488Crossref PubMed Scopus (285) Google Scholar, Langford et al., 2006Langford D.J. Crager S.E. Shehzad Z. Smith S.B. Sotocinal S.G. 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By definition, this process, in which recognition of the demonstrator’s distress triggers fear in the observer, is a form of affective (emotional) empathy and is a critical factor in the transmission of social fear (Jeon et al., 2010Jeon D. Kim S. Chetana M. Jo D. Ruley H.E. Lin S.Y. Rabah D. Kinet J.P. Shin H.S. Observational fear learning involves affective pain system and Cav1.2 Ca2+ channels in ACC.Nat. Neurosci. 2010; 13: 482-488Crossref PubMed Scopus (285) Google Scholar, Keum and Shin, 2016Keum S. Shin H.S. Rodent models for studying empathy.Neurobiol. Learn. Mem. 2016; 135: 22-26Crossref PubMed Scopus (17) Google Scholar, Kim et al., 2019Kim A. Keum S. Shin H.S. Observational fear behavior in rodents as a model for empathy.Genes Brain Behav. 2019; 18: e12521Crossref PubMed Scopus (1) Google Scholar, Olsson and Phelps, 2007Olsson A. Phelps E.A. Social learning of fear.Nat. 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Similarly, in mice, the fear response in the observer tended to be greater when the demonstrator was a sibling or long-time mating partner than when the demonstrator was an unfamiliar mouse (Gonzalez-Liencres et al., 2014Gonzalez-Liencres C. Juckel G. Tas C. Friebe A. Brüne M. Emotional contagion in mice: the role of familiarity.Behav. Brain Res. 2014; 263: 16-21Crossref PubMed Scopus (45) Google Scholar, Jeon et al., 2010Jeon D. Kim S. Chetana M. Jo D. Ruley H.E. Lin S.Y. Rabah D. Kinet J.P. Shin H.S. Observational fear learning involves affective pain system and Cav1.2 Ca2+ channels in ACC.Nat. Neurosci. 2010; 13: 482-488Crossref PubMed Scopus (285) Google Scholar, Pisansky et al., 2017Pisansky M.T. Hanson L.R. Gottesman I.I. Gewirtz J.C. Oxytocin enhances observational fear in mice.Nat. Commun. 2017; 8: 2102Crossref PubMed Scopus (7) Google Scholar). Together, these findings suggest that observational fear may constitute a fundamental feature of affective empathy (Olsson and Phelps, 2007Olsson A. Phelps E.A. Social learning of fear.Nat. Neurosci. 2007; 10: 1095-1102Crossref PubMed Scopus (298) Google Scholar, Panksepp and Lahvis, 2011Panksepp J.B. Lahvis G.P. Rodent empathy and affective neuroscience.Neurosci. Biobehav. Rev. 2011; 35: 1864-1875Crossref PubMed Scopus (109) Google Scholar). Studies on observational fear are providing significant insight into the architecture and function of neural circuit mechanisms for socially driven emotional resonance (Allsop et al., 2018Allsop S.A. Wichmann R. Mills F. Burgos-Robles A. Chang C.J. Felix-Ortiz A.C. Vienne A. Beyeler A. Izadmehr E.M. Glober G. et al.Corticoamygdala Transfer of Socially Derived Information Gates Observational Learning.Cell. 2018; 173: 1329-1342.e1318Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Carrillo et al., 2019Carrillo M. Han Y. Migliorati F. Liu M. Gazzola V. Keysers C. Emotional Mirror Neurons in the Rat’s Anterior Cingulate Cortex.Curr. Biol. 2019; 29: 1301-1312.e1306Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Jeon et al., 2010Jeon D. Kim S. Chetana M. Jo D. Ruley H.E. Lin S.Y. Rabah D. Kinet J.P. Shin H.S. Observational fear learning involves affective pain system and Cav1.2 Ca2+ channels in ACC.Nat. Neurosci. 2010; 13: 482-488Crossref PubMed Scopus (285) Google Scholar). Importantly, sharing the emotional experiences of others can initiate both learning and empathic processes. In observational fear learning, observing the demonstrator’s distress responses can serve as a vicarious unconditioned stimulus (US), resulting in an association between the affective experience of the observer and the specific environmental context (Chen et al., 2009Chen Q. Panksepp J.B. Lahvis G.P. Empathy is moderated by genetic background in mice.PLoS ONE. 2009; 4: e4387Crossref PubMed Scopus (123) Google Scholar, Jeon et al., 2010Jeon D. Kim S. Chetana M. Jo D. Ruley H.E. Lin S.Y. Rabah D. Kinet J.P. Shin H.S. Observational fear learning involves affective pain system and Cav1.2 Ca2+ channels in ACC.Nat. Neurosci. 2010; 13: 482-488Crossref PubMed Scopus (285) Google Scholar). Witnessing the suffering of others due to aversive experiences may evoke emotional contagion and can help the observer avoid potential risks, such as predation or poisoning (Heyes and Dawson, 1990Heyes C.M. Dawson G.R. A demonstration of observational learning in rats using a bidirectional control.Q. J. Exp. Psychol. B. 1990; 42: 59-71PubMed Google Scholar, Kavaliers et al., 2001Kavaliers M. Choleris E. Colwell D.D. Learning from others to cope with biting flies: social learning of fear-induced conditioned analgesia and active avoidance.Behav. Neurosci. 2001; 115: 661-674Crossref PubMed Google Scholar, Laland, 2004Laland K.N. Social learning strategies.Learn. Behav. 2004; 32: 4-14Crossref PubMed Google Scholar). Accordingly, there are many conceptual and empirical similarities between emotional learning through vicarious experiences and empathy (Debiec and Olsson, 2017Debiec J. Olsson A. Social Fear Learning: from Animal Models to Human Function.Trends Cogn. Sci. 2017; 21: 546-555Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar), and the two may often be mutually reinforcing, suggesting that empathy and observational fear recruit brain systems that partly overlap. The insights discussed in this review have been largely attained through recent studies on neural circuit mechanisms and dynamics during observational fear learning, such as the perception and processing of socially driven fear signals as well as their association with environmental cues (Allsop et al., 2018Allsop S.A. Wichmann R. Mills F. Burgos-Robles A. Chang C.J. Felix-Ortiz A.C. Vienne A. Beyeler A. Izadmehr E.M. Glober G. et al.Corticoamygdala Transfer of Socially Derived Information Gates Observational Learning.Cell. 2018; 173: 1329-1342.e1318Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Carrillo et al., 2019Carrillo M. Han Y. Migliorati F. Liu M. Gazzola V. Keysers C. Emotional Mirror Neurons in the Rat’s Anterior Cingulate Cortex.Curr. Biol. 2019; 29: 1301-1312.e1306Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Jeon et al., 2010Jeon D. Kim S. Chetana M. Jo D. Ruley H.E. Lin S.Y. Rabah D. Kinet J.P. Shin H.S. Observational fear learning involves affective pain system and Cav1.2 Ca2+ channels in ACC.Nat. Neurosci. 2010; 13: 482-488Crossref PubMed Scopus (285) Google Scholar, Keum et al., 2018Keum S. Kim A. Shin J.J. Kim J.H. Park J. Shin H.S. A Missense Variant at the Nrxn3 Locus Enhances Empathy Fear in the Mouse.Neuron. 2018; 98: 588-601.e585Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar). Focusing on brain structures associated with observational fear learning, including the cortex, amygdala, and thalamus, provides touchstones for comparing and integrating neural circuit data from rodents and humans. These insights into social fear transmission can help in understanding social cognition and empathy. Empathy and observational fear have been found to share neural substrates. In determining the emotional state of the demonstrator, the observer must activate the same neural networks in the brain as the demonstrator, a process called the perception-action mechanism (Preston and de Waal, 2002Preston S.D. de Waal F.B. Empathy: Its ultimate and proximate bases.Behav. Brain Sci. 2002; 25: 1-20, discussion 20–71Crossref PubMed Scopus (1892) Google Scholar). 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Empathy for pain involves the affective but not sensory components of pain.Science. 2004; 303: 1157-1162Crossref PubMed Scopus (2281) Google Scholar). This has been interpreted as evidence for embodied models of emotional coding in empathy. In particular, the anterior cingulate cortex (ACC) is activated when observing pain delivered to others (Avenanti et al., 2005Avenanti A. Bueti D. Galati G. Aglioti S.M. Transcranial magnetic stimulation highlights the sensorimotor side of empathy for pain.Nat. Neurosci. 2005; 8: 955-960Crossref PubMed Scopus (381) Google Scholar, Singer et al., 2004Singer T. Seymour B. O’Doherty J. Kaube H. Dolan R.J. Frith C.D. Empathy for pain involves the affective but not sensory components of pain.Science. 2004; 303: 1157-1162Crossref PubMed Scopus (2281) Google Scholar), suggesting that the ACC contains pain-responsive neurons that are activated by both self-pain and empathic responses. In humans, the affective pain processing system, which includes the ACC, the midline nuclei of the thalamus (the limbic thalamus), and the insular cortex, were shown to be involved in processing information about social cues that signal fear (Bliss et al., 2016Bliss T.V. Collingridge G.L. Kaang B.K. Zhuo M. Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain.Nat. Rev. Neurosci. 2016; 17: 485-496Crossref PubMed Scopus (110) Google Scholar, Lamm et al., 2011Lamm C. Decety J. Singer T. Meta-analytic evidence for common and distinct neural networks associated with directly experienced pain and empathy for pain.Neuroimage. 2011; 54: 2492-2502Crossref PubMed Scopus (881) Google Scholar, Olsson and Phelps, 2007Olsson A. Phelps E.A. Social learning of fear.Nat. Neurosci. 2007; 10: 1095-1102Crossref PubMed Scopus (298) Google Scholar, Singer et al., 2004Singer T. Seymour B. O’Doherty J. Kaube H. Dolan R.J. Frith C.D. Empathy for pain involves the affective but not sensory components of pain.Science. 2004; 303: 1157-1162Crossref PubMed Scopus (2281) Google Scholar). Similarly, the activity of the ACC in mice is augmented under conditions of observational fear (Pisansky et al., 2017Pisansky M.T. Hanson L.R. Gottesman I.I. Gewirtz J.C. Oxytocin enhances observational fear in mice.Nat. Commun. 2017; 8: 2102Crossref PubMed Scopus (7) Google Scholar, Sakaguchi et al., 2018Sakaguchi T. Iwasaki S. Okada M. Okamoto K. Ikegaya Y. Ethanol facilitates socially evoked memory recall in mice by recruiting pain-sensitive anterior cingulate cortical neurons.Nat. Commun. 2018; 9: 3526Crossref PubMed Scopus (1) Google Scholar), with a well-delineated neural circuit spanning from the ACC to the amygdala apparently being critical for the delivery of information about social cues that signal threat (Allsop et al., 2018Allsop S.A. Wichmann R. Mills F. Burgos-Robles A. Chang C.J. Felix-Ortiz A.C. Vienne A. Beyeler A. 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