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Neuroscience and Biobehavioral Reviews 35 (2011) 1864–1875

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

journa l homepage: www.e lsev ier .com/ locate /neubiorev

eview

odent empathy and affective neuroscience

ules B. Panksepp ∗, Garet P. Lahvis ∗∗

epartment of Behavioral Neuroscience, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, L470, Portland, OR 97239, USA

r t i c l e i n f o

rticle history:eceived 11 October 2010eceived in revised form 24 May 2011ccepted 27 May 2011

eywords:earainistressmotionocial behaviorus musculus

attus Norvegicuseciprocity

a b s t r a c t

In the past few years, several experimental studies have suggested that empathy occurs in the sociallives of rodents. Thus, rodent behavioral models can now be developed to elucidate the mechanisticsubstrates of empathy at levels that have heretofore been unavailable. For example, the finding thatmice from certain inbred strains express behavioral and physiological responses to conspecific distress,while others do not, underscores that the genetic underpinnings of empathy are specifiable and thatthey could be harnessed to develop new therapies for human psychosocial impairments. However, theadvent of rodent models of empathy is met at the outset with a number of theoretical and semanticproblems that are similar to those previously confronted by studies of empathy in humans. The distinctunderlying components of empathy must be differentiated from one another and from lay usage of theterm. The primary goal of this paper is to review a set of seminal studies that are directly relevant todeveloping a concept of empathy in rodents. We first consider some of the psychological phenomenathat have been associated with empathy, and within this context, we consider the component processes,

ltruismor endophenotypes of rodent empathy. We then review a series of recent experimental studies thatdemonstrate the capability of rodents to detect and respond to the affective state of their social partners.We focus primarily on experiments that examine how rodents share affective experiences of fear, butwe also highlight how similar types of experimental paradigms can be utilized to evaluate the possibilitythat rodents share positive affective experiences. Taken together, these studies were inspired by JaakPanksepp’s theory that all mammals are capable of felt affective experiences.

© 2011 Elsevier Ltd. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18641.1. Empathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18651.2. Foundational studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1866

2. Social modulation of pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18673. Social interaction with a recently distressed conspecific modulates subsequent learning about environmental signals that predict distress . 18674. Social transfer of fear . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18695. Synopsis and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1871

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1873

. Introduction writings of primatologist Franz de Waal, more principled and evo-lutionary based perspectives on empathy have emerged (de Waal,

Historically, empathy has been considered a high-level affec-ive/cognitive process that is expressed exclusively by humans.owever, recent scientific developments have placed this anthro-ocentric view into question. Prompted in part by the research and

∗ Corresponding author. Tel.: +1 503 494 8286; fax: +1 503 494 6877.∗∗ Corresponding author. Tel.: +1 503 346 0820; fax: +1 503 494 6877.

E-mail addresses: panksepp@ohsu.edu (J.B. Panksepp), lahvisg@ohsu.eduG.P. Lahvis).

149-7634/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.oi:10.1016/j.neubiorev.2011.05.013

2008). For instance, it is now generally accepted that many primatespecies have a capacity for empathy, that empathy can be a proxi-mate mechanism underlying the expression of altruistic behavior,and that empathy is the product of an integrated set of brain pro-cesses. Moreover, contemporary views of empathy consider itsexpression to be a product of several behavioral, affective and cog-nitive processes, each of which can vary with development, context

and species (see below). Deconstructing empathy into specifiablecomponents is useful elucidating the biological substrates that con-tribute to impairments in social interaction.

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In this paper, we consider one core feature of empathy in rodentsthe ability to share affective experiences. We review and compare

he experimental approaches and results of a series of recent papershat explored different aspects of rodent behavior in response to theistress of conspecifics. Rather than reviewing research on empathy

n primates (Davis, 1994; Farrow and Woodruff, 2007; Silk, 2007;ecety, 2010), we examine how shared affect can be modeled in

aboratory rats and mice. In this regard, studies of shared affect inodents can provide a level of biological resolution that has nevereen achieved in empathy research.

Several of the studies that we describe employ a fear-onditioning paradigm in which an individual is challenged to learnn association between a conditioned stimulus (CS), such as a toner context, and an unconditioned stimulus (UCS), such as a deliv-ry of a shock. In a standard fear-conditioning paradigm, a subjectearns to associate the CS with a UCS that engenders pain. However,

any of the studies described herein utilize a very different UCS,distress cue that has been generated by the induction of pain in

nother individual (Section 4). Consistent with the affective neuro-cience approach (Panksepp, 1998), we adopt the perspective thatuch associations can be learned because changes in an animal’subjective state occur while others are undergoing distress. In thiscenario, a subject’s subsequent responsiveness to a CS thus reflectsts previous emotional experiences with a conspecific in pain.

A basic premise of affective neuroscience is that careful behav-oral and neuroanatomical manipulations in the laboratory canield insights into how affective and cognitive processes are dis-inct both in terms of their overt expression and their respectiveeural circuitries (Panksepp, 2005). Through the lens of affectiveeuroscience, we can envision building a robust framework forlucidating the neurobiological substrates that underlie differentspects of empathy in animals.

.1. Empathy

The study of empathy is heavily influenced by questions abouterminology, and there continues to be an imprecise and there-ore confusing usage of the term ‘empathy’ both in the scientificiterature and among the lay public. In this paper, we will noteview this literature or how empathy is expressed in humansreaders are referred to MacLean, 1967; Hoffman, 1981; Davis,994; Decety, 2010). Rather, we will point out a few salient def-

nitions that can be useful in developing a concept of empathy inodents.

The word empathy has undergone a substantial evolution inhe last century. Lipps (1903) provided the original definition ofmpathy as a process by which “the perception of an emotionalesture in another directly activates the same emotion in the per-eiver, without any intervening labeling, associative or cognitiveerspective-taking processes.” (Preston and de Waal, 2002, pp. 2).uring the next one-hundred years, perspectives on empathy were

ubstantially expanded and refined. Some investigators focused onow individuals perceive and respond to the emotional expressionsf others. Such approaches emphasized a role for affective arousal,ssociative learning and motor mimicry (i.e., imitation). More cog-itive approaches to studying empathy were based on describingow an individual comes to understand the perspective of anothery actively projecting into the psychology of their social partners.ithin this context, major questions involved discerning when and

ow an individual can distinguish self from other, and whetherhere was an ability to recognize that the perspective of anotherould be different from one’s own. At the highest level, cognitive

pproaches to empathy focused on language-based abstractions inhich certain words could activate emotions in others because

hey were relevant to a past experience. Moreover, some cogni-ive approaches considered a role for compassion in the empathic

behavioral Reviews 35 (2011) 1864–1875 1865

response, which allowed individuals to relate with the emotionalstate of others even though they did not necessarily share the samestate (for an excellent review of different definitions of empathyand its historical evolution see Davis, 1994).

Theoretical developments in empathy research now view theexpression of empathy as the result of an interaction between sev-eral component processes, both affective and cognitive (Hoffman,1987; Preston and de Waal, 2002; Decety and Jackson, 2004).Preston and de Waal (2002) hypothesized that these processes uti-lize an ancient perception–action coupling mechanism in which asubject’s attention to the ‘state’ of another can automatically acti-vate the same state in the subject. Regardless of the underlyingmechanism, this model serves as a very useful heuristic insofarthat viewing empathy as a psychological phenomenon which stemsfrom several underlying processes offers a practical strategy foremploying biological approaches in empathy research. In the restof this section, we review what some of these component pro-cesses are in attempt to clarify our own hypothesis that rodentsare capable of sharing affective experiences.

Emotional contagion is a psychological process that is relevantto empathy and refers to a phenomenon in which the perception ofa behavioral change in an individual appears to automatically acti-vate the same process in another individual. Emotional contagionis thus a reflexive behavioral process among individuals within thecontext of a motivationally salient event. By definition, contagionrequires that two individuals contemporaneously express a behav-ior that reflects a common experience. Perhaps the most commonexamples of emotional contagion in humans are infectious cryingamong babies and yawning among adults. Although emotional con-tagion fits within a more generally accepted definition of empathy;“the generation of an affective state more appropriate to the sit-uation of another compared to one’s own” (Hoffman, 1975), it isexcluded from others, particularly when there is an emphasis onthe ability to distinguish self from other. Importantly, emotionalcontagion does not require an ability to discern whether the sourceof an affective experience comes from one’s self or from anotherindividual (Singer and Lamm, 2009).

The ability to distinguish self from other is a key feature of emo-tional empathy, in which directed attention to another’s emotionalstate can lead to the same state in a subject. Thus, like emotionalcontagion, emotional empathy involves ‘state-matching’ betweenindividuals. However, emotional empathy is exclusively concernedwith the affective state of individuals, as opposed to a reflex-ive behavioral response. Importantly, because emotional empathyrequires an ability to distinguish one’s self from another, it can sub-sequently lead to helping behaviors and also can be engaged byone’s personal recollection of an experience (Davis, 1994; Prestonand de Waal, 2002).

While emotional empathy inherently requires that two indi-viduals share an affective experience, its expression also canbe modulated by cognitive processes. These cognitive aspects ofempathy incorporate changes in the emotional state of one individ-ual that are subsequently experienced by another individual aftersome degree of additional processing (e.g., top–down processing).Examples of this include contextual appraisals, such as integratingpast experiences or familiarity, and high-level cognitive phenom-ena, such as perspective taking (see below). For instance, in someof the studies described in Sections 2–4, responsiveness of a sub-ject is altered if they have had previous experience with the UCS,if they have lived with or share kinship with their social partner,or if their social partner poses a concurrent threat. Moreover, inhumans, empathic responses are modulated by a subject’s per-

ceived fairness of an individual suffering from a painful stimulus,as well as by gender (Hein and Singer, 2008). In some situationsand species, a distinct form of cognitive empathy may be oper-ational, which requires an ability to distinguish that another can

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aintain a perspective distinct from one’s own. This ability to rec-gnize that the perspective of another individual is different fromne’s own is based upon a phenomenon known as ‘Theory of Mind’Farrow, 2007), a form of metacognition (see below). In this form,t is thought that cognitive empathy allows an individual to under-tand the emotional state of another without necessarily sharinghe same emotional state. In several instances, the expression ofmpathy is therefore determined not just by the ability to sharen affective experience, but also by factors that can modulate thempathic experience.

One way of broadly exemplifying the emotional versus cognitivespects of empathy is through a comparison of two commonly usedlinical tests that evaluate psychosocial functioning in humans.he ‘feigned distress test’ is used to assess whether an individualttends to emotional changes in another. During the assessment,clinician exclaims surprise in response to an accident, such as

ropping papers on the floor or burning her fingers while lightingcandle on a cupcake. Normal children look towards the clinician’syes and to the vicinity of the accident (i.e., papers on the floor,ngers), whereas some children on the autism spectrum expressbnormal responses or fail to respond (Bacon et al., 1998; Dawsont al., 2004; Hutman et al., 2010). The feigned distress test thus iden-ifies whether an individual can detect and respond to an emotionalhange in another.

Theory of Mind (ToM) is the ability of an individual to under-tand that another individual can have a separate experience fromne’s own. In one test of ToM (Wimmer and Perner, 1983), a humanubject observes a scenario in which one doll (A) places a marblen a basket and then leaves the room. Then, a second doll (B) entershe room and removes the marble from the basket and places itnto an adjacent box. When doll A returns, the subject is asked toredict where doll A will search for the marble. Individuals with aealthy ToM identify the basket, understanding that doll A wouldot have experienced doll B change the location of the marble. The

ndividual can therefore infer, through cognitive re-representation,he perspective of another and it is thought that this ability is criticalor the expression of cognitive empathy.

While empathy can include different levels of cognitive abilityhat vary according to social, temporal and environmental contexts,motions are a basic substrate for all empathic capacities. Indeed,view of empathy that focuses on affective experience brings one

loser to the original translation of einfühlung or ‘empathy’ as arocess of ‘feeling into’ another (Titchener, 1909). Within an exper-

mental context, such as the rodent studies described below inections 2–4, it may be useful to examine the features of a very prac-ical definition of empathy proposed by de Vignemont and Singer2006). In their definition, empathy occurs when an individual (A)xperiences an affective state that is isomorphic to the affectivetate of another individual (B), and is elicited by observing or recall-ng the respective expression of the affective state by individual. Within this model, the affective state of individual B is there-

ore the source of emotional change in individual A (de Vignemontnd Singer, 2006). Some investigators would also allow empathy tonclude anisomorphic emotional responses between individuals And B (see below). However, the de Vignemont and Singer modelrovides a useful framework for studies of rodent affective stateshat are activated during a social exchange.

Emotional empathy requires that individuals share a feelingtate based upon the same influence, even if these respectivexperiences are temporally disconnected (i.e., recollection). Thisype of empathy can be conceptualized within the context ofur understanding of the basic emotional systems of the mam-

alian brain and how they generate affective feelings (Panksepp,

998). For instance, an emotional experience of anger can engen-er behavioral responsiveness (aggression) in a dominant male thatubsequently induces an emotional experience in a subordinate,

behavioral Reviews 35 (2011) 1864–1875

such as fear. Importantly, this example of anisomorphic emotionalexchange is compatible with a perception–action mechanism, butparticular emphasis is placed on the distinct affective experienceof each individual (viz., anger induces fear). Employing an affec-tive neuroscience approach, with its seven basic emotion systems,allows one to identify and differentiate the affective experiencesof animals (e.g., fear or happiness in one individual leads to fear orhappiness, respectively, in another individual). It is also importantto keep in mind that empathy can engender a string of subse-quent behavioral phenomena (e.g., escalated aggression, nurturingor consolation behavior).

Observational learning studies serve as a foundation for study-ing empathy in rodents because they require an individual attendto the behavior of another individual. Numerous studies havedemonstrated that mice and rats are capable of learning fromothers (Zentall and Levine, 1972; Collins, 1988; Valsecchi et al.,2002; Carlier and Jamon, 2006). These studies typically involve atask in which an observer experiences a demonstrator acquiringa foodstuff. In these experiments, hunger serves as the putativemotivation for both the demonstrator performing the task andthe observer attending to the behavior of the demonstrator. Thus,the demonstrator and the observer experience a common motiva-tional state that does not necessarily involve a shared component.The term ‘shared’ in this review refers to an affective state in oneindividual (‘demonstrator’) that can be communicated to anotherindividual (‘observer’). Importantly, this type of shared experiencedoes not assume that a demonstrator intentionally communi-cates with an observer. Observational learning (including imitationand social facilitation) can be differentiated from empathy, whichoccurs if a subject expresses a change in affect in response to anaffective experience in a conspecific. By contrast, observationallearning occurs if changes in behavior represent modifications oftask performance in the absence of emotional signals. Readersare directed to excellent reviews by Heyes (1994) and Galef andGiraldeau (2001) for additional perspectives on rodent observa-tional learning.

We focus on the affective component of empathy in rodents, wedo not wish to imply that rodents are incapable of psychologicalprocesses related to cognitive empathy. Indeed, there is evidencethat rodents possess the prerequisite skills for this ability, suchas some forms of metacognition (Foote and Crystal, 2007). Rather,our focus on the affective aspects will build upon the solid frame-work of affective neuroscience and the basic emotional operatingsystems of the mammalian brain (Panksepp, 1998). Specifically, aseries of very recent studies is described that collectively demon-strate rodents are capable of (1) emotional contagion, (2) socialmodulation of associative learning, and (3) the shared affect com-ponent of empathy. We also describe where attempts have beenmade to identify the neural substrates that underlie these phenom-ena. Taken together, these studies underscore that rodents possessa remarkable affective sensitivity to the emotional state of others,which in the future could be developed into robust experimen-tal models of psychosocial dysfunction relevant to disorders suchas autism (Bacon et al., 1998; Dawson et al., 2004; Hutman et al.,2010).

1.2. Foundational studies

Prior to reviewing the more modern studies that are relevantto rodent empathy, it is imperative to briefly discuss two stud-ies that were conducted over 45 years ago. Each of the studies isfoundational in that they highlight the extent to which a rodent

can be attuned to the affective state of a social partner. In oneexperiment (Church, 1959), the behavior of well-trained rats wasassessed as they preformed a lever-pressing task and were con-currently exposed to a conspecific that was being shocked. The

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istress cues that were generated by a conspecific had a direct sup-ressive effect on the rate of lever pressing by subjects. The more

ntriguing part of the experiment included an ‘emotional condition-ng’ component, during which subject rats and their social partnersimultaneously received a shock paired with a CS (i.e., panel lightsn the testing apparatus). Control groups included subject rats thatxperienced shocks that were presented at a different time thanhe shocks delivered to their social partners. Another control groupncluded rats were not conditioned. Following this phase of therotocol, subjects were retested for lever pressing with intermit-ent co-exposure to conspecific distress and the CS. Subjects thatad previously been shocked contemporaneously with their socialartner during the conditioning phase of the experiment expressedrobust depression in lever pressing (relative to the other groups)

hat persisted for 10 days. Subjects that were shocked at a differentime than their social partner also decreased their lever pressing inesponse to co-presentation of the CS and conspecific distress, butheir response was not as robust and it also returned to baseliney the last day of testing. These results are particularly intriguingor two reasons: (1) Perception of social distress by a rat substan-ially disrupted its behavior even though it was depleted of a vitalesource (22-h food deprivation). (2) Shared experience of pain wasmore effective modulator of behavior than was the consecutive

xperience of pain and perception of pain in others. Thus, the find-ngs of Church (1959) were seminal because they demonstratedhat a rat could identify whether its own emotional experience wasemporally coordinated with the same experience in a conspecific.

In another study, Rice and Gainer (1962) asked whether a ratould exhibit directed helping behavior to alleviate the distress of aonspecific. In the first part of the experiment, a subject was trainedo press a lever to avoid delivery of a shock that was signaled byvisual cue. Subsequently, subjects were tested with a distressed

ocial partner that was suspended in the air via a hoist system (theseistressed rats produced squeals in response to this procedure andheir ‘wriggling’ behavior was visually perceptible to the subject). Inhis scenario, lever depression by the subject resulted in lowering ofhe conspecific and alleviation of its distress. Lever-pressing behav-or of subjects was compared to a control group of rats that couldower a Styrofoam block that was suspended in the air. Subjects thatad previous experience with conpecific distress expressed >10-

old more responses to lower a distressed conspecific compared toontrols, whereas subjects that had never experienced conspecificistress expressed >3-fold more responses to lower a distressedonspecific relative to their respective control group. Collectively,hese findings demonstrated that rats would actively work (i.e.,elp) to reduce the distress of conspecifics, another phenomenonhat is relevant to empathy.

. Social modulation of pain

Langford et al. (2006) conducted one of the first studies thatssessed empathy in rodents within the context of contemporaryeuroscience approaches. Their study adapted several traditionalehavioral assays that are used to study pain in mice to includesocial component in which a ‘partner’ also experienced a nox-

ous stimulus. They asked if pain-related behaviors (e.g., writhingfter an intra-peritoneal injection of dilute acetic acid or paw lick-ng after a subcutaneous injection of formalin) are sensitive to theehaviors of a social partner that also experiences pain. Individ-al mice were subjected to the pain-inducing manipulation, andheir subsequent behavior was evaluated in real-time under exper-mental conditions of social isolation, a painful experience with a

on-treated partner or a painful experience with a partner that was

n pain at the same time. Their experimental results can be sum-arized into three key findings: (1) If experiencing pain together,ice expressed greater levels of pain-related behavior (i.e., hyper-

behavioral Reviews 35 (2011) 1864–1875 1867

algesia) compared to when pain was experienced individually. Thiseffect was not specific to the type of noxious stimulus that wasexperienced (acetic acid or formalin) or the resulting behaviorthat was expressed (writhing or paw licking). (2) If experiencingdifferent levels of pain together (e.g., each partner was simultane-ously subjected to a different concentration of a noxious stimulus),the behavior of each mouse was modulated by the level of painexperienced by its social partner. For instance, if the forepaw ofone mouse was injected with a high concentration of formalin, itexhibited less intense licking behavior if its partner had receiveda lower concentration of formalin. (3) Observing a conspecific inpain engendered the same amount of post-stimulus hyperalgesiaas the direct experience of a painful stimulus. That is, the typi-cal increase in nociceptive sensitivity that mice undergo after apainful experience was also detected in individuals that had simplyobserved mice in pain without experiencing the noxious stimulusthemselves.

Taken together, the Langford et al. (2006) findings demonstratedthat mice are remarkably responsive to the level of pain expe-rienced by other individuals. Control experiments that evaluateddifferent sensory modalities revealed that this form of social mod-ulation of pain was communicated by visual signals. Langford andco-workers argued that their behavioral findings were best con-ceptualized within the context of emotional contagion, a processin which the behavioral state of an individual automatically acti-vates the same state in nearby conspecifics. An analogous situationto this contagion-type of responding also exists in rats, wherefreezing by an observer is positively correlated with the amountof freezing expressed by a nearby demonstrator when tested in afear-conditioning paradigm (Wöhr and Schwarting, 2008). Notably,Langford et al. (2006) found that this process in mice was stronglyinfluenced by the degree of familiarity between social partners (alsosee D’Amato and Pavone, 1993), a finding that resembles resultsfrom the human empathy literature. Moreover, the opposite effect(i.e., analgesia) was observed when the mouse in pain was pairedwith an unfamiliar male that was not in pain (Langford et al., 2006).This result was hypothesized to be due to the social threat that wasposed by the unfamiliar male, a finding subsequently confirmedand shown to be dependent upon the hormonal status of the malepartner (Langford et al., 2010). While the Langford et al. (2006)study provided strong evidence that emotional contagion can bestudied in mice, a series of studies have demonstrated that com-munication between rodents modifies their future ability to learnabout emotionally salient events.

3. Social interaction with a recently distressed conspecificmodulates subsequent learning about environmentalsignals that predict distress

Four recent papers (two studies using mice and two using rats)revealed that a brief social exposure with a demonstrator modifieshow an observer rodent subsequently performs in an associativelearning paradigm. Bredy and Barad (2009) demonstrated that theacquisition, retention and extinction of a cued-fear associationcould be modified by a social interaction with a familiar conspecificthat was itself previously exposed to the same fear-conditioningprocedure. Specifically, an observer mouse experienced a 35-minsocial exposure in its home cage with an animal that had justreceived three 2-s shocks (1 mA) that were each paired with a 2-min presentation of white noise (2-min inter-trial interval).Withinthis behavioral context, the observer did not directly experiencethe demonstrator while it was distressed. Rather, the observer

mouse interacted with the demonstrator in a familiar environmentat a time between fear conditioning of the demonstrator and itsown conditioning. The observer mouse was then subjected to thesame conditioning procedure as the demonstrator, and this expe-

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ience resulted in reduced acquisition of a fear response (freezing),iminished ability to recall the CS–UCS association, and increasedxtinction of the fearful memory. All of these changes were indexedy reduced freezing behavior in response to presentation of theS-only relative to observers that had interacted with a fear-naïveouse. It is important to note that the directionality of the observer

esponses was somewhat unexpected, as it was predicted that aearful demonstrator would respectively facilitate acquisition of aear-induced memory and inhibit its extinction.

In a similar experiment, Knapska et al. (2010) found that thebility of a rat to acquire and retain an active fear-conditionedehavioral response (escape) in a two-way avoidance paradigmas facilitated by previous interactions with a fearful demonstra-

or. In this behavioral paradigm, a demonstrator rat was exposed toen 1-s shocks (1 mA) that were delivered across a 10-min period60 s inter-trial interval) and then the demonstrator was placedack into the home cage of the observer rat for a 10-min social

nteraction period. Following the social interaction, observer ratsere removed from the home cage and placed into a novel appa-

atus where they were trained to avoid a foot shock by shuttlingack-and-forth between two chambers when cued by presenta-ion of white noise. The results of this experiment demonstratedhat when a rat was previously exposed to a distressed conspecific,he experience facilitated both the acquisition of avoidance behav-or during the training phase of the experiment and an increasedetention of the fear memory, as indexed by increased avoidanceehavior 24 h later.

Knapska et al. (2010) also demonstrated that interacting withfear-conditioned demonstrator augmented recall of a passive

ehavioral response (freezing) in a contextual fear-conditioningaradigm. In this paradigm, demonstrator and observer rats werereated as described above, but observers were subsequentlyxposed to novel context for 4 min, and received a single 1-s foothock (1 mA) at the transition between minutes 3 and 4 of theontext exposure. Increased freezing behavior by the observer ratspon re-exposure to the context was detected 24 h later. The direc-ionality of these results contrasts sharply with those of the Bredynd Barad (2009) study, where experience with a fearful conspecificeduced the expression of a fear memory. In developing a possiblexplanation for this difference, it is important to consider how thesewo experiments are similar. Careful control experiments by bothroups illustrated that changes in the ability of an observer to learnfter social interaction with a distressed conspecific could not bexplained by alterations in nociceptive sensitivity or generalizedocomotion. For example, both studies demonstrated that interac-ion with a recently distressed animal did not alter the behavior ofbservers in a hot-plate test of nociceptive sensitivity. Moreover,he differential ability of an observer to learn after social interac-ion with a distressed conspecific did not result from locomotorrousal. Bredy and Barad (2009) found that interaction with a dis-ressed mouse did not alter the exploratory response of observerso a novel environment. This control experiment suggests that thencreased freezing of observer mice was specific to the learningxperience. Knapska et al. (2010) found that social interaction withdistressed rat engendered faster acquisition of learned behavioral

esponses irrespective of whether the learned response required anncrease (escape) or decrease (freezing) in movement. It thereforeppears that an event during the social interaction with the dis-ressed animal directly changed the propensity of the observers toearn a new association. Indeed, Bredy and Barad (2009) identified-phenylethylamine as a pheromone signal that communicatedistress to observer mice. Overall the findings of these two stud-

es demonstrate that the social experience of distress in others canelp rodents learn about fearful situations in the future. The expla-ation for the difference between mice and rats remains unknownnd warrants further experimental attention.

behavioral Reviews 35 (2011) 1864–1875

Knapska and co-workers conducted additional in-depth analy-ses of social interactions with a distressed conspecific. When ratswere reunited with a recently distressed conspecific, they directed>10-fold more allogrooming towards the individual compared torats that were reunited with a non-distressed conspecific (Knapskaet al., 2010). In rodents, allogrooming is a social activity, in whichone individual repeatedly licks the head/neck/mouth/ear area ofanother. It is intriguing to speculate that the facilitation of thisbehavior after detecting distress in another is an attempt to com-fort the afflicted individual, as has been previously suggested forprimates (Preston and de Waal, 2002). Interestingly, Knapska et al.(2006) demonstrated a mutual and heightened induction of theinducible transcription factor c-fos in the amygdala of distresseddemonstrator rats and observers following a brief social interac-tion. Although heightened c-fos activity was detected in severalnuclei of the amygdala (e.g., lateral, basal, basal medial, medial andcentral nuclei) of both distressed rats and the respective observers,increased c-fos induction in the central nucleus of the amygdaladifferentiated these two groups. This finding suggests that partic-ular sectors of the amygdala are responsive to distress in others.Overall, it appears that a coordinated set of changes in the amyg-dala, a brain region implicated in numerous emotional processes,occurs following the experience of self-distress and the experienceof distress in others.

Using an approach similar to the two studies described above,Guzmán et al. (2009) found that observations of non-fearfuldemonstrator mice modified subsequent learning about a CS–UCSassociation. In this study, observer mice were exposed to a novelcontext (3 min) on two successive days with a demonstratorthat had previously received a 2-s shock (0.7 mA) in the samecontext. The observers were then trained with the same condi-tioning paradigm. In this behavioral model, observations of fearfuldemonstrators did not alter subsequent learning of the fear-conditioning association by observers. However, if mice observeda non-fearful demonstrator, it inhibited their ability to recall theCS–UCS association themselves. Previous experience with a fear-naïve demonstrator therefore ‘buffered’ the likelihood that micewould become fear-conditioned. It is also worth noting that thepresence of a non-fearful partner during the presentation of CSthat predicts application of a painful UCS retards the expressionof freezing in fear-conditioned rats (Kiyokawa et al., 2009).

Unlike Bredy and Barad (2009) and Knapska et al. (2010),observer mice in the Guzmán et al. (2009) study were able to derivespecific information about the experience of the respective demon-strators. While observers in all of the studies ultimately had to learnan association themselves, mice in the Guzmán et al. (2009) studywere sensitized to the appropriate context prior to the learningexperience. Thus, while the Bredy and Barad (2009) and Knapskaet al. (2010) studies illustrated that experience with social distresscan subsequently modify the acquisition of a new behavior, theGuzmán et al. (2009) study extended this finding further by demon-strating that observers can make a direct connection between thedistress state of others and the specific environmental signals (i.e.,context) that are proximal to its occurrence.

In a related experiment with rats, Bruchey et al. (2010) fearconditioned demonstrators with 0.5-s shocks (0.7 mA) that wereeach paired with a tone (three pairings), a protocol that engen-dered robust freezing responses to presentation of the CS 24 hlater. By contrast, rats that were subjected to the same fear-conditioning procedure, but with a less painful UCS (0.4 mA shock),exhibited much less CS-induced freezing behavior. Importantly,if observer rats were allowed to socially interact with demon-

strators that were simultaneously expressing conditioned freezing(what was referred to as ‘fear-conditioning by-proxy’), and thensubjected to the 0.4 mA-conditioning protocol, they expressedfreezing responses comparable to individuals that had underwent

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he 0.7 mA-conditioning protocol. Thus, it appears that rats exhibitacilitated learning about cues that predict a painful stimulus if theyave previously interacted with a conspecific that expresses fear tohe same CS (see below).

Differences between the studies described in this sectionighlight several important issues that should be addressed sys-ematically in future studies of rodent empathy: To what extents prior experience with the affect-inducing UCS required forbservers to respond? When do observers acquire informationbout the affective state of demonstrators (e.g., as the demonstra-or is becoming distressed by a UCS, after the UCS is removed, or ashe demonstrator changes its behavior in response to a CS that pre-icts fear)? What factors play a role in directing changes in observerehavior towards a similar or different response relative to that ofemonstrators?

. Social transfer of fear

The experiments that have been reviewed so far illustrate thatodents are immediately sensitive to the distress of others (Section), and that experience with conspecific distress can modulate howrodent subsequently learns about environmental cues and con-

exts that predict fearful situations (Section 3). A critical questionegarding empathy in rodents is whether an individual can respondo a CS that has been associated with the distress of a conspecific asf it were paired with the direct experience of a UCS. Below weescribe five studies that indicate rodents can be responsive inhis way, which suggests that rodents are capable of experiencinghared affect.

Employing a highly innovative and ethologically relevantaradigm, Kavaliers et al. (2003) asked whether a mouse could

earn via social observation to avoid a predatory attack. Demonstra-or mice were placed in a compartment lined with wood shavingsnd exposed to ≈50 biting flies for 30 min while an observeresided in an adjacent compartment that was separated by a mesharrier. During this period, the demonstrator mouse exhibitedeveral defensive behaviors in response to the biting flies and ulti-ately buried itself under the bedding to avoid further attack.

esting included placing a demonstrator or observer in the sameontext 24 h later and exposing them to flies that had their mouth-arts removed, which eliminated the ability to bite. Demonstratorsxpressed robust burying responses when they were re-exposed toies, even though the UCS (i.e., biting) was not present. Importantly,bserver mice also avoided the non-biting flies by burying them-elves, a response that was stimulus-specific because observersid not attempt to avoid non-biting flies of a different species.hus, the observer mice responded to the CS (i.e., flies) as ifhey anticipated a bite even though they had no direct experi-nce with the UCS. Additional studies by Kavaliers et al. (2003)evealed that exposure to non-biting flies following a single expe-ience with a distressed demonstrator engendered conditionedorticosterone release and analgesia in observers. Moreover, theubsequent behavioral responses of an observer were dependentn visual cues and NMDA-signaling (Kavaliers et al., 2001) duringts experience with the demonstrator.

Using a cue-conditioned fear paradigm, Kim et al. (2010) showedhat an observer rat can acquire a freezing response by observ-ng fear-conditioned demonstrators, but only if the observer hasad prior experience with the UCS itself. In this paradigm, demon-trators were fear conditioned with ten 20-s tones that eacho-terminated with a 1-s shock (2 mA). During testing, demonstra-

ors were presented with the CS-only in the presence of an observerat (i.e., paired testing). The fear-conditioning procedure engen-ered a robust fear response in demonstrators, evidenced by high

evels of CS-induced freezing and production of aversive 22 kHz-

behavioral Reviews 35 (2011) 1864–1875 1869

ultrasonic vocalizations (USVs). Naïve observers did not exhibit fearresponses to presentation of the CS or the conditioned responses(freezing and 22 kHz-USVs) of the demonstrator. However, if theobserver had previous experience with a UCS (three unsignaled1 mA-shocks), then paired testing resulted in robust observer freez-ing responses. The authors conducted a series of lesion/inactivationexperiments that targeted the medial geniculate nucleus (MGN) ofthe thalamus (i.e., auditory thalamus) and found that MGN activ-ity during the experience of unsignaled shocks was necessary forfuture observer responses in the paired testing situation. Moreover,during paired testing the largest freezing responses were expressedby observer rats that had produced 22 kHz-USVs concurrently withpresentation of the unsignaled shocks. It was hypothesized thatrats need to process their own 22 kHz-USVs during a painful expe-rience before they can respond appropriately to the distress stateof demonstrators during paired testing. Thus, in this paradigm, aCS triggered a conditioned fear response in demonstrators, whichin turn engendered a fear response in ‘experienced’ observers.

In another experiment, the Bruchey et al. (2010) study (alsodescribed in Section 2) found that rats acquire a freezing responsesimply by observing a demonstrator that is expressing a condi-tioned fear response to a CS. In this experiment, demonstrator ratswere fear conditioned with the same protocol described in Sec-tion 2 (e.g., three tone-shock pairings). 24 h later, observers wereallowed to interact with demonstrators that were being presentedwith three playbacks of the CS-only. During a testing session 24 hlater, observer rats expressed appreciable freezing responses whenthey were presented with the CS-only. Thus, in this experiment, aCS that predicted distress in another engendered a fear responseas if the observer rat had experienced the UCS itself. Based onthe results of the Kim et al. (2010) study, it is possible that thedistress of demonstrators was communicated to observer rats via22 kHz-USVs. Interestingly, Bruchey et al. (2010) found that theresponsiveness of observer rats to the CS was positively corre-lated with the amount of social interaction they directed towardsdemonstrators during the observation session. The findings of Kimet al. (2010) can be distinguished from those of Bruchey et al.(2010), because observers did not require prior experience witha UCS or presence of a demonstrator during testing (i.e., observersresponded to the CS-only).

Employing a contextual conditioning paradigm, Jeon et al.(2010) demonstrated that observer mice express freezing behaviorwhen they are adjacent to a fearful demonstrator mouse receiv-ing repeated shocks over a 4-min period. This response by itselfis consistent with emotional contagion because freezing of thedemonstrator and observer mice occurred at the same time. Afterthe observer was placed back into the specific context where thedemonstrator had experienced the UCS 24 h earlier (equivalent toa long-term memory test), it also expressed freezing behavior, sug-gesting that an association had been made between the distressof a conspecific and the CS. This subsequent effect was distinctfrom emotional contagion because freezing behavior expressed bythe observer mouse occurred well after exposure to the distressedconspecific and observers had never experienced the UCS them-selves. In other words, the freezing behavior of the observer mousewas expressed as if it anticipated initiation of distress in another.Freezing behavior in rodents is a direct, behavioral readout of fear(LeDoux, 2000) and thus this finding reflects the social transfer ofan emotional state from one mouse to another.

In earlier work (Chen et al., 2009), we developed a simi-lar experimental procedure in which observer mice experienceddistressed conspecifics that underwent a series of tone-shock pair-

ings (Fig. 1). While the demonstrators were receiving the shock,observer mice did not express appreciable freezing behavior them-selves, but they immediately oriented towards the demonstratormice while the shock was being applied (Chen et al., 2009). This

1870 J.B. Panksepp, G.P. Lahvis / Neuroscience and Biobehavioral Reviews 35 (2011) 1864–1875

Fig. 1. Conditioning apparatus to assess social transfer of fear among mice. Mice are habituated to the apparatus and then an observer (left) is exposed to a demonstrator(right) receiving 10 consecutive forward-pairings of a 30-s tone and a 2-s shock (90-s inter-trial interval). After 2 days of conditioning, the observer is placed on the side oft e presT heread

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he apparatus where the demonstrator was conditioned and it is then exposed to fivhe steel bars on the demonstrator side of the apparatus deliver electrical current wuring the dark phase of the circadian cycle under dim red illumination.

nding differs from what was reported for observer mice by Jeont al. (2010), where individuals froze during the experience ofistress in conspecifics. The discrepancy may be due to the facthat Jeon et al. (2010) provided a very strong UCS to observers20 2-s shocks [1 mA] delivered over a 4-min period) to demon-trator mice, whereas our study utilized a more modest UCS (10-s shocks [0.5 mA] delivered over a 20-min period). Addition-

lly, observers and demonstrators were familiar in the Jeon et al.2010) study, whereas the mice in our study were unfamiliar (Chent al., 2009). While the reason for this difference between thexperiments is unknown, it does highlight important issues regard-

ig. 2. Freezing behavior of mice. (a) Without conditioning or observations of fearful demoreezing responses to the tone. Freezing was measured for 30 s during each CS presentatiad prior experience with fearful demonstrators. Freezing was measured for 30 s durinrevious experience with distressed demonstrators also expressed increased acquisitionontingency. Freezing was measured for 28 s during each CS presentation on trials 7–10. (xpressed more freezing behavior than B6 mice to the CS when it was paired with a UCS.epresent a significant difference (P < 0.05) between the two genetic backgrounds. All datt al. (2009).

entations of the CS-only followed by five presentations of the CS–UCS contingency.s the bars on the observer side are inactive. Conditioning and testing are conducted

ing the relationship between the strength of the UCS provided tothe demonstrator and the expression of emotional contagion andshared affect.

During the first half of the testing phase, 20 min after the lastexperience with demonstrators (equivalent to a short-term mem-ory test), each observer mouse was individually placed back intothe conditioning apparatus and their freezing behavior was exam-

ined in response to the CS-only (the CS was not behaviorally salientprior to conditioning; Fig. 2a). Observer mice expressed freezingbehavior during playback of the CS as if they anticipated the ini-tiation of distress in others (Fig. 2b). Thus, similar to Jeon et al.

nstrators, mice from both the BALB and B6 genetic backgrounds expressed minimalon. (b) B6 mice expressed more freezing behavior than BALB mice to the CS if theyg each CS presentation on trials 1–5 and for 28 s on trial 6. (c) B6 mice that hadof freezing behavior relative to BALB mice when they were exposed to the CS–UCSd) BALB mice that did not have previous experience with distressed demonstratorsFreezing was measured for 28 s during each CS presentation on all trials. Asterisksa are presented as the mean ±standard error and were originally reported in Chen

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2010), the observer mice in our study were responsive to a CS thatas associated with the induction of distress in others. Importantly,

his behavioral response were readily expressed by observer micerom C57BL/6J (B6) strain, but not in individuals from the BALB/cJBALB) strain, which indicates that genetic background can influ-nce the degree to which a mouse is responsive to distress in others.his strain-dependent difference is provocative because heritablempairments in psychosocial functioning often include a compo-ent where individuals fail to empathize (Goldenfeld et al., 2007;obson, 2007; Silani et al., 2008; Greimel et al., 2010).

During the second half of the testing phase, observer mice werehemselves exposed to the CS–UCS contingency and their freezingehavior was evaluated. B6 mice also expressed increased acquisi-ion of the CS–UCS association relative to BALB observers (Fig. 2c).y contrast, without the prior experience of distress in demon-trators, BALB mice expressed increased acquisition of the CS–UCSssociation relative to B6 mice (Fig. 2d). Thus, a genetic influencen acquisition of a fearful memory (i.e., BALB > B6) was moderatedy prior experience with social distress (i.e., B6 > BALB).

We were able to reproduce the strain-dependent effect on freez-ng behavior in response to the CS-only and acquisition of theS–UCS association by exposing observer mice to pairings of theS and playbacks of conspecific distress vocalizations (Chen et al.,009). This finding suggests that vocal communication plays a cru-ial role in the social transfer of fear among mice. A similar findingas been demonstrated in rats, where the number of 22 kHz-USVsmitted by a fearful demonstrator was positively associated withhe amount of fear that was expressed by an observer (Wöhr andchwarting, 2008). Importantly, both BALB and B6 observers ori-nted to the distress vocalizations of demonstrator mice (Chent al., 2009), and age-matched mice from these strains exhibitomparable thresholds for evoked auditory brainstem responses totimuli that are presented at frequencies similar to the CS (1 kHz)nd the distress vocalizations (≈20 kHz) (Zheng et al., 1999; Willottt al., 1998). Furthermore, BALB mice were able to acquire theS–UCS association when they were directly administered the UCS.hus, it appears that a difference in the hearing ability of micerom these two strains does not account for the difference in theirensitivity to conspecific distress.

The BALB and B6 mouse strains have been developed asn experimental model of sociability by several laboratoriesSankoorikal et al., 2006; Moy et al., 2007; Panksepp and Lahvis,007), and it has been suggested that the BALB mouse may be aalid mouse model of autism (Brodkin, 2007). By contrast, B6 micexpress high levels of gregariousness and social reward follow-ng social isolation, and are behaviorally sensitive to the inductionf distress in others (Panksepp and Lahvis, 2007; Panksepp et al.,007; Chen et al., 2009). In this regard, it is interesting to note thatpositive association between measures of empathic responsive-ess and personality-trait indices of sociability is a common finding

n the human empathy literature (Eisenberger et al., 2006). Thus,urther assessments of the inter-relationships between these socialariables in B6 mice are warranted and may yield insights into theechanisms underlying such phenotypic associations.In addition to behavioral responsiveness, studies from both

ur lab (Chen et al., 2009) and the Shin lab (Jeon et al., 2010)emonstrated that observer mice exhibit physiological correlatesf empathy while they experience conspecific distress. For instance,he heart rate of observer mice from the B6 strain increased imme-iately at the beginning of the experience of conspecific distressnd then decreased below baseline with repeated exposures toistressed conspecifics. BALB mice also exhibited heart rate accel-

ration upon the induction of distress in conspecifics, but there waso ensuing heart rate deceleration with repeated exposures to con-pecific distress. These results were particularly intriguing because

series of studies in humans has demonstrated a relationship

behavioral Reviews 35 (2011) 1864–1875 1871

between heart rate deceleration and empathic concern for others(Zahn-Waxler et al., 1995, also see Anastassiou-Hadjicharalambousand Warden, 2008).

Jeon et al. (2010) examined neuronal activity, specifically thetheta rhythm frequency (≈6 Hz) in the anterior cingulate cortex(ACC) and the lateral amygdala (LA), and found that observingconspecific distress synchronizes these oscillations. When theseinvestigators used lidocaine to locally inactivate discrete brainregions, they revealed that ACC activation was required to engenderfreezing to demonstrator distress, but not subsequent context-specific freezing behavior in observers. By contrast, LA activationwas essential for both freezing responses during the experienceof conspecific distress and the subsequent expression of context-specific freezing behavior by observers. Thus, Jeon et al. (2010)proposed that the ACC was an essential brain region for the percep-tion of conspecific distress in mice, whereas the LA was crucial forrecalling this experience. As far as we know, the Jeon et al. (2010)study is the first of its kind in that it identified a neuronal sub-strate underlying a phenotype relevant to empathy in mice. Theirfindings are especially important because the ACC, a brain regionlong implicated in the regulation of social processes (Panksepp,2003; Eisenberger and Lieberman, 2004), has been shown to acti-vate when humans detect distress in others (Singer et al., 2004;Jackson et al., 2005).

The experiments in this section are distinct from other studiesdescribed in this review because they demonstrated that rodentsdo not require direct experience with a CS–UCS contingency inorder to express a behavior that reflects an affective response topresentation of the CS-only. Rather, observers gained an explicitunderstanding of the CS–UCS association through a shared socialexperience. Many questions remain regarding the extent to whichthis type of empathy is expressed in rodents. The studies that havebeen considered in this review implicate several key variables thatappear to modulate rodent sensitivity to distress in others; thesefactors include familiarity with the demonstrator, prior experi-ence with the UCS and the strength of the UCS delivered to thedemonstrator, among others. For the sake of clarity, we summarizethe key points of similarity and distinction among the studies inTable 1. In our view, it is likely that the expression of shared affectamong rodents in any given behavioral paradigm is influenced bya dynamic interaction between these factors.

5. Synopsis and conclusions

All mammalian species are universally equipped with brainscapable of generating felt, emotional experiences (Panksepp, 1998).Although this assertion has been speculated for years (Darwin,1872/1998; Crowcroft, 1966), only recently has it become foun-dational, largely through Jaak Panksepp’s seminal contributions.Within this context, it becomes almost axiomatic that rodents arecapable of empathy, a process where the affective feelings of oneare conveyed to another and then generate the same feelings in thatindividual. Consistent with the affective neuroscience approach,this argument is nevertheless a working hypothesis that can be fal-sified. Perspectives on empathy in rodents should derive from anintegration of behavioral, psychological, neural and evolutionaryapproaches that are continuously updated based upon the availableexperimental evidence.

Essentially all of the mouse studies described in thisreview utilized individuals that were derived from the C57line and it will be interesting to see if these findings gen-

eralize to mice from additional strains. If empathy manifestsitself on a phenotypic continuum (see Decety et al., 2007 fora review), than we would anticipate that a graded empa-thy response should be found when comparing several strains.

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Table 1Summary of key variables from recent studies that focused on the detection and response of rodent observers to conspecific (demonstrator) distress. Except for experiments 1 and 2 from Langford et al. (2006), and the firstobserver responses in Chen et al. (2009) and Jeon et al. (2010), demonstrator pain experiences occurred prior to testing of the observer rodent. Demonstrators expressing a conditioned fear response were present during thetesting of observers in Kim et al. (2010). Non-fearful demonstrators were present during the testing of observers in Kiyokawa et al. (2009).

Study (Experiment) Species Demonstratorexperience

Observer experience Observer response Observerpainexperiencerequired?

Familiarityrequired?

Sensorymodality

Kavaliers et al. (2003) Mouse Exposure to biting flies Demonstrator distress ⇒ Exposure tonon-biting flies of the same species

↑ avoidance tonon-biting flies of thesame species

No No Visual

Langford et al. (2006) (1) Mouse 0.9% acetic acidinjection

0.9% acetic acid injection + Demonstratordistress

↑ writhing Yes Yes Visual

Langford et al. (2006) (2) Mouse 1% formalin injection 5% formalin injection + Demonstrator distress ↓ paw licking Yes Not tested Not tested

Langford et al. (2006) (3) Mouse 0.9% acetic acidinjection

Demonstrator distress ↑ thermal painbehavior

No Not tested Not tested

Bredy & Barad (2009) (1) Mouse 2-s shock(1 mA) + cue × 3, 120-sITI

Social interaction w/ demonstrator ⇒ 2-s shock(1 mA) × 3, 120-s ITI

↓ freezing to cue Yes Not tested Olfactory

Bredy & Barad (2009) (2) Mouse 2-s shock(1 mA) + cue × 3, 120-sITI

2-s shock (1 mA) × 3, 120-s ITI ⇒ Socialinteraction w/ demonstrator ⇒ Extinctiontraining

↓ freezing to cue (i.e.,↑extinction)

Yes Not tested Olfactory

Bredy & Barad (2009) (3) Mouse 2-s shock(1 mA) + cue × 3, 120-sITI ⇒ 10 extinctiontrials

2-s shock (1 mA) × 3, 120-s ITI ⇒ Socialinteraction w/ demonstrator ⇒ Extinctiontraining

↑ freezing to cue (i.e., ↓extinction)

Yes Not tested Non-olfactory

Chen et al. (2009) Mouse 2-s shock(0.5 mA) + cue × 10 (2sessions), 90-s ITI

Demonstrator distress + cue ↑ orientation todemonstrator distress,↑ freezing to cue thatpredicts demonstratordistress

Not tested(observershad 1 priorexperiencew/shock)

No Auditory

Guzmán et al. (2009) Mouse Exposure to context Non-fearful demonstrator in context (2sessions) ⇒ 2-s shock (0.7 mA) + context

↓ freezing to context Yes Not tested Visual

Kiyokawa et al. (2009) Rat No experience 0.5-s shock (0.7 mA) × 7, 30-180-sITI ⇒ Non-fearful demonstrator present duringtesting

↓ freezing to cue Yes No Olfactory

Knapska et al. (2010) (1) Rat 1-s shock(1 mA) + context × 10,60-s ITI

Social interaction w/ demonstrator ⇒ Activeavoidance training to 5-s shock (1 mA) + cue

↑ cue-based avoidancebehavior

Yes Not tested Not tested

Knapska et al. (2010) (2) Rat 1-s shock(1 mA) + context × 10,60-s ITI

Social interaction w/ demonstrator ⇒ 1-s shock(1 mA) + context

↑ freezing to context Yes No Not tested

Jeon et al. (2010) Mouse 2-s shock(1 mA) + context × 20,10-s ITI

Demonstrator distress + context ↑ freezing todemonstrator distress,↑ freezing to contextthat predictsdemonstrator distress

No Enhancedby

Visual

Bruchey et al. (2010) (1) Rat 0.5-s shock(0.7 mA) + cue × 3,180-s ITI

Demonstrator conditioned response to cue × 3 ↑ freezing to cue No Not tested Not tested

Bruchey et al. (2010) (2) Rat 0.5-s shock(0.7 mA) + cue × 3,180-s ITI

Demonstrator conditioned response tocue × 3 ⇒ 0.5-s shock (0.4 mA) + cue × 3, 180-sITI

↑↑ freezing to cue Yes Not tested Not tested

Kim et al. (2010) Rat 1-s shock(2 mA) + cue × 10,120-s ITI

1-s shock (1 mA) × 3, 60-s ITI ⇒ Demonstratorresponse to cue (8 min continuous) duringtesting

↑ freezing to cue Yes Not tested Auditory

[+] refers to a concurrent experience. [ITI] refers to inter-trial interval. [⇒] refers to a transition between experiences. [↑] and [↓] refers to an increase and decrease in behavioral responsiveness of the observer, respectively. [↑↑]refers to an increase in the behavioral responsiveness of the observer relative to the first experiment in the study.

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uch a finding would be highly amenable to employingorward genetic approaches to understand mouse endophenotypeshat are relevant to empathy. On a related note, an associationetween sociability and empathic responding (Chen et al., 2009;ruchey et al., 2010; Knapska et al., 2010) has not been thoroughlytudied in rodents and this too could be evaluated via assess-ents of multiple strains. Another impending question entails how

he affective components of empathy in rodents can be modu-ated by environmental and pharmacological factors. Several ofhe studies described above demonstrated that greater familiarityetween partners enhances empathic responding in mice (Langfordt al., 2006; Jeon et al., 2010), a finding that is consistent withhe human empathy literature (reviewed by Davis, 1994; Prestonnd de Waal, 2002). Moreover, given that many mental illnessesnclude heightened or diminished abilities for empathy, includ-ng schizophrenia (Derntl et al., 2009, Haker & Rossler, 2009),bsessive compulsive disorders (Fontenelle et al., 2009), anorexia-ervosa (Kucharska-Pietura et al., 2004), the neurochemical basisf empathic responding in rodents should be explored and candi-ate molecules from a class of drugs termed ‘empathogens’ (Valeand Hautefeuille, 2007) should be evaluated in rodents.

By definition, empathy requires that an individual be attunedo the potential for an emotional experience in another. Whilehe studies described in this review, as well as most work withumans, have focused on empathy within the context of negativelyalenced emotions (e.g., pain, sadness), the capacity for empathyhould also be considered when rodents experience positive emo-ions. The induction of negative emotional states has been easiero study in animals because they have an immediate impact on theikelihood for survival. However, ‘positive empathy’ happens everyay. A good example of this in human life is when an individualnswers a phone call and through the vocal prosody of a friendr colleague, the individual immediately becomes invigorated byxcitement, even though he or she does not yet possess a propo-itional knowledge of what underlies the excitement. The positivespects of empathy have been difficult to document in non-humannimals, but there are some provocative recent examples that coulde developed into rodent models of positive empathy. For exam-le, a recent study demonstrated that adolescent B6 mice become

pseudosensitized’ to the locomotor-activating effect of morphineimply by observing other mice that had been treated with the drugHodgson et al., 2010). Thus, mice were exposed to demonstra-or mice that were subjected to a typical morphine-sensitizationrotocol across multiple days. On the test day, mice that hadeceived repeated treatments of morphine expressed the expectedyperlocomotion phenotype in response to a standard dose oforphine. Remarkably, observer mice exhibited an enhanced loco-otor response to the same morphine dose as if they had previous

xperience with the drug. The doses of morphine used by Hodgsont al. (2010) were within that range that is typically used to measureeward in conditioned place preference studies. Since locomotorensitization is thought to reflect a state of reward, it is intriguingo speculate that the observer mice shared the reward state withemonstrator mice during the sensitization protocol, and that thenhanced locomotor response of observers during testing was aeflection of this shared experience. It is important to note thathe actions of a pharmacological compound, such as morphine, inhe brain may be quite different than a more natural stimulus, andhe mechanisms underlying pseudosensitization may thus be veryifferent than those described in Sections 2–4.

Another case where positive empathy might come to play isn an experimental paradigm where rats are trained to cooperate

o pull in a baited platform to their cage to procure an oat flakeRutte and Taborsky, 2007). A subject would pull for an unfamiliaronspecific that was adjacent to its cage as long as the act had beenreviously performed for the subject; it did not matter whether the

behavioral Reviews 35 (2011) 1864–1875 1873

specific individual adjacent to the rat was a prior altruist, just thatthe subject had been a prior recipient of helping behavior from anyother individual. Rutte and Taborsky (2007) referred to this pro-cess as ‘generalized reciprocity’ and suggested that positive affectmight be a mechanism underlying this phenomenon. In our view,it is conceivable that positive social affect results from both the actof helping and receiving, and thus shared pleasure might be a psy-chological consequence of this type of cooperative behavior for rats(also see Schuster and Perelberg, 2004; de Waal et al., 2008).

Rough-and-tumble play is a robust and rewarding form of socialactivity that is expressed among young rats. In studies of rat playbehavior, pharmacological or environmental manipulation of thestate of one rat in a dyad drastically alters the behavior of the otherwithin this behavioral context (Poole and Fish, 1979; Humphreysand Einon, 1981; Varlinskaya et al., 1999; Deak and Panksepp,2006), which suggests that playful rats are very attuned to thestate of their partners. Indeed, adolescent rats prefer to be in thecompany of social partners that express greater amounts of 50 kHz-USVs (Panksepp and Burgdorf, 2003), which are a vocal reflectionof positive social affect (Knutson et al., 2002). Thus, rats have a pref-erence for socially positive partners and appear to modulate theirplay behavior accordingly when the behavior of their partner is dis-cordant with their own. Taken together, these findings imply thatrats enjoy play bouts with individuals that are able to share a similarexperience with them within the context of social interaction.

A final and critical question regarding empathy in rodents isassociated with its underlying neural circuitry. It will be interestingto see how future brain studies involving rodent empathy corre-spond to the human counterpart experiments. Indeed, the initialcomparisons are promising (Jeon et al., 2010). However, rodentbrains can also be studied at levels of analysis that are either difficultor unavailable in humans, apes and monkeys (e.g., brain region-specific manipulation of neurochemical signaling, high-throughputgenetic approaches including altering the activity of single genes). Itwill be critical to integrate findings regarding the neural substratesof empathy in rodents with what is known about this process inhumans. Consistent with the pioneering work of Jaak Pankseppin affective neuroscience, as more sophisticated models of rodentempathy emerge (including models of positive empathy), it will becrucial to assess the extent to which the neural underpinnings ofempathy overlap with the basic emotional operating systems of themammalian brain (Panksepp, 1998).

The possibility of empathy in rodents beckons several addi-tional issues. First, if empathy exists in rodents, then it immediatelyoffers an opportunity to study this process at levels of analysis thatheretofore have been impossible. The field of mouse genetics iscontinually evolving, but with the technologies that are currentlyavailable, it is realistic that the genetic substrates underlying theability to detect and respond to distress in others can be discoveredand eventually developed into targets for pharmacotherapeuticintervention. At a still greater level, Panksepp’s approach to affec-tive neuroscience has provoked us to consider that several basicaffective states can be experienced by all mammalian species. Ifsome of these emotional experiences can be induced in animals viaother individuals (i.e., shared affect) then many of us will be forcedto reconsider our own worldview of animal nature. Similarly, therecognition that rodents possess a capacity for empathy will requirescientists to carefully evaluate their own research practices in anattempt to reduce the potential for excessive communication ofpain or fear between individuals.

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