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What can rodents teach us about empathy?

Current Opinion in Psychology

Volume 24, December 2018, Pages 15-20

Ksenia Meyza and Ewelina Knapska

Highlights

• Sharing emotions is evolutionarily conserved and common for many species, including rodents.

• Several rodent behavioral paradigms model simple forms of empathy and prosocial behaviors.

• Animal studies provide an insight into the network of brain structures involved in emotional contagion and prosocial behavior.

While many consider empathy an exclusively human trait, non-human animals are capable of simple forms of empathy, such as emotional contagion, as well as consolation and helping behavior. Rodent models are particularly useful for describing the neuronal background of these phenomena. They offer the possibility of employing single-cell resolution mapping of the neuronal activity as well as novel techniques for manipulation of in vivo activity, which are currently unavailable in human studies. Here, we review recent developments in the field of rodent empathy research with special emphasis on behavioral paradigms and data on neuronal correlates of emotional contagion. We hope that the use of rodent models will enhance our understanding of social deficits in neuropsychiatric disorders characterized with empathy impairments and the evolutionary continuity of the empathic trait.

Current Opinion in Psychology 2018, 24:15–20

This review comes from a themed issue on Social neuroscience

Edited by David Amodio and Christian Keysers

For a complete overview see the Issue and the Editorial

Available online 13th March 2018

https://doi-org.unr.idm.oclc.org/10.1016/j.copsyc.2018.03.002

Defining empathy

We usually think of empathy as an ability to take perspective of another human being, ‘put ourselves in his/her shoes’, which allows for understanding of how others feel. This definition centers our thinking about empathy on cognitive rather than emotional capabilities. But to feel into another's situation we need an emotional connection. Impaired ability to share affect through facial expressions and eye contact is at the core of social deficits observed in autistic patients and can explain their difficulties in taking another person's perspective [1, 2]. The sharing of affect (i.e. moods and emotions) occurs very frequently and is an important aspect of social life. People share these states with others through emotional contagion, which improves intragroup communication and facilitates group bonding [3, 4]. Even though emotional contagion is relatively automatic and unintentional, spread of shared affect can be modulated by many external and internal factors, including our previous experience, contextual cues and/or individual differences (for review see [5]). With that many interacting factors, our understanding of how they influence our empathic behavior depends on our knowledge on how the brain integrates such complex information.

To decipher how our brains are wired for these difficult tasks, we need to break empathy down into more fundamental processes. The most influential theory describing the complexity of empathy has been proposed by Stephanie Preston and Frans de Waal [6]. Their Perception-Action model states that, at the simplest level, empathy is a capacity to be affected by and to share the emotional state of another individual. Perception of such emotional state automatically activates shared representations and evokes a matching emotional state in the observer. This process has been described in many mammals (or more precisely Amniote species [5, 7, 8, 9]), not only in humans. According to Preston and de Waal, with increasing cognition, the emotional core of state-matching evolved into more complex forms, including concern for the other and perspective-taking. This theory, though not thoroughly tested yet, encourages further studies of the evolutionary roots of empathy. In his work with monkeys, apes, and elephants, de Waal has found many cases of emotional responses to the distress of others [10], which suggests a deep-rooted propensity for feeling the emotions of another individual in these species. Empathy-driven prosocial behaviors, such as consolation or helping also were, until recently, considered to be restricted to humans and great apes. Consolation, however, has been recently observed also in dogs [11] and prairie voles, a highly social and monogamous rodent species [12•]. Together with rat helping behavior ([13, 14, 15, 16] but see also [17, 18]), they strongly point toward evolutionary continuity of both empathy and its prosocial outcomes.

Animal models

Emotional contagion

The discoveries which showed that rodents are able to sense what their fellow rodents are experiencing opened the way to study the brain mechanisms underlying social sharing of emotions. To explore the biological mechanisms underlying empathic behavior simple animal models are needed. Such models, in which rats or mice receive emotional information from their conspecifics, allow the role of precisely defined neuronal pathways involved in emotional sharing to be studied. Being in tune with each other can be studied using several behavioral paradigms. Most prominent of these paradigms include: immediate and remote fear transfer, fear learning by proxy and exposure to a conspecific in pain (Figure 1). With the use of these models, it was demonstrated that rodents can experience emotional contagion both during direct observation of an adverse event (e.g. a footshock administered to the paws of a conspecific) [19] and during exposure to a stressed cagemate in the safe environment of the home cage [20, 21]. Such phenomenon was also observed in a ‘Fear-by-Proxy’ paradigm, where information about the stressor is transmitted to a cagemate during exposure of the demonstrator to a stimulus (tone) previously associated with a shock [22]. State-matching was also observed in rats cohabiting a cage with an animal repeatedly exposed to social defeat [23•]. Studies exploring shared pain experiences confirmed that rodents display increased pain sensitivity in the company of an animal in pain [24, 25].

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Prosocial behaviors

Rats display prosocial approach, helping and consoling behaviors toward distressed cagemates [13, 16, 26]. They also can act cooperatively, especially if they have benefited from a similar behavior before [14, 15]. The paradigms exploring these behaviors (Figure 2) include: instrumental cooperative task [14, 15], freeing a restrained individual [13] and rescuing a soaked conspecific [16]. Even given choice between highly palatable food and freeing a cagemate, rats choose to act altruistically and often later share the food with the freed animal [13]. The exact motivation for helping another individual is, however, still heavily debated [17, 18].

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Social Buffering

The experimental paradigms described above, for the most part, employed emotional transfer from the stressed to the non-stressed animal. However, sharing emotions has also an interesting consequence for the stressed individual. The presence of a conspecific, especially a familiar/friendly one [27], reduces stress levels, attenuates behavioral arousal (e.g. freezing response to a fearful stimulation) and expedites recovery from trauma. The phenomenon, dubbed ‘social buffering’, has been studied in depth by Yasushi Kiyokawa and collaborators (for review see [28]). They found that the behavioral outcome depends on the type and timing of the interaction (i.e. pair-exposure to the stressor versus pair-housing after the shock) and that the main modality responsible for the effect is olfaction.

Neuronal correlates of empathy

Animal studies provided an insight into the network of brain structures involved in emotional contagion and the underlying neural mechanisms. Animal models offer the possibility of blocking selected brain structures, changing the level of neurotransmitters and observing or inducing changes in synaptic plasticity. Very few of these approaches can be employed in human studies [29]. In mice, however, inactivation of neurons within the anterior cingulate cortex (ACC) or only of a specific ion channel (the Cav1.2 Ca2+ channel), which contributes to synaptic transmission and neuronal excitability in this structure, led to impairments of observational fear learning [30]. Interestingly, inactivation of this structure did not disrupt fear memory retrieval and classical fear conditioning. On the other hand, inactivation of the lateral amygdala resulted in deficits in both classical and observational fear. Using unilateral inactivation as well as electrical stimulation of the ACC, Kim et al. showed that observational fear learning depends on the activation of the right but not the left ACC [31]. Further, it has been shown that observational fear learning relies on dopamine D2 receptors and the amount of serotonin neurotransmitter in the ACC [32]. Using the model of fear conditioning by proxy, Jones and Monfils [33] confirmed that social fear transmission shares certain neuronal pathways with direct fear learning (such as the activation of the lateral amygdala), but also involves other regions, such as the ACC...removed... Further, bilateral lesions of the prefrontal cortex (but not of the amygdala or the entorhinal cortex) were sufficient for inhibition of pain empathy in rats [36], governed by the noradrenergic input from locus coeruleus to the dorsal root ganglia [37]. The abovementioned inactivation studies point to the involvement of the ACC, dmPFC and the amygdala in fear and pain contagion.

Aside from specific inactivation of selected brain structures or manipulation of neurotransmitter levels, the animal models enable mapping of the activity of the brain with single-cell resolution, which is not possible in human imaging studies (except for very few clinical cases of pre-surgery monitoring of brain activity). For instance, such detailed mapping showed functional heterogeneity of the amygdala ...removed... However, the pattern of activation in the demonstrators and observers was different, pointing to a distinct neural mechanism involved in acquisition of direct and socially transmitted fear. Much less is known about neuronal mechanisms underlying prosocial behaviors. The importance of the amygdala in the shaping of prosocial responses was recently demonstrated. A lesion of the basolateral nucleus of amygdala was shown to impair the expression of mutual reward preferences in the Prosocial Choice Task [42]. Although an emotional response is a central component of empathy, mere contagion of affect is not sufficient to induce prosocial behavior...removed...

Modulators of empathy

Animal models enable and encourage a systematic study of factors influencing emotional contagion. Similar to humans, emotional contagion in rodents is heavily influenced by familiarity. Rodents, just like humans, are more likely to experience shared emotions and exhibit prosocial behaviors such as help or consolation toward familiar individuals (cagemates, siblings, partners in monogamic species [12•, 43]), Reduced anxiety conditions help ‘stranger’ mice develop pain empathy [44], but at the same time, they impair helping behavior toward a restrained rat [45]. Similar previous experience also facilitates the development of shared emotional state. Rats that have previously experienced, for example, footshocks [46] or pain [47] show stronger responses to observed aversive stimulation. In-group membership and previous social experience, rather than resemblance to another member of the same rat strain are also important for the initiation of helping behavior [48]. So are housing conditions during adolescence (single versus group) for the development of empathic skills [49, 50, 51] as well as dominance structure within the given group of animals [33]. Most of the studies discussed here are based on a single exposure to a stressed cagemate. However, some studies show that chronic exposure changes behavioral responding, increasing anxiety, pain nociception, and altering mouse defensive responses to a rat [52].

One of the possible mechanisms of social behaviors modulation is through so-called social hormones, oxytocin and arginine vasopressin, which have been shown to affect a wide range of behaviors, including pair bonding, in-group and out-group relationships, social communication, and social stress response (for review see [53]). Most of the studies till now have been focused on oxytocin, which as a neuropeptide with profound prosocial effects, has a clinical potential. Animal models allow us to study the mechanisms underlying effects of oxytocin supplementation and inhibition. The administration of exogenous oxytocin, however, often produces contradictory results. A recent study by Pisansky and colleagues [54•] showed that intranasal oxytocin (both acute and chronic) increases freezing in response to a stressed unfamiliar mouse. Similar effect was observed upon chemogenetic activation of oxytocinergic neurons. At the same time, systemic administration of an oxytocin receptor antagonist impaired fear acquisition from familiar individuals [54•]. On the other hand, chronic intranasal oxytocin impairs sociability of B6 mice [55], fails to improve sociability of the BTBR mice [56] and results in deficient pair bonding in prairie voles [57]. The discrepancies may stem from different behavioral protocols and oxytocin doses but also from different roles of oxytocin in distinct brain regions involved in specific behaviors, for example, oxytocin in the central nucleus of the amygdala reduces fear [58], whereas in the septum it has an opposite effect [59]. Thus further studies of brain-specific oxytocin effects are well justified and needed. Such structure-specific manipulation has shown that rat pups learned fear responses from their mothers, only if oxytocin neurotransmission in the central nucleus of the amygdala was intact [60•]. On the other hand, infusion of oxytocin receptor inhibitor within the ACC abolished empathic prosocial responses in prairie voles [12•]. In sum, to fully understand the complex, region-specific and behavior-specific mechanisms behind oxytocin modulation of social behaviors further studies are required.

Lastly, there are several reports on distinct strains of rodents (mostly mice) that differ from one another in empathic responsiveness [21, 61, 62•]. This variability makes mouse models of empathy especially suited for studying the genetic background of propensity for empathy. First studies exploring the emotional contagion in mouse models of autism spectrum disorder showed decreased responsiveness in an idiopathic model (the BTBR mouse [21]) and increased stereotypy in the Fragile X syndrome model mice (Fmr1KO/FVB, in prep.) upon exposure to a stressed cagemate. An elevated emotional contagion was also observed in a mouse model of Alzheimer's disease, in which it was linked to increased network synchrony between the anterior insula and basolateral amygdala [63]. Further studies are, however, needed to fully explore this subject.

Summary

Rodent models of empathy have become an indispensable tool of contemporary neuroscience. New techniques of imagining and manipulating neuronal circuits with singe-cell resolution allow for very detailed, mechanistic insight into the brain mechanisms underlying empathy. In contrast, current neuroimaging techniques used in human or primate studies provide data with spatial and temporal resolution too low for studying specific circuits, often residing within the same brain structure. In rodents, such information becomes available through a combined use of chemogenetic or optogenetic tools along with modern in vivo imaging techniques, such as the frame-projected independent fiber-photometry imaging based on genetically encoded calcium indicators [64]. Such methods offer single-cell precision required to disentangle mechanisms underlying emotional contagion and prosocial behaviors and shed some light on their relationship. The genetic diversity of mouse and rat strains also allows for in depth studies of individual differences in empathic abilities, which at both ends of spectrum can be associated with neurodevelopmental disabilities. This opens rodent empathy research field for preclinical testing of drugs aiming at improving social deficits in these conditions. Further, thanks to a fast maturation time, rodents constitute a highly practical model for studying the ontogeny of empathic abilities. Special emphasis should be laid here on early behavioral therapy, its effect on the neuronal circuits involved and the long-lasting effects of such intervention. One should, however, bear in mind that the rapid technological progress in the development of rodent models poses a new challenge for the translatability of the results obtained with these models. This issue is bound to become an interesting research topic in the near future.

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest

Acknowledgements

This work was supported by the European Research Council Starting Grant (H715148) to E.K. and the Polish National Science Center [grant number 2015/18/E/NZ4/00600] to K.M.

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