Variability in empathic fear response among 11 inbred strains of mice

Empathy is an important emotional process that involves the ability to recognize and share emotions with others. We have previously developed an observational fear learning (OFL) behavioral assay to measure empathic fear in mice. In the OFL task, a mouse is conditioned for context‐dependent fear when it observes a conspecific demonstrator receiving aversive stimuli. In the present study, by comparing 11 different inbred mouse strains that are commonly used in the laboratory, we found that empathic fear response was highly variable between different strains. Five strains – C57BL/6J, C57BL/6NTac, 129S1/SvImJ, 129S4/SvJae and BTBR T⁺ Itpr3^tf/J – showed observational fear (OF) responses, whereas AKR/J, BALB/cByJ, C3H/HeJ, DBA/2J, FVB/NJ and NOD/ShiLtJ mice exhibited low empathic fear response. Importantly, day 2 OF memory was significantly correlated with contextual memory in the classical fear conditioning among the 11 strains. Innate differences in anxiety, locomotor activity, sociability and preference for social novelty were not significantly correlated with OFL. Interestingly, early adolescent C57BL/6J mice exhibited an increase in acquisition of OF. The level of OFL in C57BL/6J strain was not affected by sex or strains of the demonstrator. Taken together, these data strongly suggest that there are naturally occurring OFL‐specific genetic variations modulating empathic fear behaviors in mice. The identification of causal genes may uncover novel genetic pathways and underlying neural mechanisms that modulate empathic fear and, ultimately, provide new targets for therapeutic intervention in human mental disorders associated with impaired empathy.     

The other side of the coin: Hypersociability

Affiliative social motivation and behavior, that is, sociability that includes attachment, prosocial behavior (sharing, caring and helping) and empathy (the ability to understand and share the feelings of others), has high variability in the human population, with a portion of people outside of the normal range. While psychiatric disorders and autism spectrum disorders are typically associated with a deficit in social behavior, the opposite trait of hypersociability and indiscriminate friendliness are exhibited by individual with specific neurodevelopmental disorders and following early adverse care. Here we discuss both genetic and environmental factors that cause or increase the risk for developing pathological hypersociability from human to rodent models.     

Affective empathy and prosocial behavior in rodents

Empathy is an essential function for humans as social animals. Emotional contagion, the basic form of afffective empathy, comprises the cognitive process of perceiving and sharing the affective state of others. The observational fear assay, an animal model of emotional contagion, has enabled researchers to undertake molecular, cellular, and circuit mechanism of this behavior. Such studies have revealed that observational fear is mediated through neural circuits involved in processing the affective dimension of direct pain experiences. A mouse can also respond to milder social stimuli induced by either positive or negative emotional changes in another mouse, which seems not dependent on the affective pain circuits. Further studies should explore how different neural circuits contribute to integrating different dimensions of affective empathy.     

Oxytocin receptor and vasopressin receptor 1a genes are respectively associated with emotional and cognitive empathy

Empathy is the ability to recognize and share in the emotions of others. It can be considered a multifaceted concept with cognitive and emotional aspects. Little is known regarding the underlying neurochemistry of empathy and in the current study we used a neurogenetic approach to explore possible brain neurotransmitter pathways contributing to cognitive and emotional empathy. Both the oxytocin receptor (OXTR) and the arginine vasopressin receptor 1a (AVPR1a) genes contribute to social cognition in both animals and humans and hence are prominent candidates for contributing to empathy. The following research examined the associations between polymorphisms in these two genes and individual differences in emotional and cognitive empathy in a sample of 367 young adults. Intriguingly, we found that emotional empathy was associated solely with OXTR, whereas cognitive empathy was associated solely with AVPR1a. Moreover, no interaction was observed between the two genes and measures of empathy. The current findings contribute to our understanding of the distinct neurogenetic pathways involved in cognitive and emotional empathy and underscore the pervasive role of both oxytocin and vasopressin in modulating human emotions.     

Animal models of social avoidance and social fear

Social fear and avoidance of social situations represent the main behavioral symptoms of social anxiety disorder (SAD), a highly prevalent anxiety disorder that is poorly elucidated and has rather unsatisfactory therapeutic options. Therefore, animal models are needed to study the underlying etiology and pathophysiology of SAD and to verify the efficacy of possible novel treatment approaches. In this review, we describe and discuss the most important paradigms that have been shown to induce social avoidance and fear in rodents, including foot shock exposure, restraint stress, social isolation, social instability, social defeat, conditioned defeat, social defeat/overcrowding, chronic subordinate colony housing, chronic mild stress, maternal separation and social fear conditioning. We also describe some of the behavioral paradigms used to assess social avoidance and fear in rodents, including the social interaction test, the social preference-avoidance test, the social approach-avoidance test, the three-chambered social approach test, the partition test and the modified Y-maze test. We focus on the behavioral alterations these paradigms induce, especially on social interaction, general anxiety and depressive-like behavior given that SAD is strongly comorbid with anxiety and affective disorders.     

Does Sympathy Motivate Prosocial Behaviour in Great Apes?

Prosocial behaviours such as helping, comforting, or sharing are central to human social life. Because they emerge early in ontogeny, it has been proposed that humans are prosocial by nature and that from early on empathy and sympathy motivate such behaviours. The emerging question is whether humans share these abilities to feel with and for someone with our closest relatives, the great apes. Although several studies demonstrated that great apes help others, little is known about their underlying motivations. This study addresses this issue and investigates whether four species of great apes (Pongo pygmaeus, Gorilla gorilla, Pan troglodytes, Pan paniscus) help a conspecific more after observing the conspecific being harmed (a human experimenter steals the conspecific’s food) compared to a condition where no harming occurred. Results showed that in regard to the occurrence of prosocial behaviours, only orangutans, but not the African great apes, help others when help is needed, contrasting prior findings on chimpanzees. However, with the exception of one population of orangutans that helped significantly more after a conspecific was harmed than when no harm occurred, prosocial behaviour in great apes was not motivated by concern for others.     

Empathy Is Moderated by Genetic Background in Mice

Empathy, as originally defined, refers to an emotional experience that is shared among individuals. When discomfort or alarm is detected in another, a variety of behavioral responses can follow, including greater levels of nurturing, consolation or increased vigilance towards a threat. Moreover, changes in systemic physiology often accompany the recognition of distressed states in others. Employing a mouse model of cue-conditioned fear, we asked whether exposure to conspecific distress influences how a mouse subsequently responds to environmental cues that predict this distress. We found that mice are responsive to environmental cues that predict social distress, that their heart rate changes when distress vocalizations are emitted from conspecifics, and that genetic background substantially influences the magnitude of these responses. Specifically, during a series of pre-exposure sessions, repeated experiences of object mice that were exposed to a tone-shock (CS-UCS) contingency resulted in heart rate deceleration in subjects from the gregarious C57BL/6J (B6) strain, but not in subjects from the less social BALB/cJ (BALB) strain. Following the pre-exposure sessions, subjects were individually presented with the CS-only for 5 consecutive trials followed by 5 consecutive pairings of the CS with the UCS. Pre-exposure to object distress increased the freezing responses of B6 mice, but not BALB mice, on both the CS-only and the CS-UCS trials. These physiological and behavioral responses of B6 mice to social distress parallel features of human empathy. Our paradigm thus has construct and face validity with contemporary views of empathy, and provides unequivocal evidence for a genetic contribution to the expression of empathic behavior.     

The manifold nature of interpersonal relations: the quest for a common mechanism

It has been proposed that the capacity to code the 'like me' analogy between self and others constitutes a basic prerequisite and a starting point for social cognition. It is by means of this self/other equivalence that meaningful social bonds can be established, that we can recognize others as similar to us, and that imitation can take place. In this article I discuss recent neurophysiological and brain imaging data on monkeys and humans, showing that the 'like me' analogy may rest upon a series of 'mirror-matching' mechanisms. A new conceptual tool able to capture the richness of the experiences we share with others is introduced: the shared manifold of intersubjectivity. I propose that all kinds of interpersonal relations (imitation, empathy and the attribution of intentions) depend, at a basic level, on the constitution of a shared manifold space. This shared space is functionally characterized by automatic, unconscious embodied simulation routines.     

The comparative study of empathy: sympathetic concern and empathic perspective‐taking in non‐human animals

While empathy is a century‐old psychological concept, its study in non‐human animals has become the focus of much recent scientific interest, as it promises to provide the clues to understand the evolutionary origins of our social and moral nature. A review of the comparative study of empathy is thus timely to complement and constrain anthropocentric views, and to integrate current findings. However, this is not an easy task. The study of animal empathy has developed using different paradigms, different concepts of the phenomena involved, and the absence of a systematic program. Herein, we carry out a comprehensive review of the literature on complex forms of empathy in non‐human animals: sympathetic concern and empathic perspective‐taking. In particular, we focus on consolation and targeted helping, as the best examples of each category. In so doing, we try to shed light on the current debate concerning whether these phenomena are exclusively human traits. First, we try to clarify the terminology and taxonomy of forms of empathy, providing operative criteria for these phenomena that are applicable to both human and non‐human animals. Second, we discuss whether the available evidence qualifies such behaviour as empathic. Third, we aim to provide an integrative view of the field, clarifying the challenges and conditions to satisfy. We also hope to highlight the importance of the study of these processes for elucidating the evolutionary history of this capacity across the animal kingdom.     

Social neuroscience of disgust

Disgust can be thought of as an affective system that has evolved to detect signs of pathogens, parasite and toxins as well as to stimulate behaviors that reduce the risk of their acquisition. Disgust incorporates social cognitive mechanisms to regulate exposure to and, or anticipate and avoid exposure to pathogens and toxins. Social cognition entails the acquisition of social information about others (ie, social recognition) and from others (ie, social learning). This involves recognizing and assessing other individuals and the pathogen/parasite/contamination/toxin threat they pose and deciding about when and how to interact with and, or avoid them. Social cognition provides a frame‐work for examining the expression of disgust and the associated neurobiological mechanisms. Here, we briefly consider the relations between social cognition and pathogen/parasite/toxin avoidance behaviors. We briefly discuss aspects of: (1) the odor mediated social recognition of actual and potentially infected individuals and the impact of parasite/pathogen threat on disgust mate and social partner choice; (2) the roles of “out‐groups” (strangers, unfamiliar individuals) and “in‐groups” (familiar individuals) in the expression of disgust and pathogen avoidance behaviors; (3) individual and social learning of disgust and empathy for disgust; (4) toxin elicited disgust and anticipatory disgust; (5) the neurobiological mechanisms, and in particular the roles of the nonapeptide, oxytocin and estrogenic mechanism associated with social cognition and the expression of disgust. These findings on the social neuroscience of disgust have a direct bearing on our understanding of the roles of disgust in shaping human and nonhuman social behavior.     

Perception of a Common Fate in Human—Animal Relations and its Relevance to our Concern for Animals

ABSTRACT

Considering violence against animals and violence against people as one and the same problem presupposes a comprehensive concept of violence, a concept of suffering uniting humans and animals, and a specific relationship to nature and life. The thesis of this paper is that the greater concern for animals that has developed in western societies, particularly in the last few decades, is fundamentally related to the perception of a common fate that humans and animals share, especially in the face of the threat of an ecological or nuclear catastrophe and the awareness of the competitiveness in human relationships that now prevails the world over. Two literary works and a social psychology study are referred to in order to illustrate this thesis. The perception of a common fate is considered an integral part of identification with others, either humans or animals, of empathy with them, and of an attitude of respect toward nature in general.     

Evidence that accent is a dimension of social categorization,not a byproduct of perceptual salience,familiarity, or ease-of-processing

Certain features of language, such as accent, are acquired from the local social environment during an acquisition period starting at infancy and ending roughly at puberty. If the scale of social interaction expands after puberty, humans will encounter variance in these linguistic features, and the linguistic similarity between people will indicate the degree to which they share a common early social history. There is reason to believe that such a dynamic is not a modern phenomenon, but has likely occurred throughout our species’ evolutionary history since the advent of language. Consequently, the human mind may contain systems for categorizing others according to their linguistic repertoires, including their accents. Four studies demonstrate that (i) accent differences—both native versus non-native accents and also two different non-native accents‚ are the basis of spontaneous and implicit social categorization, and (ii) this is not driven by general acoustic-differences, low level sound differences, or differences in familiarity or ease-of-processing. Results are consistent with the hypothesis that human mind contains systems for categorizing others according to their accents.     

Murine Features of Neurogenesis in the Human Hippocampus across the Lifespan from 0 to 100 Years

Background

Essentially all knowledge about adult hippocampal neurogenesis in humans still comes from one seminal study by Eriksson et al. in 1998, although several others have provided suggestive findings. But only little information has been available in how far the situation in animal models would reflect the conditions in the adult and aging human brain. We therefore here mapped numerous features associated with adult neurogenesis in rodents in samples from human hippocampus across the entire lifespan. Such data would not offer proof of adult neurogenesis in humans, because it is based on the assumption that humans and rodents share marker expression patterns in adult neurogenesis. Nevertheless, together the data provide valuable information at least about the presence of markers, for which a link to adult neurogenesis might more reasonably be assumed than for others, in the adult human brain and their change with increasing age.

Methods and Findings

In rodents, doublecortin (DCX) is transiently expressed during adult neurogenesis and within the neurogenic niche of the dentate gyrus can serve as a valuable marker. We validated DCX as marker of granule cell development in fetal human tissue and used DCX expression as seed to examine the dentate gyrus for additional neurogenesis-associated features across the lifespan. We studied 54 individuals and detected DCX expression between birth and 100 years of age. Caveats for post-mortem analyses of human tissues apply but all samples were free of signs of ischemia and activated caspase-3. Fourteen markers related to adult hippocampal neurogenesis in rodents were assessed in DCX-positive cells. Total numbers of DCX expressing cells declined exponentially with increasing age, and co-expression of DCX with the other markers decreased. This argued against a non-specific re-appearance of immature markers in specimen from old brains. Early postnatally all 14 markers were co-expressed in DCX-positive cells. Until 30 to 40 years of age, for example, an overlap of DCX with Ki67, Mcm2, Sox2, Nestin, Prox1, PSA-NCAM, Calretinin, NeuN, and others was detected, and some key markers (Nestin, Sox2, Prox1) remained co-expressed into oldest age.

Conclusions

Our data suggest that in the adult human hippocampus neurogenesis-associated features that have been identified in rodents show patterns, as well as qualitative and quantitative age-related changes, that are similar to the course of adult hippocampal neurogenesis in rodents. Consequently, although further validation as well as the application of independent methodology (e.g. electron microscopy and cell culture work) is desirable, our data will help to devise the framework for specific research on cellular plasticity in the aging human hippocampus.     

Behavioral responses to physical vs. social novelty in male and female laboratory rats

Most behavioral tests used with laboratory rodents involve measuring behavioral responses to physical novelty. However, laboratory rodents are often derived from highly social species for which novel social stimuli may induce different levels of fear or curiosity compared to novel physical objects. We hypothesized that behavioral responses will differ in response to novel physical vs. social cues, and that females may show more exploration of social novelty, based on prior studies indicating that females more actively seek social support during duress compared to males. We compared young (55-day-old) Sprague-Dawley rats’ responses to an arena filled with novel objects (“physical”) or a novel same-sex caged conspecific (“social”). Rats were more active and spent twice as much time in contact with the novel social stimulus compared to novel physical stimuli. Although females were more active than males, females were not particularly more exploratory in the social arena compared to males. The results indicate that a novel social partner (even a caged one with limited ability to interact) elicits more exploration than novel objects for both male and female rats.     

Standardizing the analysis of conditioned fear in rodents: a multidimensional software approach

Data comparability between different laboratories strongly depends on the individually applied analysis method. This factor is often a critical source of variation in rodent phenotyping and has never been systematically investigated in Pavlovian fear conditioning paradigms. In rodents, fear is typically quantified in terms of freezing duration via manual observation or automated systems. While manual analysis includes biases such as tiredness or inter‐personal scoring variability, computer‐assisted systems are unable to distinguish between freezing and immobility. Consequently, the novel software called MOVE follows a semi‐automatized approach that prefilters video sequences of interest for the final human judgment. Furthermore, MOVE allows integrating additional data sources (e.g. force‐sensitive platform, EEG) to reach the most accurate and precise results. MOVE directly supports multi‐angle video recordings with webcams or standard laboratory equipment. The integrated manual key logger and internal video player complement this all‐in‐one software solution. Calculating the interlaboratory variability of manual freezing evaluation revealed significantly different freezing scores in two out of six laboratories. This difference was minimized when all experiments were analyzed with MOVE. Applied to a genetically modified mouse model, MOVE revealed higher fear responses of CB1 deficient mice compared to their wild‐type littermates after foreground context fear conditioning. Multi‐angle video analysis compared to the single‐camera approach reached up to 15% higher accuracy and two fold higher precision. Multidimensional analysis provided by integration of additional data sources further improved the overall result. We conclude that the widespread usage of MOVE could substantially improve the comparability of results from different laboratories.     

Bonobos Share with Strangers

Humans are thought to possess a unique proclivity to share with others – including strangers. This puzzling phenomenon has led many to suggest that sharing with strangers originates from human-unique language, social norms, warfare and/or cooperative breeding. However, bonobos, our closest living relative, are highly tolerant and, in the wild, are capable of having affiliative interactions with strangers. In four experiments, we therefore examined whether bonobos will voluntarily donate food to strangers. We show that bonobos will forego their own food for the benefit of interacting with a stranger. Their prosociality is in part driven by unselfish motivation, because bonobos will even help strangers acquire out-of-reach food when no desirable social interaction is possible. However, this prosociality has its limitations because bonobos will not donate food in their possession when a social interaction is not possible. These results indicate that other-regarding preferences toward strangers are not uniquely human. Moreover, language, social norms, warfare and cooperative breeding are unnecessary for the evolution of xenophilic sharing. Instead, we propose that prosociality toward strangers initially evolves due to selection for social tolerance, allowing the expansion of individual social networks. Human social norms and language may subsequently extend this ape-like social preference to the most costly contexts.     

Yawn contagion and empathy in Homo sapiens

The ability to share others' emotions, or empathy, is crucial for complex social interactions. Clinical, psychological, and neurobiological clues suggest a link between yawn contagion and empathy in humans (Homo sapiens). However, no behavioral evidence has been provided so far. We tested the effect of different variables (e.g., country of origin, sex, yawn characteristics) on yawn contagion by running mixed models applied to observational data collected over 1 year on adult (>16 years old) human subjects. Only social bonding predicted the occurrence, frequency, and latency of yawn contagion. As with other measures of empathy, the rate of contagion was greatest in response to kin, then friends, then acquaintances, and lastly strangers. Related individuals (r≥0.25) showed the greatest contagion, in terms of both occurrence of yawning and frequency of yawns. Strangers and acquaintances showed a longer delay in the yawn response (latency) compared to friends and kin. This outcome suggests that the neuronal activation magnitude related to yawn contagion can differ as a function of subject familiarity. In conclusion, our results demonstrate that yawn contagion is primarily driven by the emotional closeness between individuals and not by other variables, such as gender and nationality.     

I feel how you feel but not always: the empathic brain and its modulation

The ability to share the other's feelings, known as empathy, has recently become the focus of social neuroscience studies. We review converging evidence that empathy with, for example, the pain of another person, activates part of the neural pain network of the empathizer, without first hand pain stimulation to the empathizer's body. The amplitude of empathic brain responses is modulated by the intensity of the displayed emotion, the appraisal of the situation, characteristics of the suffering person such as perceived fairness, and features of the empathizer such as gender or previous experience with pain-inflicting situations. Future studies in the field should address inter-individual differences in empathy, development and plasticity of the empathic brain over the life span, and the link between empathy, compassionate motivation, and prosocial behavior.     

Experience Modulates Vicarious Freezing in Rats: A Model for Empathy

The study of the neural basis of emotional empathy has received a surge of interest in recent years but mostly employing human neuroimaging. A simpler animal model would pave the way for systematic single cell recordings and invasive manipulations of the brain regions implicated in empathy. Recent evidence has been put forward for the existence of empathy in rodents. In this study, we describe a potential model of empathy in female rats, in which we studied interactions between two rats: a witness observes a demonstrator experiencing a series of footshocks. By comparing the reaction of witnesses with or without previous footshock experience, we examine the role of prior experience as a modulator of empathy. We show that witnesses having previously experienced footshocks, but not naïve ones, display vicarious freezing behavior upon witnessing a cage-mate experiencing footshocks. Strikingly, the demonstrator''s behavior was in turn modulated by the behavior of the witness: demonstrators froze more following footshocks if their witness froze more. Previous experiments have shown that rats emit ultrasonic vocalizations (USVs) when receiving footshocks. Thus, the role of USV in triggering vicarious freezing in our paradigm is examined. We found that experienced witness-demonstrator pairs emitted more USVs than naïve witness-demonstrator pairs, but the number of USVs was correlated with freezing in demonstrators, not in witnesses. Furthermore, playing back the USVs, recorded from witness-demonstrator pairs during the empathy test, did not induce vicarious freezing behavior in experienced witnesses. Thus, our findings confirm that vicarious freezing can be triggered in rats, and moreover it can be modulated by prior experience. Additionally, our result suggests that vicarious freezing is not triggered by USVs per se and it influences back onto the behavior of the demonstrator that had elicited the vicarious freezing in witnesses, introducing a paradigm to study empathy as a social loop.