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Complex Behaviors

Rodent Models of Empathy Disorders

By May 31, 2021No Comments

Introduction to Empathy

Empathy is the capability to not only recognize and understand another individual’s emotional state and experience, but to also share these feelings and respond with concern or care when appropriate.[1] This trait is essential when acting with compassion, making decisions that are morally based, and building strong relationships. Empathy also encourages an individual to act in a prosocial way that comes from an intrinsic will to do good.

Psychologists have identified two different types of empathy; emotional and cognitive.[2]

Cognitive empathy, also known as perspective-taking or Theory of Mind, is having the knowledge of another person’s emotions and beginning to place yourself in their shoes in order to achieve an understanding of how they are feeling.[2,3] This type of empathy is mainly based on acknowledging the feelings that another person is having from an intellectual viewpoint.

Emotional empathy is physically experiencing what another person is emotionally and mentally going through, it is a progression from a purely cognitive point of view to a shared emotional experience.[2,3] This type of empathy relies on the brain’s mirror neurons, a distinctive group of motor neurons that not only fire when an individual is performing an action, but also when watching another performing the same or similar action.[4]

In humans, the normal development of empathy begins in early infancy with newborn babies crying when hearing another baby cry.[5,6] This phenomenon is a result of emotional contagion, where one person (demonstrator) triggers another person (observer) into experiencing similar emotions and behaviors.[7] Emotional contagion exists as its own entity but is vital for empathy and the communication thereof.[8] Before learning a language, emotional empathy undergoes substantial development, after which development of the cognitive aspect increases.[9] Once both types of empathy have been developed, they normally occur together; however, unbalanced development of these two can result in social dysfunction.[9]

Multiple factors affect the development of empathy in humans, these include temperament, genetic and environmental factors, socialization, and neural development.[10]

This article will look at the available models used to study empathy disorder in rodents. Since empathy is controlled by numerous factors it is important to incorporate different models that will focus on these factors. Therefore this article covers the behavioral, anatomical, genetic, and neuromodulation models in empathy studies.

How does Empathy Occur?

One of the main theoretical systems used to explain how empathy occurs is the Perception-Action Model of Empathy, first described by theorists de Waal and Preston.[11] This model suggests that when observing another person’s emotional state, the observer should have an automatic activation of their own memories with the state, resulting in them experiencing the event as if it were personally happening to them.[11,12]

This process is believed to be the foundation for higher levels of empathy and the theorists credit mirror neurons with allowing it to occur. It is expected that someone lacking this ability will have a deficit in empathy.

Pathology of Empathy

Empathy deficit disorder (EDD) is characterized by the inability of an individual to perceive, recognize and be in tune with another’s emotions.[13] These individuals may not be as responsive to emotional contagion as those with ‘normal empathy’ and usually express behaviors or emotions that are unsuitable in a given situation.[2] This often presents the affected individual with challenges in establishing and maintaining relationships.

Symptomatology of Empathy Disorder

Individuals who have EDD may present with a range of undesirable behaviors; these include not being able to listen to others, the swift criticism of other individuals, and an intense sense of entitlement.[13] They also have a lot of trouble forming emotional connections with others and making friends.

EDD may also result in the individual having difficulty in expressing appreciation towards others.[13]

An impairment in empathy can be a symptom of numerous cognitive disabilities and psychological disorders; such as bipolar disorder (BD), autism spectrum disorder (ASD), borderline personality disorders (BPD), and antisocial and narcissistic personality disorders.[2, 13, 14] Depending on the cause of EDD, it may result in the impairment of both types of empathy or only one, with emotional empathy being more commonly affected.[13]

Using Rodents in the Study of Empathy Disorder

Early studies into empathy and empathy disorders were only conducted on humans due to the belief that animals were not capable of experiencing this trait, especially towards those outside of themselves and their offspring. The extent of research was limited to neuropsychological observations, such as the false belief task which tests the Theory of Mind and neuroimaging studies, such as using fMRI to establish which brain region is damaged in patients presenting with skewed empathy.[15]

In subsequent years, it has been discovered that animals are also able to experience empathy. Examples of this include observation of animals responding with emotion to the distress of another, with de Waal[12] reporting to have observed this behavior in apes, monkeys, and elephants.[12,16] There have also been reports of dogs and prairie voles experiencing consolation, a prosocial behavior that is driven by empathy.[17,18]

Recent studies have shown that rodents are also capable of empathy. These include them choosing not to harm a conspecific instead of receiving food and fear aversion after observing another rodent experience a harmful event.[19,20]

Simple animal models, in which mice or rats are presented with emotional information from others of the same species, are required in order to study the fundamental biological mechanisms regarding empathic behavior. These models are extremely helpful in determining the role of precise neuronal pathways that are concerned with the sharing of emotions and afford researchers the opportunity to look into the genetic and neurodevelopmental basis of EDD.[16]

Strains of Rodents Normally Used in Empathy Studies

Keum et al[21] compared the empathic abilities of eleven strains of inbred mice using the observational fear behavioral assay (explained later in this article). The results indicated that five of the eleven strains, namely the C57BL/6NTac, C57BL/6J, 129S4/SvJae, 129S1/SvImJ, and BTBR T+ Itpr3tf/J strains, showed empathic behaviors. Whilst the other six responded with very low empathy. In addition to this, it was reported that the C57BL/6J strain of mice began to obtain empathic behaviors already in early adolescence.[21]

In a study conducted by Li et al[22], they discovered that Sprague-Dawley rats displayed empathic behaviors. A follow-up study by Silva et al[23] tested the empathic behavior in Wistar rats and found them to be even faster in releasing a trapped cagemate when compared to the Sprague-Dawley rats, even without previous training.

Behavioral Models Used to Research Empathy Disorder in Rodents

Behavioral models are used in the evaluation of a rodent’s ability to exhibit a certain behavior, in this case, empathy, under certain circumstances. It will generally be used with one of the other types of models mentioned below when studying empathy disorders since the effects of modifications in these models can only thoroughly be observed using a behavioral model.

Observational Fear Model

The observational fear model is a behavioral assay that was described by Jeon and Shin[24] and can be used to study empathic fear, as well as emotional contagion in rodents.

This model requires an observer rodent to be directly exposed to the demonstrator rodent experiencing an adverse event, such as a shock to their paws. A double-chambered fear conditioning apparatus with a transparent middle partition is used in this experiment, which requires two days to complete. The first day is mainly used for training the rodents and the second day is for the 24-hour memory test.[24,25]

A normal response from the observer to their conspecific receiving shocks should be vicarious freezing, which is a result of the demonstrator’s emotional state being socially transmitted to the observer.[26] This response correlates with trait measures of empathy in humans. Certain factors should be taken into account when using this model; such as familiarity and previous exposure to the adverse event, both of which increase the freezing response, as well as social conditions, where social isolation results in decreased freezing response.[26]

A variant of this model can be produced by adding a tone just before administering the shock. The observer should associate the sound of the tone with the adverse event and act accordingly.

Prosocial Model

Behaviors that are intended to help others are referred to as prosocial and are driven by empathy. Therefore, models that test these behaviors, or lack thereof, are beneficial in the study of EDD.

Bartal et al[27] developed a prosocial model for rats. In this study, they placed a pair of rats in an arena, trapping one of them in a restrainer located in the center and allowing the other rat to freely roam the arena. Given enough time to learn how to tip over the restrainer door, the free rat helped their trapped cage mate escape. This result persisted even when the free rat was given the choice between freeing their cage mate or receiving chocolate chips, going so far as to share their chocolate with their newly-freed cage mate.[27]

A subsequent study by Bartal et al[28] found that familiarity was not a factor in prosocial behavior. Even though free rats were quicker in releasing their cage mate than strangers, they still released these stranger rats.

Thus, it can be concluded that rats behave in a prosocial way in order to end the distress of another, thereby exhibiting empathy. The absence of such behaviors will be consistent with EDD.

Consolation Models

Consolation, the act of physically comforting an individual who has had a harmful experience, is another behavior representative of empathy. Burkett et al[18] described a consolation model in which naïve prairie vole observers were paired with distressed demonstrators that had been subjected to foot shocks. The observers showed consoling behavior by grooming and licking their distressed partners. It was also discovered that the consolation behavior observed was in conjunction with higher levels of activity of oxytocin receptors and the anterior cingulate cortex.[18]

The downside of this model is that consolation appears to be reliant on familiarity as this behavior was not seen between strangers.[18]

Anatomical Models for Empathy Disorder

The use of fMRI in neuroimaging studies of humans has helped determine the brain regions associated with empathy. It has long been known that the limbic system is responsible for regulating and processing emotions.[29] The two main areas within this system that are involved in empathy and affective processing are the anterior cingulate cortex (ACC) and the anterior insula. The ACC is the limbic motor cortex whereas the anterior insula is the limbic sensory cortex. It has been suggested by Craig et al[30] that a group of spindle neurons located in these two regions connect the more developed segments to each other allowing rapid, advanced, and highly connected emotional behaviors. It was also found that older individuals have more of these spindle neurons when compared to children.[29]

The same brain regions are activated in rats when they are expressing empathic behaviors.[20]

Anterior Cingulate Cortex Deactivation

The ACC is the more dominant brain area used when an individual is observing another in distress and mirror neurons found here have been identified as being responsible for associating the pain of another with a first-hand painful event.[31] For this reason, it is the common brain region studied. Individuals who have impaired empathy have been known to have less activity in the ACC than more empathic individuals. Therefore, to replicate this in rodent models, the ACC is deactivated. This can either be achieved by microinjecting the ACC with muscimol, a selective GABAA receptor agonist, or by forming a lesion in the ACC.[31,32]

A behavior model, usually the observational fear model or tone-based variant mentioned above, is used to ensure that deactivation of the ACC has successfully occurred.

The area of the ACC that researchers mainly focus on in rats is area 24, more formally known as Cg1 and Cg2. This area has similarities in its connectivity and cytoarchitecture to that seen in the ACC of humans. It has also been reported that this area is activated when a rat observes another in distress.[32]

Using muscimol is preferred over a lesion as it is a temporary deactivation of this brain region rather than a complete removal.

Genetic Models for Empathy Disorder

The role of genes in the development of empathy disorders must also be taken into account, that is why the following three genetic models are mentioned. Nrxn1, Nrxn3, Cav1.2, and Chd5 have been identified as the major genes involved in the process of empathy and therefore knockout models of these genes will result in rodent models that are consistent with that seen in humans who have an empathy disorder.

Dysregulation of the Nrxn1, Nrxn3, Cav1.2, and Chd5 genes have also been identified as risk factors for autism spectrum disorder.[26]

Neurexins (Nrxn1 and Nrxn3) Knockout Mice

Neurexins are a group of mainly presynaptic proteins forming trans-synaptic complexes with binding partners, such as neuroligins, which shapes vital synaptic functions.[33]

The role of the Nrxn genes in empathy was brought to light after discovering that the 129S1/SvimJ (129S1) mouse strain exhibits a much greater freezing response when compared to other strains of mice. When investigated further, a missense variant (Arg498Trp or R498W) in the Nrxn3 gene of this strain was found to be responsible for their enhanced empathy.[26] A further study found that somatostatin positive (SST+) interneurons in the ACC are dependent on Nrxn3 in controlling the empathic fear behavior in mice.

It is often the Nrxn1 gene that undergoes a knockout (KO) in empathy studies. This KO is first introduced in embryonic stem cells of SV129 sub-strain mice because this cell line is very compliant when using homologous recombination in gene targeting.[33] The resultant mice are then crossed with C57BL6 mice to produce C57BL6/SV129 progeny. These mice are backcrossed for eight generations in order to pass on the KO allele to a C57BL/6J genetic background, in addition to the host genome sequences being lost with each new generation to minimize the number of innate genes that might surround the targeted gene. It is vital to transfer the target mutation to a single genetic background so that numerous genes are not present that may make interpretation of the selected gene difficult.[33] Nrxn1 heterozygote offspring from the F8 generation are crossed, resulting in wild-type (+/+) mice, Nrxn1 heterozygote KO (+/-) mice, and homozygote KO (-/-) mice.

When using the tone-based observational fear model, Nrxn1 KO rats had reduced observational fear and social fear memory when compared to wild-type rats.[26] Kim et al[26] attributed this result to decreased synaptic transmission from the lateral nucleus (LA) to the medial nucleus (MeA) within an intra-amygdala circuit. This circuit was also found to be essential for the observer rodent to associate the social cues of the distressed rodent with predictive cues of the external environment. The researchers further showed a positive correlation between the strength of the LA-MeA circuit to the level of freezing observed.[26]

L-type Cav1.2 Calcium Channel (Cacna1c) Knockout Mice

In a study conducted by Jeon et al[34], it was found that L-type Cav1.2 calcium channels located in the ACC are essential in observational fear behavior. It has not yet been revealed how these calcium channels regulate observational fear. When observing mice that had a deletion of the Cav1.2 gene in their ACC, it was reported that they had weakened behavioral pain responses and diminished observational fear learning.[34]

Another study found that deletion of the Cav1.2 gene in excitatory neuron-specific areas of the forebrain resulted in mice with a deficit in sociability when tested in the three-chamber test.[35]

Chd5 Knockout Mice

The Chd5 gene encodes the chromatin remodeling protein, chromodomain helicase DNA-binding 5, which is involved in the regulation of neuronal differentiation.[26] A study by Pisansky et al[36] discovered that the Chd5 gene is also involved in observational fear. When observing Chd5 KO mice, they reported that the observational fear expressed by these mice was similar to the wild-type control mice; however, the Chd5 KO mice did not exhibit an enhanced response to familiar demonstrators portraying fear.[36] The researchers theorized that this result was caused by impeded social recognition more than likely as a result of the KO gene.

Neuromodulation Models for Empathy Disorder

The final type of rodent models mentioned focus on the biological molecules, namely oxytocin and serotonin, that are associated with normal empathy processes. Altering the levels of these molecules in rodent models in a way that is consistent with that seen in empathy disorders allows researchers to better understand the role they play in the development of such disorders.

Oxytocin Receptor Antagonist Model

The hormonal neurotransmitter, oxytocin, is not only vital in mother-infant care but is also involved in the formation of strong social bonds.[37] In recent years, its role in empathy has also come to light with numerous studies reporting an increase in emotional empathy after oxytocin administration.[38]

Ferguson et al[39] demonstrated that inducing a mouse with an oxytocin antagonist results in the rodent having an impaired social memory for fellow mice and a normal nonsocial olfactory memory. This implication in social memory formation can have an impact on the development of empathy in the mouse, thereby producing a helpful model for EDD.

In addition to the oxytocin antagonist model, a genetic model for oxytocin can also be used. This is achieved by using a KO model of the transmembrane protein CD38, which is involved in triggering the release of oxytocin.[39] Therefore in the absence of this protein, less oxytocin is secreted which has been reported to cause a reduction of both social recognition and empathy.

Increased Levels of Serotonin Model

Serotonin (5-HT) is one of the neurotransmitters responsible for mood regulation and altered levels have been proven to be involved in mood disorders, such as bipolar disorder.[40,41]

In a study conducted by Kim et al[42], injection of 5-HT into the ACC of mice resulted in reduced observational fear; however, the molecular mechanisms behind this are not yet known. It is theorized that high levels of 5-HT cause hyperactivation of the 5-HT1A receptor, which is involved in emotion-related behaviors such as sociability, aggression, and empathy. Thus, high activity of the 5-HT1A receptor can result in the dysregulation of these behaviors, causing a mimicked empathy disorder phenotype.[26]

Clinical Relevance of Studying Empathy Disorders

There appears to be a shortage when it comes to the study of empathy disorders. Most studies involving the pathologies with EDD as an associated symptom focus on other aspects of the disease, such as mood disorders or aggression.

This has increased the demand for studies into EDD so that the origin and development of these diseases can be understood better. These studies will also assist in the treatment and management of empathy disorders and associated disorders.


This article has summarized the available rodent models used to investigate the cause and development of empathy disorders. Empathy is a multifaceted trait and for that reason, it is essential that the roles of neurodevelopment, genes, and the environment are considered when studying empathy disorders.

Using one of the behavioral models in conjunction with either a genetic, neuromodulator or anatomical model helps researchers study empathy disorders in all its dimensions. It would be advisable to use multiple models simultaneously to study the different factors concurrently. An example of this would be using the Nrxn1 KO model together with the observational fear model.

Although rodents can be used to study particular aspects of empathy, discovering the common molecular mechanisms fundamental to both empathy and sociability should be the aim of future studies.[26]


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