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Disease Models

Rodent Models of Social Anxiety Disorders

By November 19, 2021No Comments

Fear, anxiety, and social contexts – can rodents help us better understand social phobia/anxiety in humans?

Fear is something we try to do without in life – which is also the very reason they exist, to provide salient physical and psychological cues and help us survive and adapt to our environments. As with many mental conditions, maladaptive behaviors like avoidance and violence can become debilitating when things go wrong.

Fear disorders can manifest in many different ways, from persistent worrying about the perceived danger to full-on panic attacks. In the current DSM-IV designation, these symptoms fall under the larger umbrella of anxiety disorders that include post-traumatic stress disorder (PTSD), specific phobias (such as social phobias), and panic disorders.[1]

As a whole, anxiety disorders have a high (>28%) lifetime prevalence and generally affect more women than men,[2, 3] by decreasing general physical and mental wellbeing [3, 4] with high socioeconomic costs.[1, 5, 6]

Firstline treatment options include cognitive-behavioral therapy (CBT) and pharmacological agents ranging from traditional anxiolytics such as benzodiazepines to antidepressants such as selective serotonin reuptake inhibitors (SSRIs).[7, 8]

Unfortunately, there is a general problem with achieving long-term remission.[9] This results from a broader issue in psychiatry where the biological basis of brain dysfunction and efficacious therapeutic mechanisms are incompletely understood, hampering our efforts to address the rapidly escalating mental health crisis.[10]

We need to have better and more varied animal models and hypotheses to address the more tangible biological mechanisms of dysfunction and treatment as the first step towards better management of fear and anxiety disorders.

The amygdala, an almond-like shape structure in the medial temporal lobe, has been central in processing fear and anxiety in the brain.[11] Not surprisingly, overactivation of the amygdala has been consistently reported in all prevalent anxiety disorders [12] including PTSD,[13, 14] panic,[15] obsessive-compulsive disorder (OCD),[16, 17] generalized anxiety disorder (GAD),[18, 19] and phobias [20, 21] such as a social phobia.[22, 23]

These amygdala-centric findings, consistent with selective increase or decrease of intra-amygdalar activity can respectively bias changes in anxiety-related behaviors in rats.[24] Sharing reciprocal connections with the amygdala,[25, 26] the medial prefrontal cortex (PFC) also appears to be heavily involved in regulating fear responses. Still, the predominantly reported change in activity depends on the disorder, where a decrease has been reported for PTSD [27] but increases for panic,[28] GAD,[29, 30] OCD,[31] and mixed for phobias.[21, 23, 32, 33]

Social phobia, now defined as a social anxiety disorder (SAD), is the most common anxiety disorder [1, 34] and can increase the risk of developing depression and substance abuse.[8] As with other affective and anxiety disorders, the prevalence of social anxiety is higher in females than males and has an early onset at the mean age of 13.[2, 35, 36]

The genetic contribution to developing social anxiety disorders (or social deficits in general) has been reported.[37, 38] Still, there is strong evidence in the literature that social learning during development may play a larger role.[35, 39, 40] As with other anxiety disorders, social anxiety dramatically increases the risk of developing major depressive disorder [41] and is often comorbid with depression.[42]

As in other anxiety disorders, first-line treatments often fail, and up to 30-40% of the patients may not respond to pharmacological or cognitive-behavioral treatments [8, 43]; better animal models to understand and treat SAD is an unmet need.

The Neurobiology of Social Anxiety Disorders

Although the classification of psychiatric disorders is mainly symptom-based, there is significant biological overlap between SAD and other anxiety disorders. Social cognition circuits in primates,[44] humans,[45] and rodents[46, 47] all extensively implicate the amygdala and prefrontal cortex.

The key involvement of the amygdala in social behavior is evident from lesion studies in rodents[48] and non-human primates.[49] Emotional human facial expressions are a standard stimulus to elicit activity in the amygdala. The strength of the activation is correlated to the severity of SAD symptoms,[50] further supporting the critical involvement of the amygdala in both social and fear processing relevant to SAD.

Studies have identified PFC neurons to respond to social stimuli[51, 52] and may represent the saliency and novelty of social stimuli.[53] Social avoidance can be increased by disrupting the excitation/inhibition balance in the prefrontal cortex,[46] which appears to be actuated by downstream structures in the brainstem[54] and maintained by upstream thalamic inputs.[55] In sum, social and fear processing circuits appear to intersect at the prefrontal-amygdalar circuit.[45, 47, 56, 57]

The involvement of serotonin is ambiguous at best, as the genetic variation of a serotonin transporter gene (SLC6A4 – often identified as a marker in other anxiety disorders) is linked to the presentation of SAD,[58] and SSRIs are often used as the first-line treatments for SAD.[8]

Yet, SAD patients appear to have increased serotonin by default.[59] The latter finding is somewhat consistent with the observation that SSRI administration (which increases serotonin availability) can decrease social interactions[60, 61] in rats; however, 5HT(1A) receptor agonists can improve social interactions.[62]

The hormone oxytocin was brought into the spotlight by studies on its effects on pair-bonding in prairie voles. Indeed, it strongly influences social behaviors in general, albeit in a species-dependent way.[63] There is indeed a genetic and physiological link between SAD and oxytocin in humans, with oxytocin treatments having a positive effect on SAD symptoms,[64] supported by similar findings in rodent models.[65]

Despite the biological and symptomatic overlap between SAD and anxiety disorders, SAD appears to be symptomatically distinct from GAD,[66] despite extensive overlaps in neuronal circuitries, neurotransmitters, and effective treatments. In preclinical studies, drugs used to treat SAD do not always have the same effects on social behaviors, whereas SSRIs may decrease social behavior.[60, 61]

At the same time, benzodiazepine anxiolytics can increase social interactions.[67, 68] Therefore, despite the robustness of social deficits elicited by preclinical stress models, the social avoidance observed is likely to be secondary to the strong induction of anxiety/depression-like states rather than the reverse.

Rodent Models of Social Anxiety

Stress is a crucial player in the development and maintenance of many psychiatric disorders. In animals, stress-induction essentially results in increased anxiety and depression-like behavioral phenotype.

Social Defeat Paradigm

Social defeat (SD) is perhaps the most ethological and translatable stress model, specifically for SAD given the social nature of the stressor. In essence, the size-based dominance in rodent social colonies is exploited by exposing experimental animals to a larger, breeding male to facilitate SD. While acute SD is stressful, the SAD-like social avoidance-inducing effects depend on chronic SD by different males.

Conventionally, larger, currently breeding, or recently retired breeder males are used as the social stimulus. Prior to introducing the experimental animal as the intruder, other animals (i.e. paired mate) are removed from the cage, and the resident and intruder are allowed to physically interact.

Initially, mutual sniffing would occur, followed by chasing the intruder by the resident, which may quickly escalate to full-on fights. In the majority of the cases, the smaller intruder will display submissive behaviors such as lying on its back and exposing its underside, running away from the attacking resident, and/or emitting stress calls.

Given the goal of the manipulation is to establish SD and animal welfare needs to be considered, most studies stop the exposure if the intruder experimental animal displays at least five instances of submissive behavior within the first five minutes of exposure. Also, if there is excessive fighting or no/insufficient display(s) of submissive behavior from the intruder after five minutes, the exposure is also interrupted.

To facilitate the effect of SD while keeping the animals safe, a perforated divider is used to physically separate the two animals while allowing olfactory and visual cues to consolidate the SD experience for up to another 25 minutes. This process is repeated 7-10 more times, once per day, with different larger, (retired) male breeders as residents to elicit social avoidance and other behavioral outcomes.

In humans, while (peer) bullying may not be the source of developing SAD for many, the presence and amount of bullying certainly correlates with the incidence and severity of SAD and plays a role in maintaining and worsening the symptoms.[69]

Therefore, the validity of social avoidance induction modeling human SAD etiology is questionable. A major weakness of the conventional chronic SD studies is that the subjects are male, which is necessary since the manipulation depends on gender-specific territorial aggression. However, SAD prevalence is much higher in females, as in other anxiety/affective disorders.

While there is female (maternal) aggression in rodents, there is currently no robust, established protocol to elicit ethologically relevant chronic SD in female rodents. Several protocols artificially elicit male-female aggression to achieve SD in females such as the application of male odorants to female mice,[70] which recapitulates the behavioral and physiological outcomes of SD at the expense of the ethological validity.

In addition, this is a standard protocol to induce anxiety and depression-like behaviors in rodents and not just social avoidance/anxiety (but see [71]). Since other non-social stress-inducing paradigms also elicit social avoidance, it is not currently clear if the social deficits caused by chronic SD are primarily driven by the negative social interactions or a generalized response to stress itself.

Regardless, given the high comorbidity between SAD and other anxiety/affective disorders, chronic SD is a useful model to recapitulate many aspects of SAD presentation in humans.

Lastly, chronic SD does not guarantee a social avoidance phenotype, as up to half of the rodents exposed to chronic SD may not display increased social avoidance or other anxiety/depression-like symptoms, presumably due to stress resilience mechanisms.

This caveat can be leveraged to study how biological differences between resilient and susceptible rodents relate to SAD but may increase the number of subjects needed if generating animals with social avoidance is essential to study design.

Social Isolation

Social isolation is a relatively straightforward manipulation, often implemented chronically[71] and from an early age.[72] Simply, animals are singly housed instead of group-housed. Social deficits such as social avoidance and increased vocalization have been reported in early social isolation in mice.[72]

As in other stress implementations, the behavioral determinants are not limited to the social domain; increases in anxiety (avoidance of open areas in the open field, elevated plus maze, and increased preference for dark over lightboxes) and depression (sucrose preference test for anhedonia and forced swim test for behavioral despair)-like behaviors are also present,[72, 73] given rodents are highly social and normally live in communal groups.

This paradigm may be relevant to developing, or the lack thereof, social skills/experience to overcome SAD in some patients. Certainly, social isolation[74] and parental “shielding” [75, 76] from social experiences are risk factors in human SAD. Also, the increased impact on early isolation and the propensity to be more stressful to female rodents strengthens its construct validity as both developmental, and gender factors play critical roles in SAD.

Social Instability

In the wild, rodents live in relatively stable social groups with established hierarchies. In this paradigm, the group’s stability is disrupted by the persistent and chronic rotation of cagemates in group-housed animals. In the original implementation,[77] interleaved crowding (7-8 animals per cage; however, cage sizes were not defined) and isolation was administered for 15 days with isolation (i.e., single caging) on the first and last days of the protocol.

The composition, identity, and the number of mixed-gender conspecifics in group-housed days were varied. The original study mainly used physiological readouts (e.g., adrenal weight and corticosterone changes) to assess stress, but note more frequent female-on-female aggression than other gender pairings in this mixed-gender context.

From the physiological (but not behavioral) readouts, the authors also concluded that males appear to be more affected by SD while females to social instability. Similar to other stress paradigms, social instability results in a host of anxiety and depression-like behavioral deficits,[78, 79] in addition to deficits in social behavior.[80]

As described, social instability appears to have a more detrimental effect on females than male rodents. This strengthens the construct validity of the paradigm, as SAD and other anxiety/affective disorders are more prevalent in females than males in the human population.

The social nature of stress is relevant to the domain of interest. However, the implementation of the paradigm has little ethological relevance compared to SD as it is unusual for animals in the wild to have unstable social groups and to undergo intermittent social isolation.

Also, although item-based (i.e., bites, approach, etc.) quantification has been used to measure social deficits,[77] it is unclear how they directly relate to more common behavioral measures in social interaction and preference tests (see later).

Overall, this paradigm is a reliable way to elicit social stress and behavioral deficits in both male and female animals with a relevant bias towards females as seen in SAD, albeit in a less ethological way compared to SD.

Finally, a practical concern for the paradigm is the impact of group housing on potential damage to brain implants such as electrodes for neurophysiology or probes for microdialysis. Concurrent neural readouts are extremely difficult, if not impossible to obtain under group housing where the goal is to induce aggression and stress within the group.

Other Stressors

The chronic unpredictable stress paradigm is another common manipulation to induce anxiety and depression-like behaviors in rodents. Consistent with other stress paradigms, social interaction has been consistently decreased after the administration of an array of mild stressors.[81, 82]

Chronic restraint stress can selectively induce deficits in social but not spatial cognition.[83] In contrast, acute restraint appears to be ineffective,[84] despite both forms of restraint stress leading to increased anxiety and depression-like behaviors.

Finally, maternal separation has been used to model negative (e.g., neglect, abuse) treatments early in life to investigate their deleterious effects later in life. Although maternal separation is indeed a stressor, the behavioral and physiological outcomes depend on many variables in its application (e.g., predictability, amount of time, grouped or individually isolated during separation, frequency), with certain combinations endowing stress resilience later in life.[85, 86]

The specific effects on social function mirror those found for anxiety and depression in general,[85] being highly variable[86, 87] and presumed to be dependent on differences in the separation protocols.

Fear Conditioning With a Conspecific Stimulus

Chronic stress-induced social deficits co-present with increased anxiety and depression-like behaviors. While there is high comorbidity and overlap in symptomatology between these conditions, anxiety and depression are likely the primary states induced in chronic stress paradigms.

To address this issue, an operant conditioning paradigm with a social (conspecific) stimulus was developed to produce social-specific fear behaviors.[88] In this paradigm, male mice were acclimatized in the testing chamber and an empty internal enclosure designed to hold the social stimulus.

A male stimulus mouse is introduced in the internal enclosure in the testing chamber, and each time the experimental mouse makes contact with the stimulus mouse, a brief mild shock is delivered. The session is terminated if no social contact is made in a 2 min period.

Testing social avoidance is done similarly to the conventional social interaction test (see below), but since the mice display fearful responses to the internal enclosure used during conditioning, the enclosure is placed in the animals’ home cages to extinguish the fear for the enclosure itself. Also, all testing was done in the experimental animals’ home cages.

The authors report a specific increase in social avoidance and fear behaviors such as freezing, apprehension to investigate socially, and defensive burying but not behaviors on the elevated plus maze (general anxiety) or forced swim test (learned helplessness/depression).

In addition to the specificity, experimental animals were also responsive to anxiolytic, antidepressant, and extinction training in reducing social avoidance/fear behaviors, lending more support for the paradigm as a specific model for SAD. The paradigm is also reported to be effective in females and rats.[88, 89]

The social fear conditioning paradigm is an excellent model for SAD, as the social avoidance behaviors appear to be the primary outcome of the manipulation with little change in other anxiety and depression-related behaviors. The improvement of social avoidance with effective SAD treatments used in the clinic (drugs and extinction akin to CBT) further cements its use as a model-specific to SAD.

However, it is unclear how much operant conditioning contributes to the development of SAD in humans and the social fear elicited in this model is comparatively less ethological than those elicited by stress models.

Genetic Models

There are many lines of genetically modified mice displaying social deficits, but these have largely targeted genes related to autism. There is currently no established genetic model for SAD in mice.

The Fawn-Hooded rats have been noted for their disposition to depression, anxiety, and addiction-like behaviors. When tested in pairs in an open field, male FH rats are less social (both in aggression and interest in conspecifics) compared to other strains (Wistar, Long-Evans) of rats under variable stress (light levels, novelty of the testing arena).[90]

These data support that FH rats can be considered to be a selectively bred genetic model of social anxiety in rats. Of note, the Wistar-Kyoto strain has been used extensively as a genetic model for anxiety and depression and displays decreased social interaction compared to other strains.[91]

Measuring Social Behaviors

Social Preference Test

There are two forms of social preference test: 1) testing the animals’ preference between a social (conspecific) stimulus over an object and; 2) testing the animals’ preference between a familiar and a novel social stimulus.

The most common implementation of social preference is to have the social (conspecific) and non-social (inanimate object) stimuli in different spatial locations. The amount of time spent in the proximity of, frequency of visits to, and/or the spatial occupancy of the whole testing arena is used to determine preference.

This test has been implemented in a T/Y-maze setting,[92, 93] a three-chamber open arena, [46, 94, 95] or open fields with wire-mesh enclosure inserts for the stimuli. The most used setting is perhaps the three-chamber social preference test, with some variations implementing a habituation phase to the arena and stimuli presentation locations to focus targeted exploratory behavior.[96]

Since social interactions are generally sought after by unmanipulated rodents, a recent study has leveraged the rewarding aspect of social interaction to measure preference via operant conditioning [97] with success.

Social Interaction Test

Social interaction in the field is somewhat loosely defined; some merely count the number of times animals come into proximity with each other[46] while some extensively catalog the nature of the interaction, such as sniffing, biting, grooming, following, and freezing.

Introduced in the 1970s,[98] the test originally investigated if social behavior readouts can be used to measure anxiety. The test consisted of pairing two male rats in an open field and found the rats’ familiarity to the testing arena and ambient light levels biased the amount of social interaction, where a novel environment and brighter lighting inhibited social interaction, but these decreases are associated with decreased exploration in general, hence not a specific effect on social behaviors.

The simplest implementation of this test is to introduce the test animal as an intruder into a resident animal’s home cage, or vice versa. In the majority of the cases, the resident would assume the dominant role in the interaction, but this can be biased by using animals of different ages/sizes as the intruder/resident to force the test animals’ roles into a submissive or dominant one.

In a better controlled but perhaps less ethological test, social interaction is tested by placing the stimulus animal in a perforated enclosure in a larger enclosure, where the test animals are free to roam.

This test is essentially a “non-choice” version of the social preference test, where the spatial occupancy of the larger enclosure by the test animal is quantified to measure social approach/avoidance behavior. This is one of the key tests used to measure the effect of stress on the development of depression-like behaviors, where social avoidance is a robust outcome

Future Directions

Species-specific Differences

The fear of judgment characterizes the clinical definition of SAD by others in complex social contexts which cannot be recapitulated in other animals. For example, public speaking is the most commonly feared social context in SAD patients[99]; there are no directly relevant behaviors in the rodents’ social repertoire to model this aspect of the dysfunction.

While it is unknown if feelings such as humiliation, embarrassment, and rejection have homologs in rodents or other primates, avoidance behavior is perhaps the most suitable readout in modeling human social anxiety.

An under-explored line of research is the trait of behavioral inhibition. Surprisingly, despite behavioral inhibition being the single most dominant and predictive risk factor in developing SAD later in life,[100] no preclinical studies have directly examined its relation to social behaviors.

Another species-dependent factor to consider is that rodents, by default, prefer to interact with novel conspecifics. That is, rodents by nature prefer to engage in novel social interactions,[94, 97] whereas this is generally not the case in humans.

Although olfaction,[101, 102] and (ultra)sonic vocalizations[103, 104] play key roles in social communication in rodents, there have been little to no studies investigating how the production, perception, reaction, and utilization of such cues may be used to measure social anxiety.

Emerging Methods

Neuroscience research is constantly bolstered by improvements in automation and computational approaches. There are integrated housing and measurement systems available to produce an ethologically more suitable environment to study social behaviors in mice, where enriched habitats model better the communal living patterns observed in the wild with less aggression[105] and allow higher-order social behavior to be tracked[106] modeled beyond the traditional paired testing.[107]

Modeling any human disease process in laboratory animals has its caveats. The most salient difference between fear/anxiety-related behaviors elicited in controlled laboratory settings and the human condition is perhaps the lack of a simple trigger (unconditioned stimulus) in human fear/anxiety.

Another feature in SAD and fear/anxiety disorders, in general, is the persistence of out-of-context, anticipatory anxiety, which may be unique to humans with more complex frontal cortices and higher-order forward-planning capacities.

These challenges, along with clear cross-species differences in social structure and tangible outcomes from social interactions (e.g. embarrassment and fear of being judged in humans), need to be considered for translating findings and improving preclinical models of SAD.

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