Using Social Rank as the Lens to Focus on the Neural Circuitry Driving Stress Coping Styles

Abstract

Social hierarchy position in humans is negatively correlated with stress-related psychiatric disease risk. Animal models have largely corroborated human studies showing that social rank can impact stress susceptibility and is considered to be a major risk factor in the development of psychiatric illness. Differences in stress coping style is one of several factors that mediate this relationship between social rank and stress susceptibility. Coping styles encompass correlated groupings of behaviors associated with differential physiological stress responses. Here we discuss recent insights from animal models that highlight several neural circuits that can contribute to social rank associated differences in coping style.

Introduction:

Coping can serve as the mediator between the pathological outcomes of stress and the stressful stimuli triggering the outcomes. To understand coping, one needs to first investigate the trigger, stress. Stress, while a ubiquitous aspect of everyone’s life experience, has had multiple definitions over the years. An integrated definition spanning stress domains was proposed in 1997, where stress was defined as a tri-part process involving the initial triggering stimuli, the stressor, the processing of the stimuli, stress perception, and finally the physiological reaction to the stimuli, the stress response[1]. This stress response is a cascading series of biological processes that begins with the release of three major hormones, norepinephrine, epinephrine, and cortisol. This release coupled with changes in other neuroendocrine factors including adrenocorticotropic hormone (ACTH), vasopressin, oxytocin and multiple cytokines can trigger significant alterations in a host of biological processes[2]. Stressors of all kinds can trigger this stress response. Chronic stress, marked by sustained activation of the stress response and high levels of circulating stress markers, is associated with significant pathological consequences; individuals exposed to chronic stress have increased risk of many diseases including hypertension, major depressive disorder, ulceration, and type II diabetes[3,4]. However, across the population strong individual differences exist in both the rates of these chronic stress associated pathologies and in levels of circulating markers that are hallmarks of the stress response. Understanding the biological underpinnings of these differences can help identify paths to mitigate the consequences of chronic stress.

Cross species examination of social hierarchy and stress responses

Epidemiological studies have demonstrated a graded relationship between socioeconomic status (SES) and health at all levels[5]. This relationship exists even when adjusting for SES-associated lifestyle factors, such as smoking, general health and fitness[6,7]. This has led to the hypothesis that differential exposure to chronic psychosocial stress plays a part in contributing to individual differences in stress responses including SES-associated health disparities[8]. Findings from animal models mirror aspects of these human studies with animals from different ranks exhibiting differences in stress sensitivity[8–13]. For additional discussion of these stress pathologies across species see the following cited reviews[8,14–17]. One caveat when interpreting animal hierarchy and dominance research is that animal rank is not directly equivalent to human SES. Human social status is a complex phenomenon influence+d by a host of internal and external factors including wealth, education, gender, and race and is synthesized across multiple domains[18]. While studies across multiple animal species demonstrate that subordinate rank is associated with increased stress pathologies, primate research has described a more complex relationship between social status and stress response. For example, one primary factor influencing the interaction between hierarchy and stress is the structure of the social environment, particularly the means by which dominant animals achieve and maintain dominance within the social structure[19]. Dominant animals that must frequently and aggressively assert and maintain their dominant position show high levels of stress, reflecting the physical demands of their position. However, when dominant animals can maintain their position through threats of aggression, rather than outright aggression, subordinate animals show markedly higher stress levels[8,20]. There are additional factors observed in primates that can mediate the level of stress response: stability of the hierarchy, social support such as affiliation and coalition forming, and coping [2,21]. In many cases coping can work at the interplay between stressor and stress response and is a pattern of behavioral responses seen in response to the stressor that can impact the degree to which stress effects an individual’s mental or physical well-being.

Stress coping has been observed across species and is not only limited to the human experience. Given this ubiquity, research has looked to identify biological underpinnings of these behaviors. Early work in coping defined two personality types (Type A vs Type B) that showed alternate patterns of physiological and neuroendocrinological activity in response to stress[22]. As the field evolved two divergent styles of coping have been identified: active and passive. Active versus passive coping styles have also been described as proactive, bold, approach and fight, versus reactive, shy, avoidant and flight[23–27]. This plethora of descriptors highlights how these styles span more than any single behavior but instead are a consistent pattern of behavioral and biological responses to multiple kinds of stressors, both social and non social. Defined in opposition to each other, active/proactive individuals tend to be more bold and aggressive, and inflexible with higher sympathetic activity and lower hypothalamic pituitary axis (HPA) activation, importantly these individuals tend to be more dominant, whereas passive/reactive individuals show a reverse physiological profile and pattern of behaviors[28–30]. These clusters of behavior while frequently seen together are not necessarily synonymous and have, in part, separable biological regulation and roles. For example, while aggression is often present in dominant animals an aggressive animal is not always dominant and a dominant animal may not always display frequent aggression. This separation between social status and aggressive behavior is further underscored by the differences in rank found when using different assays. Some dominance methodologies rely on directly pitting two or more animals against each other in competition for access to a resource such as food, water, or a warm spot. These tests rely on the assumption that more dominant animals gain priority access to these resources. Others rely on naturalistic observations of behaviors observed in the home cage assuming differential displays of social behaviors by status, such as giving or receiving approach, chase or aggressive behavior. First used in 1967, the tube test has since been frequently employed to assay dominance and works by pitting animals against each other in a narrow tube with the animal that forces the other backwards out of the tube assigned the dominant rank[31,32]. Additional behaviors can be used to distinguish rank such as patterns of urine marking, ultrasonic vocalizations and barbering. While strong correlations exist between these behaviors, and thus their assigned social ranks, they do not perfectly overlap. These results point towards separable domain specific aspects of social dominance[33]. Therefore, conclusions drawn from synthesizing hierarchy literature should be tempered with an understanding that dominance is a multi-faceted behavior composed of overlapping but potentially independent elements.

In a similar manner, displays of coping behavior are associated with complex displays of multiple behavior, collectively termed active versus passive coping, which can change depending on the context. Early research used immediate early genes, such as c-FOS, that serves as a marker of neuronal activity, to identify neural regions associated with active or passive coping style to a stressor. These studies identified a wide range of regions spanning the brain that include, but are not limited to, frontal cortical regions, including orbitofrontal cortex and prefrontal cortex, subcortical limbic areas, such as the hypothalamus, hippocampus, amygdala and ventral striatum, and as well as the bed nucleus of the stria terminalis, periaqueductal grey and suprachiasmatic nucleus[34–38]. The diversity of neural activity altered by displays of coping behavior is partially due to the variety of stress contexts that trigger coping behavior which range from social stress, such as resident intruder to physical stress, such as a forced swim test (FST) or shock probe burying, as well as the kinds of behaviors encompassed by coping, which range from approach to avoidance, freezing and aggression fighting back.

Given the overlap between displays of social rank, aggression and coping style there is likely overlapping circuitry mediating aspects of these behaviors. By probing these overlapping circuits, we may gain insight into their contributions to individual differences in stress response, and in particular, differences in rank associated stress susceptibility. This review will focus on overlapping circuits that have been demonstrated to have a causal relationship to dominance, aggression or stress coping behaviors.

Neural circuitry mediating interactions between social rank and stress susceptibility Cortical top down facilitation of social dominance

The mPFC, with connections to downstream striatum, midbrain and hypothalamus, is considered to provide top-down executive control[39]. Activity of the mPFC has been closely tied to social dominance, active behaviors during stressor exposure and dominance-associated stress resilience, all behaviors encompassed by an active coping style. Within the mPFC, extensive gene expression differences have been found between dominant and subordinate animals independent of any behavioral or anxiety-like differences[40]. Lesioning the mPFC causes rats to rapidly lose their hierarchy rank position[41]. This control of rank is highly specific; with increasing or decreasing synaptic efficacy of layer V pyramidal neurons within the mPFC raising or lowering the animals rank respectively[33]. This change in rank may be driven by active behaviors during competitions for hierarchy position. Single unit recordings taken from the dorsal mPFC during the tube test demonstrated correlated neural activity with effort related behaviors, such as resisting against the other animal or pushing back against them. Optogenetic activation of this region was able to rapidly cause winning within the tube test. Importantly, such stimulation-dependent winning in the tube test carried over to another measure of dominance suggesting this may permanently alter the animal’s social rank[42]. In a parallel manner mPFC activity closely correlates with active behaviors during stress coping. Deep brain stimulation to trigger increased ventral mPFC activity during a forced swim test (FST) was sufficient to decrease the time spent immobile, an outcome associated with active coping[43]. The mPFC likely mediates these effects on stress resilience via its downstream projections. However, the mPFC may itself also adapt in response to stress exposure causing feedback effects on an animal’s social status. Chronic restraint stress predisposes mice to later social subordination in parallel with altering AMPA receptor phosphorylation within the mPFC. This stress induced social subordination could be rescued by fluoxetine treatment with a parallel increase in AMPA receptor phosphorylation[44]. While correlational it suggests that chronic restraint stress decreases AMPA phosphorylation leading to reduced synaptic incorporation of the AMPA receptors, reducing synaptic efficacy, which then leads to social subordination.

Within the mPFC, the infralimbic (IL) and prelimbic (PL) cortical pyramidal neurons send glutamatergic projections to basolateral amygdala (BLA) GABAergic interneurons, which in turn inhibit activity of the BLA, a region with a well-established role in stress processing. Dominant hamsters following social defeat show more active coping behaviors along with low submissive and defensive postures compared to subordinates when subsequently exposed to a social stimuli, a behavioral response termed conditioned defeat[45,46]. The BLA plays an important role in mediating this stress coping; activation of GABA_A receptors within the BLA prevented hamsters from acquiring conditioned defeat[47]. This effect may be rank specific. Using the retrograde tracer cholera toxin B to label BLA projections from the PL and IL, it was found that dominant animals showed increased cFOS in these projections following social defeat[48]. In a similar manner, restraint stress induced increased cFOS in the PL of dominant animals only, suggesting a generalizable role of the PL/IL to BLA circuit in active stress coping[49]. Selective activation of these BLA projecting neurons within the IL reduced activity of the BLA and reduced the conditioned defeat seen in subordinate but not dominant hamsters following social defeat[50]. Highlighting a rank specific role of the mPFC to BLA projection in mediating protection to social defeat stress.

This inhibition of the BLA may be temporally specific. Activation of the IL only reduced freezing to a conditioned tone when directly paired with the tone but not when activated 1 second before or after[51]. Adaptive changes in BLA neuron morphology also occur in response to stress exposure with defeated rats showing increased dendritic arborization within the BLA[52]. Intriguingly the BLA may have sex differences in mediating rank specific stress resilience. In both male and female hamsters dominant and subordinates show extensive differences in gene expression within the BLA, however when comparing across sexes there was no consensus between the patterns of gene expression changes in males and females[53].

The mPFC also projects to the dorsal raphe nucleus (DRN), which has a demonstrated role in stress coping. Selective activation of the DRN projecting mPFC neurons alter levels of active coping behavior during the FST, suggesting a specific role for the projection in coping[54]. Using high or low responding rats, differentiated by their behavior during the shock probe test, proactive vs reactive respectively, high responding rats showed greater activation in the DRN following shock compared to low responding rats, pointing towards the role of DRN activation in active coping[35].

DRN neurons contribute specifically to the stress of social subordination. Using whole cell recording, genetically labeled DRN GABA and 5-HT neurons showed activation during social defeat. In susceptible mice—those that displayed social avoidance following defeat—there was enhanced activation of DRN GABA neurons. Optogenetic silencing of these neurons reduced social avoidance following the defeat[55]. Social defeat is built on the principle of differential stress susceptibility even in genetically identical animals exposed to similar levels of social stress. Therefore coping, a primary mediator of the stress response, is a vital component of this paradigm. Evidence points towards this mPFC to DRN projection playing a part in mediating this stress response by encoding information about the controllability of the stress.

To probe this role specifically, researchers built upon a previously established paradigm where it was demonstrated that animals given the ability to cease a shock by wheel turning showed reduced physiological effects of the stressor versus rats who received a similar but uncontrollable level of shock[56]. Exposing mice to a controllable stress alone, caused enhanced c-FOS expression selectively in neurons projecting from mPFC to the DRN[57]. Exposure to a controllable stress does not reduce future escape learning in a novel stress context nor enhance fear expression, termed behavioral immunization. Blockade of activity within the mPFC at the time of experiencing a controllable stressor prevented behavioral immunization. Inhibition of protein synthesis in the mPFC during the initial stressor exposure also had the same effect[58]. This suggests that the mPFC is necessary to process information regarding controllability over the stressor which in turn buffers the negative consequences of future stress experience.

In line with this, activation of mPFC during exposure to an uncontrollable stressor elicited behavioral responses as if the stress was controllable when later exposed to a novel stressor[59]. These observations can be replicated in a different stress context; using a social exploration task, it was demonstrated that mPFC activity is required for the stressor to be perceived as controllable, measured as no changes in future social exploration anxiety[60].

The downstream action of DRN activation is likely mediated, in part, via corticotropin releasing factor (CRF) and the serotonergic system. Low levels of CRF can preferentially activate CRF1 receptors leading to a reduction in DRN serotonergic activity causing reduced serotonin release in downstream target regions and is associated with active coping, swimming in a forced swim. In an opposite manner, higher levels of CRF, triggered by social defeat stress or an uncontrollable shock, would cause activation of CRF2 receptors leading to high levels of serotonin output in downstream target regions and is associate with more passive coping strategies[61,62]. Taken together this suggests that under instances of controllable stress, the mPFC can reduce DRN activity via a potentially GABA-ergic mechanisms leading to a reduction in serotonergic activity which limits the impact of the stress and can maintain the behavioral immunization of stress exposure. However, if the stress is very strong and perceived as uncontrollable the mPFC does not exert this inhibition and DRN activity leads to high serotonergic output.

Mesolimbic dopamine circuitry in dominance and aggression

While traditionally considered to modulate reward seeking and encode reward the mesolimbic dopamine circuitry also has a well-established role in the mediation of stress across multiple species [63]. In addition, mesolimbic circuitry also plays a role in establishment and expression of dominance, aggression and coping behavior. For example, in lizards dominance is associated with distinct patterns of dopamine (DA) availability in a variety of limbic regions, including the nucleus accumbens (NAc), dorsal striatum, ventral tegmental area (VTA), in addition to the dorsal raphe, septum and locus coeruleus[64]. Whole body depletion of dopamine in crickets prevented recovery of social aggression following social subordination, while administration of a DA receptor agonist potentiated aggression recovery[65].

Mediation of aggression within the mesolimbic dopamine circuitry is, in part, controlled by the VTA, and seems to be differentially activated in dominant and subordinate hamsters potentially via differential displays of active or passive coping. A social encounter after experience of social defeat induced higher levels of cFOS in the VTA in dominant versus subordinate hamsters with concurrently higher levels of aggression in the dominant hamsters[66]. In mice, direct optogenetic activation of dopaminergic neurons within the VTA was able to increase aggression with longer periods of time spent attacking[67]. The VTA mediates not just displays of aggression but associated behaviors such as increased social status and active coping behaviors. Optogenetic stimulation of VTA DA neurons during training and then subsequent testing of social competition increased social dominance in rats in a water competition and palatable reward seeking task[68]. Optogenetic Inhibition of VTA dopamine activity also served to reduced active coping in the FST and decreased preference for sucrose. While activation of these neurons had the opposite effects on the same behavioral readouts[69]. In a parallel study, it was shown that silencing of the VTA by infusion of the GABA_A receptor agonist, muscimol, decreased anxiety-like behaviors and improved social competition with opposing behavioral results seen from administration of a GABA_A receptor antagonist[70]. While much of this work has been conducted in male rodents, data suggest there may be sex differences in mediation of stress coping; female rats, that displayed social avoidance following 3 days of social defeat, had higher levels of cFOS expression in the DA neurons in the ventral but not dorsal portion of the VTA, while males showed no behavioral or neuronal differences[71]. The VTA may, in part, mediate these displays of dominance, aggression and coping behavior via its projection to the nucleus accumbens.

Diazepam administration to the VTA increased an individual’s social dominance, reduced anxiety-like behavior in the EPM, and enhanced NAc mitochondrial respiration, as demonstrated by increased ATP levels in the NAc. Inhibition of NAc mitochondrial function was sufficient to prevent VTA diazepam administration in potentiating social dominance [72]. Intriguingly inhibition of NAc activity by infusion of the GABA agonist muscimol prior to social defeat did not affect the acquisition of conditioned defeat in hamsters. However NAc inhibition during later social subordination testing did increase aggression and reduce submissive behavior suggesting a role of the NAc not in consolidation of learned coping behaviors following stress, but rather in the expression of these behaviors during latter stress experience[73]. This role in mediating aggression may also be stress specific, administration of a mixed dopamine antagonist in the NAC prior to conditioned defeat testing in hamsters enhanced aggression towards an intruder, but did not increase aggression in un-defeated hamsters[74]. Dominant mice, who were more susceptible to social defeat, displayed higher levels of energy-related metabolites within the NAC, compared to subordinates who had lower levels that were then upregulated by the social defeat, an effect that could be partially rescued via treatment of Acetyl-L-carnitine (LAC), a mitochondria-boosting supplement [75,76]. This NAc DA signaling may also be specific to the type of coping behavior displayed. Fast scanning cyclic voltammetry to measure dopamine in NAc reveals a concomitant decrease in dopamine concentration and increase in pH when mice transitioned from immobility to struggling in the FST, with DA inhibition increasing active behaviors[77]. Such effects on NAc may be mediated, in part, through glucocorticoid signaling that occurs during stress exposure. Downregulation of glucocorticoid receptors (GR) in the NAc enhanced social dominance and animals lacking GR were biased towards social dominance in group housing[78].

The NAc is principally composed of GABAergic output neurons characterized as medium spiny neurons (MSN’s), further subdivided by enrichment of either dopamine receptor 1 (D1) or dopamine receptor 2 (D2)[79–83]. Traditionally these classes of MSN’s are considered to have opposing effects in reward and stress behavior due to differences in their projection patterns [84–86]. In a similar manner, evidence points towards distinct roles of D1 and D2 MSN’s in mediation of dominance and coping behavior. Distinct differences in D1 and D2 receptor availability are seen between high and low ranking individuals across species including primates and rodents as well as distinct correlations between receptor availability and aspects of human personality and SES[87–92]. Importantly these differences in receptor availability in primates are not present when animals are single housed, and recombining previously subordinate primates led to an increased D2/D3R availability in newly dominant animals suggesting that these differences are functional adaptations occurring along with social hierarchy position and not merely intrinsic differences[93–95].

NAc MSN’s play a role in controlling hierarchy position and associated active coping behaviors. Administration of a D1 receptor antagonist increased dominance of mice in the middle of the social hierarchy, while a D2 receptor antagonist decreased dominance of high-ranking mice[96,97]. As described in fish, exploratory boldness in a novel environment, marked by increased exploration, was associated with greater expression of D2 receptors and delta opioid receptors with a positive correlation between expression of D2 receptors and boldness[98]. While, D1 KO mice display greater levels of active behaviors during tail suspension, D2 KO mice did not[77]. In the case of social stress, high frequency optogenetic stimulation of D1 MSN’s following social defeat restored social interaction in susceptible mice, whereas priming stimulation of D2 MSN’s prior to a sub-threshold social defeat induced greater social avoidance[99]. Functional knockdown of NLGN-2, a component of the inhibitory synapse, in D1 and D2 MSN’s had bidirectional effects with D1 knockdown associated with enhanced subordination and stress susceptibility and D2 knockdown altering displays of active defensive behavior, including running away from the intruder and fighting back against them. Direct interpretation of these findings is complicated as knockdown (KD) of NLGN-2 had dissimilar effects in D1 and D2 MSN’s, such that KD in D1 MSN’s increased mini inhibitory postsynaptic current frequency, whereas KD in in D2 MSN’s decreased mini inhibitory synaptic current frequency[100]. However, when mice are food restricted they show less D2 mRNA and lower cFOS expression in the striatum following forced swim. Most importantly, these mice do not display retention of an immobile coping strategy to subsequent forced swim experiences. Administration of a D2/D3 agonist subsequent to the first forced swim experience mimicked the effects of food restriction; mice did not display retention of an immobile coping strategy. These results point towards a role for D2 receptors in the consolidation of coping strategy[101].

Fully disassociating the roles of D1 and D2 MSN’s in their control of active and passive coping behavior remains to be elucidated. However, these results suggest that they have separate roles in mediating the response to stress while also changing hand in hand with social hierarchy rank. This mediation of coping style selection may be due to their divergent downstream projections. Differential expression or availability of D1 or D2 receptors may then bias towards passive or active coping respectively. Further work should continue to investigate the role of signaling within the mesolimbic dopamine circuitry and its role in mediating social status, aggression and stress coping.

Hypothalamic circuitry in dominance and aggression

The hypothalamus has a well characterized role in control of aggression. Estrogen receptor positive neurons within the ventrolateral part of the ventromedial hypothalamus (VMHvl) are capable of bidirectional modulation of aggression in both males and females. For a thorough review of recent literature see Yamaguchi et al[102]. A substantial breadth of research has also demonstrated a role in the hypothalamus for the regulation of social hierarchy in fish. African cichlid fish provide a unique model to study social hierarchy. Male fish exist in two states depending on hierarchy status: dominant, reproductively active, territorial fish that aggressively maintain their position and subordinate, reproductively inactive, non-aggressive fish that spend their time fleeing dominant fish[103]. Importantly, fish can rapidly transition from one state to another. These fish exhibit a host of rank-dependent biological differences ranging from genome wide expression differences, differentially methylated DNA, and altered stress profiles. These profiles reveal increased CRF in subordinate fish relative to dominant fish, suggesting subordinates may be more stressed [104,105]. When subordinate fish transition to a dominant state they had increased immediate early gene egr-1 in the preoptic area (POA) of the hypothalamus, an area containing dense GnRH1 neurons. This response was not seen in either stably dominant or subordinate fish [106,107]. Dominant fish have 4-fold larger somatostatin containing neurons in the hypothalamus and 8-fold larger GnRH1 neurons within the POA of the hypothalamus[108,109]. Intriguingly research in male mice parallels some aspects of the work in cichlids. Following the removal of the dominant male mouse from an established hierarchy the subdominant male mouse rapidly responds with increased aggression and elevated GnRH mRNA levels within the mPOA [110]. In female mice, subordinates within an established social hierarchy display increased basal corticosterone and substantial genetic differences within the hypothalamus [111].

The hypothalamus also seems to play a role in displays of coping behavior. Arctic charr separated into either proactive or reactive coping styles in response to net restraint and confine stress test displayed differential hypothalamic glucocorticoid and mineralocorticoid ratios[112]. Defense against a conspecific induced cFOS within estrogen receptor positive neurons in the VMHvl. Inhibition of these neurons prevented animals from displaying active coping in response to an attack while activation caused an increase in active coping behaviors[113]. Further dissection of the circuitry within the VMHvl reveals that there is dissociable activation whether an animal is performing or receiving aggression. Activation of the latter neurons ceases aggression and induces retreat away from a conspecific. In an opposing manner activating these neurons can recover levels of resident investigation following an acute social defeat[114]. The VMH also shows activation in response to social threat or predator threat with the former associated with more dorsomedial activation and the latter with ventrolateral activation. Inhibition within either subregion causes inhibition of displays of passive defensive behaviors, such as freezing or submissive posture to their associated threat alone. Both of these subregions of the VMH project to the dorsal periaqueductal gray (PAGd) and inhibition of the PAGd cause reduced displays of aggressor and predator fear[115].

In a strikingly similar manner the premammilarly nucleus dorsal (PMD) seems to exert control over passive coping displays in response to both predator and aggressor threat. The PMD showed dissociable patterns of cFOS in response to predator or conspecific threat. Lesioning this region ablated displays of submissive postures, importantly these animals still displayed active coping behaviors during conspecific threat[116]. Taken together these results suggest that the hypothalamus plays a role in gating displays of passive coping behavior in response to a variety of threats. Neurons with in the ventral premammillary nucleus also serve to control aggressive displays that can alter social hierarchy position. Activation or inhibition of these neurons could elicit or inhibit aggression respectively. In established dyads, inhibition of these neurons in dominants with a parallel activation in subordinate mice was sufficient to reverse the established social hierarchy[117].

The lateral hypothalamus (LH) also selectively produces the neuropeptide, orexin. Discovered in 1998, orexin was first implicated in controlling the sleep/wake cycle, but since then has had a demonstrable role in mediating aggression and aspects of stress coping. Activation of glutamic acid decarboxylase 2 (GAD2) neurons within the lateral habenula via orexin neurons in the lateral hypothalamus can promote male on male aggression as well as enhance conditioned place preference when paired in an aggression context[118]. Within the human population, orexin gene variants correlate with increased levels of aggression, particularly in conjunction with experience of stressful live events[119].

Gene expression of orexin also tracks with social hierarchy position. In zebrafish pairing for 4 days creates stable dominant and subordinate relationships. Within the dominant fish there was a significantly higher gene expression of orexin/hypocretin[120]. This dominance may be in part regulated by aggression itself. In zebrafish, starvation increased chances of winning in a social conflict by potentiating activity within the dorsal habenula via orexin by increasing AMPA-type glutamate receptor activity[121]. Using brain wide imaging in zebrafish, there was enhanced activity of neurons within the ventral lateral habenula and a transition from active to passive coping. The role of these neurons in passivity was further underscored by inhibiting these neurons and limiting transition to passivity[122]. Although the exact nature by which hypothalamic orexin secretion in downstream regions regulates social rank remains to be delineated, orexin signaling within the habenula has been shown to mediate aggression and dominance leading us to speculate that it may contribute to an animal’s social hierarchy position.

Summary

Coping with stress provides a mediation between stressor exposure and pathological outcome. Coping is a complex host of behaviors that span domains. Two divergent styles of coping, active and passive, are associated with decreased or increased risk for pathological outcome. A wideranging host of neural regions are implicated in regulating aspects of coping. More specifically, signaling from the mPFC to DRN likely encodes information about the extent of a stressor to be controllable, with controllable stress triggering fewer deleterious physiological outcomes. The mPFC can inhibit BLA activity to help prevent the acquisition of learned submissive or passive behaviors in response to stressor exposure. Within the mesolimbic dopamine circuitry a host of differences exist between dominant and subordinate animals. NAc D1 and D2 MSN’s differentially regulate social hierarchy position, vary in response to housing condition and may then contribute alternately to active or passive coping strategies when triggered by increased dopamine in response to stress. The hypothalamus seems to be selectively involved in expression of passive or submissive coping behaviors in response to a variety of threats. Finally, orexin signaling has been newly implicated in regulation of aggression and social hierarchy position with intriguing evidence for a hand in mediating physiological responses to stress. Additional research needs to be done to continue to identify regions regulating coping style, synthesizing these results to a more complete whole, and focus more on female strategies of stress coping and delineating the overlap between aggression, dominance and coping.

Future Directions

Here we have discussed recent insights that begin to define some neural circuits underlying differential selection of active and passive coping in a social rank associated manner. However, we still have a limited understanding of the complex brain-wide mechanisms mediating interactions between stress, dominance and social status. As the field evolves, the ability to simultaneously record from multiple regions at a time as an animal is freely behaving may prove to be the key to synthesizing the wide ranging results surrounding regions controlling coping style. Clearly coping is a complex phenomenon that involves assessment of strength of the stressor, memory of prior experiences with similar or dissimilar stressors, evaluation of the extent to which a stressor can be controlled, and mediation of selection of an action that is best for the stressor exposure. The ability to understand the interplay of these regions will likely provide great insights into how coping style can provide mediation between stress exposure and pathological outcome. In addition, there still remains a substantial lack of parallel research investigating coping in females. The current assumption of a heavy overlap between aggression and coping style may not necessarily be transferrable to understanding mediators of coping in female animals that do not use aggression to achieve their hierarchy position. Future studies are critical to better define female social hierarchies and their impact on stress specifically so that we can understand the neural circuits mediating interactions between stress and social rank in females.

Figure: 1. Neural Circuitry Implicated in Social Hierarchy, Stress Coping and Aggression.

A simplified schematic showing connections between the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), Amygdala (Amy), hypothalamic nuclei including the lateral hypothalamus (LH) ventral medial hypothalamus (MH) premammillary nucleus dorsal (PMD), lateral habenula (LHb) ventral tegmental area (VTA), periaqueductal gray (PAG), and the dorsal raphe nucleus (DRN) with glutamatergic projections in red, dopaminergic in green, GABAergic in blue and orexinergic in yellow. Each of these projections has been demonstrated to play a causal role in behaviors related to active or passive stress coping, such as social dominance, aggression, immobility or struggling in the forced swim test or tail suspension, response to an aggressive resident or intruder, as well as exposure to shock or other aversive stressors.

Table 1: Summary of Literature Supporting Neural Engagement Across Behavioral Domains:

An upwards arrow indicates neuronal activity in this region is associated with displays of dominance, aggression or coping and a downwards arrow indicates reduced activity is associated with dominance, aggression or coping. These directional associations between activity and behavioral displays are based on cumulative evidence from calcium imaging, neurotransmitter release, immediate early gene expression, and electrophysiology in conjunction with optogenetic, genetic or pharmacological manipulations.

Region	Dominance	Aggression	Active Coping	Passive Coping	Reference
mPFC	↑		↑	↓	33, 42, 43, 54, 57, 59,
IL/PL			↑	↓	48, 49, 50, 57
VTA	↑	↑	↑	↓	65, 66, 67, 68, 69, 70, 72
NAc	D1 ↓ D2 ↑		↓ ↑*	↓ ↑*	72, 73, 74, 77, 96, 97, 98, 101, 99, 100
DRN			↓ ↑*	↓ ↑*	54, 35, 55, 57
Hb	↑	↓ Gad2 : ↑	↓	↑	118, 121, 122
POA	↑				106
VMH		↑	↑	↓	113, 114, 115, 116
PMD			No Change	↑	116, 117
PAG			No Change	↑	115

^*Some conflicting evidence exists regarding the specific role of activity in these regions and the associated behavioral outcome. These differences are likely due to differences in cell type activation, timing, and stressor exposure. Further research delineating the exact role of these regions and cell type specific contributions to coping behaviors across stressor types is necessary.

Table 2: Summary of Methodology to Determine Social Rank:

Reference for the methodology employed to determine social status.

Section	Reference	Summary	Organism	Sex	Dominance Measurement
Cortical Top-down Facilitation of Social Dominance	[40]	Dominants and subordinates have differential gene expression in mPFC	C57BL/6J Mice	Male	Tube Test
	[41]	mPFC lesion reduces rank	Long Evans Rats	Male	Observations of agnostic behavior in semi naturalistic environment
	[33]	Synaptic efficacy within the mPFC bidirectionally controls social rank	C57BL/6J Mice	Male	Tube test (primary), visible Burrow System, observations of agnostic behavior, barber test, ultrasonic vocalizations, urine marking, ultrasound events
	[42]	Optogenetic activation of mPFC caused increased rank	C57BL/6J mice	Male	Tube test, warm spot competition
	[45]	Dominants had to maintain rank for 14 days to be protected from social defeat	Syrian Hamsters	Male	Agnostic behavior observations during resident intruder from daily social encounters in paired dyads
	[46]	Dominants display more active coping behaviors following social defeat		Male	Agnostic behavior observations during resident intruder from daily social encounters in paired dyads
	[48]	Dominants had increased cFOS in BLA projections from mPFC	Syrian Hamsters	Male	Agnostic behavior observations during resident intruder from daily social encounters in paired dyads
	[49]		Syrian Hamsters	Male	Agnostic behavior observations during resident intruder from daily social encounters in paired dyads
	[50]	Activating BLA projections from mPFC increased active behaviors to social defeat in subordinates only	Syrian Hamsters	Male	Agnostic behavior observations during resident intruder from daily social encounters in paired dyads
	[53]	Genetic expression differences in the BLA between dominants and subordinates	Syrian Hamsters	Male + Female	Agnostic behavior observation from a single day of resident intruder pairings
Mesolimbic Dopamine circuitry in dominance and aggression	[64]	Dominants had altered dopamine availability across multiple brain regions	Anolis carolinensis Lizard	Males	Assessment of physical markings of social status (eye spots)
	[66]	Increased cFOS in VTA of dominants associated with higher aggression	Syrian Hamsters	Male	Assessment of either aggression and/or flank marking or submissive behavior during a social interaction
	[68]	Optogenetic stimulation fo VTA DA neurons increased rank	Long Evans Background Transgenic Rats	Male	Performance in social competition tasks (palatable reward and water competition)
	[72]	Diazepam administration to VTA did not alter rank	Wister Rats	Male	Agnostic behavior observation in established dyads
	[75]	Differences in NAc metabolism between ranks	C57BL/6J Mice	Male	Tube test, urine marking, agnostic behavior observation
	[76]	Treatment of dominants with mitochondria boosting supplement improved stress outcome	C57BL/6J Mice		Tube Test
	[78]	Downregulation or knockout of glucocorticoid receptors increased rank.	Wistar Rats		Agnostic behavior observation in established dyads
	[90]	SES and social status positivity correlated with D2/D3 receptor availability		Male and Female	Socioeconomic status (SES) measured with the Hollingshead scale
	[92]	Dominants had increased D2/3 binding in NAC	Listar Hooded rats	Male	Resource competition task, tube test
	[93]	No difference between ranks when individually housed. Dominants had more D2/D3 receptor availability	Cynomolgus monkeys	Male	Observations of agnostic behavior in group housing condition
	[94]	No difference between ranks when individually housed. Dominants had more D2/D3 receptor availability	Cynomolgus monkeys	Female	Observations of agnostic behavior in group housing condition
	[95]	Subordinates who then became dominant had increased D2/D3 receptor availability	Cynomolgus monkeys	Male	Observations of agnostic behavior in group housing condition
	[96]	D2 receptor antagonist decreased rank of dominants	Japanese macaques: CD1 Mice	Male + Female: Male	Agnostic behavior observation, resource competition task (food priority test): tube test
	[97]	D1 receptor antagonist increased rank of intermediates	Japanese macaques: CD1 Mice	Male + Female: Male	Agnostic behavior observation, resource competition task (food priority test): tube test
	[100]	Altering D1 and D3 MSN activity altered rank, coping behaviors, and stress susceptibility	C57BL/6J Background Transgenic Mice	Male	Tube Test
Hypothalamic circuity in dominance and aggression	[104]	Rank dependent biological differences	Cichlid Fish	Male	Focal behavioral observations and morphological differences (eyebar and body coloration)
	[105]	Gene expression differences between ranks	Cichlid Fish	Male	Behavioral observations and morphological differences (eyebar and body coloration)
	[106]	Subordinates becoming dominant had immediate early gene activity in the hypothalamus	Cichlid Fish		Behavioral observations and morphological differences (eyebar and body coloration)
	[107]	Subordinates becoming dominant had reduced cortisol and down regulated CRF receptor expression	Cichlid Fish	Male	Behavioral observations and morphological differences (eyebar and body coloration)
	[108]	Dominants have larger somatostatin neurons in the hypothalamus		Male	Behavioral observations and morphological differences (eyebar and body coloration)
	[109]	Dominants have larger GnRH1 neurons within the hypothalamus	Cichlid Fish	Male	Behavioral observations and morphological differences (eyebar and body coloration)
	[110]		CD1 Mice	Male	Agnostic behavior observation in established group housing
	[111]	Subordinates have increased corticosterone. Genetic differences in hypothalamus between ranks.	CD1 Mice	Female	Agnostic behavior observation in established group housing
	[117]	inhibition of neurons in premammilary nucleus in dominants with activation in subordinates swapped ranks	C57BL/6J Mice and BALB/c Mice	Male	Hierarchy Corridor Test (Adaptation of tube test)
	[120]	Dominants had higher orexin gene expression	Zebrafish	Male	Agnostic and subordinate behavioral observation in home tank
	[121]	Starvation increased rank via orexin by increasing AMPA-type glutamate receptor activity	Transgenic and WT Zebrafish	Male	Agnostic behavior in newly combined dyads

Highlights.

• Coping style can mediate the effects of stress and its associated disease risks and pathologies.

• Projections from the mPFC encode stressor information and mediate behavioral responses.

• D1 and D2 MSN’s may differentially control active or passive coping behavior selection.

• Hypothalamic signaling mediates passive coping behaviors to a variety of threats.