Chronic Social Defeat Stress: Animal Models and Behavior

Chronic social defeat stress (CSDS) is a widely used model for studying prolonged psychological stress, particularly in relation to mood disorders like depression and anxiety. Repeated exposure to social subordination leads to lasting behavioral and physiological changes, making it a valuable tool for understanding stress-related mental health conditions.

Research using CSDS has provided insights into how chronic stress affects neural circuits, hormonal balance, and behavior. By examining these mechanisms, scientists aim to develop better treatments for stress-induced psychiatric disorders.

Animal Model Insights

The CSDS model relies on repeated encounters between a test rodent, typically a male mouse, and a larger, more aggressive conspecific. This paradigm mimics prolonged social subordination, a stressor linked to mood disorders in humans. The standard protocol involves daily confrontations over 10 days, during which the test mouse is exposed to physical aggression followed by sensory contact with the dominant mouse. This combination of direct and indirect stressors enhances the model’s ecological validity, as it mirrors the persistent social stress experienced in hierarchical animal groups.

A defining feature of CSDS is its ability to produce both stress-susceptible and resilient animals. Susceptible mice exhibit social avoidance, anhedonia, and heightened anxiety-like behaviors, while resilient mice maintain normal social interactions despite repeated stress exposure. This variability allows researchers to investigate the biological mechanisms underlying susceptibility and resilience, offering potential therapeutic targets.

CSDS consistently induces behavioral phenotypes that align with human psychiatric conditions. Social withdrawal in defeated mice parallels social anhedonia in major depressive disorder, while increased passive coping strategies resemble learned helplessness, a hallmark of chronic stress exposure in humans. The model has also been instrumental in evaluating antidepressant treatments, as chronic administration of selective serotonin reuptake inhibitors (SSRIs) reverses social avoidance behaviors in susceptible mice. This pharmacological validation underscores the utility of CSDS in preclinical drug development.

Neurological Pathways

CSDS profoundly alters neural circuits involved in emotional and cognitive processing, with the mesolimbic dopamine system playing a central role in mediating stress susceptibility and resilience. The ventral tegmental area (VTA) and its projections to the nucleus accumbens (NAc) undergo significant neuroadaptations following repeated social stress. Susceptible mice display hyperactivity in dopaminergic neurons, leading to excessive dopamine release in the NAc, a hallmark of maladaptive stress responses. In contrast, resilient mice maintain balanced dopaminergic activity, preventing pathological behaviors. Optogenetic inhibition of VTA-NAc projections has been shown to mitigate social avoidance in susceptible mice, highlighting this circuit as a potential therapeutic target.

Beyond the mesolimbic system, the prefrontal cortex (PFC) undergoes significant remodeling under chronic social stress. Susceptible mice exhibit hypoactivity in the medial PFC, a region crucial for regulating emotional responses. This diminished activity correlates with impaired synaptic plasticity, particularly reduced dendritic spine density on pyramidal neurons. These structural deficits weaken inhibitory control over subcortical stress-responsive regions like the amygdala, exacerbating maladaptive behaviors. Resilient animals maintain stable PFC activity, preserving cognitive flexibility and adaptive stress coping mechanisms. Pharmacological enhancement of PFC excitability reverses stress-induced social avoidance, reinforcing its role in resilience.

The amygdala, a key hub for emotional processing, exhibits heightened excitability following chronic social defeat, particularly in the basolateral and central nuclei. Increased glutamatergic transmission in these regions amplifies fear and anxiety-related behaviors, reinforcing social avoidance. Concurrently, the bed nucleus of the stria terminalis (BNST), a structure implicated in sustained stress responses, shows hyperactivation in susceptible mice, perpetuating prolonged anxiety states. Chronic stress enhances corticotropin-releasing factor (CRF) signaling in these circuits, further sensitizing the stress response system. Blocking CRF receptors in the BNST alleviates anxiety-like behaviors, underscoring this pathway’s contribution to prolonged stress-induced dysfunction.

Hormonal Regulation

CSDS triggers widespread endocrine alterations, with the hypothalamic-pituitary-adrenal (HPA) axis playing a central role in mediating physiological responses to prolonged social stress. Repeated aggression leads to dysregulation of corticotropin-releasing factor (CRF) secretion from the hypothalamus, driving sustained activation of the anterior pituitary. This results in excessive release of adrenocorticotropic hormone (ACTH), promoting adrenal hypersecretion of glucocorticoids such as corticosterone in rodents and cortisol in humans. Elevated baseline glucocorticoid levels in stress-susceptible mice mirror findings in individuals with mood disorders, where chronic HPA axis overactivity impairs stress regulation.

Prolonged exposure to high corticosterone levels leads to glucocorticoid receptor (GR) downregulation in the hippocampus, weakening negative feedback control over the HPA axis. This impaired feedback loop results in exaggerated stress reactivity, reinforcing maladaptive behavioral responses such as social withdrawal and heightened anxiety. Conversely, resilient mice exhibit preserved GR sensitivity, allowing for more efficient recovery from stress-induced neuroendocrine activation. Pharmacological interventions aimed at enhancing GR function, such as selective GR modulators, show promise in restoring HPA axis balance and mitigating stress-induced behavioral impairments.

CSDS also disrupts hormonal pathways regulating social and emotional behaviors, particularly those involving oxytocin and vasopressin. Oxytocin, associated with social bonding and stress buffering, is significantly reduced in the hypothalamus of stress-susceptible mice, contributing to deficits in social interaction. Reduced oxytocin signaling within the nucleus accumbens and amygdala has been linked to increased social avoidance. Experimental administration of intranasal oxytocin reverses social deficits in defeated mice, highlighting its potential as a therapeutic target for stress-induced social dysfunction. Vasopressin, on the other hand, is upregulated in stress-responsive regions such as the BNST, amplifying stress reactivity and promoting anxiety-like behaviors.

Behavioral Alterations

CSDS induces persistent behavioral changes resembling mood and anxiety disorders in humans. One of the most pronounced effects is social avoidance, where previously sociable mice withdraw from interactions with novel conspecifics. This behavior is assessed using the social interaction test, in which defeated mice spend significantly less time near a social target compared to unstressed controls. The severity of avoidance correlates with prolonged exposure to aggression, suggesting that cumulative stress experiences exacerbate social disengagement.

Beyond social withdrawal, CSDS leads to anhedonia, a hallmark of depressive-like states. This is measured using the sucrose preference test, where stress-susceptible mice exhibit reduced motivation to consume a normally preferred sweet solution. The decline in reward-seeking behavior mirrors blunted responsiveness to pleasurable stimuli seen in individuals with major depressive disorder. Additionally, defeated mice display heightened thigmotaxis in open field tests, a pattern associated with increased anxiety-like states. These behavioral shifts indicate broad dysregulation of emotional processing, extending beyond social deficits to affect general motivation and stress coping strategies.