Cortical control of affective networks.

Transcranial magnetic stimulation and deep brain stimulation have emerged as therapeutic modalities for treatment refractory depression; however, little remains known regarding the circuitry that mediates the therapeutic effect of these approaches. Here we show that direct optogenetic stimulation of prefrontal cortex (PFC) descending projection neurons in mice engineered to express Chr2 in layer V pyramidal neurons (Thy1-Chr2 mice) models an antidepressant-like effect in mice subjected to a forced-swim test. Furthermore, we show that this PFC stimulation induces a long-lasting suppression of anxiety-like behavior (but not conditioned social avoidance) in socially stressed Thy1-Chr2 mice: an effect that is observed >10 d after the last stimulation. Finally, we use optogenetic stimulation and multicircuit recording techniques concurrently in Thy1-Chr2 mice to demonstrate that activation of cortical projection neurons entrains neural oscillatory activity and drives synchrony across limbic brain areas that regulate affect. Importantly, these neural oscillatory changes directly correlate with the temporally precise activation and suppression of limbic unit activity. Together, our findings show that the direct activation of cortical projection systems is sufficient to modulate activity across networks underlying affective regulation. They also suggest that optogenetic stimulation of cortical projection systems may serve as a viable therapeutic strategy for treating affective disorders.

Histone serotonylation in dorsal raphe nucleus contributes to stress- and antidepressant-mediated gene expression and behavior.

Mood disorders are an enigmatic class of debilitating illnesses that affect millions of individuals worldwide. While chronic stress clearly increases incidence levels of mood disorders, including major depressive disorder (MDD), stress-mediated disruptions in brain function that precipitate these illnesses remain largely elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding direct roles for serotonin in the precipitation and treatment of affective disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this non-canonical phenomenon has not yet been explored following stress and/or AD exposures. Here, we employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress, as well as in DRN of human MDD patients, to examine the impact of stress exposures/MDD diagnosis on H3K4me3Q5ser dynamics, as well as associations between the mark and depression-related gene expression. We additionally assessed stress-induced/MDD-associated regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy in mice to reduce H3K4me3Q5ser levels in DRN and examine its impact on stress-associated gene expression and behavior. We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to attenuate stress-mediated gene expression and behavior. Corresponding patterns of H3K4me3Q5ser regulation were observed in MDD subjects on vs. off ADs at their time of death. These findings thus establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity, observations of which may be of clinical relevance to human MDD and its treatment.

Histone H3 serotonylation dynamics in dorsal raphe nucleus contribute to stress- and antidepressant-mediated gene expression and behavior.

Background: Major depressive disorder (MDD), along with related mood disorders, is a debilitating illness that affects millions of individuals worldwide. While chronic stress increases incidence levels of mood disorders, stress-mediated disruptions in brain function that precipitate these illnesses remain elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding precise roles for serotonin in the precipitation of mood disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this phenomenon has not yet been explored following stress and/or AD exposures. Methods: We employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress to examine the impact of stress exposures on H3K4me3Q5ser dynamics, as well as associations between the mark and stress-induced gene expression. We additionally assessed stress-induced regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy to reduce H3K4me3Q5ser levels in DRN and examine the impact on stress-associated gene expression and behavior. Results: We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to rescue stress-mediated gene expression and behavior. Conclusions: These findings establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity in DRN.

Escalated or suppressed cocaine reward, tegmental BDNF, and accumbal dopamine caused by episodic versus continuous social stress in rats.

The neural link between ostensibly aversive stress experiences and intensely rewarding drug taking remains to be delineated. Epidemiological data associate stress and the abuse of various drugs, and experimental data identify the conditions that determine how episodic social stress intensifies the motivation for cocaine and the actual self-administration of cocaine. Two types of social stress have been the focus of experimental study in Long-Evans rats, since they engender divergent changes in drug- or sugar-rewarded behavior and in neuroadaptation. Episodic social defeat stress consists of four brief confrontations between the experimental rat and an aggressive resident rat of the Long-Evans strain over the course of 10 d. Subordination stress involves the continuous exposure to an aggressive resident for 5 weeks, while living in a protective cage within the resident's home cage with brief daily confrontations. These stress experiences result in (1) increased intravenous cocaine self-administration under a fixed ratio schedule with prolonged binge-like access in episodically defeated intruder rats but suppressed cocaine intake by continuously subordinate rats; (2) deteriorated sugar preference and intake and decreased exploratory behavior in subordinate, but not intermittently defeated, rats; and (3) a sensitized dopamine (DA) response in the nucleus accumbens via in vivo microdialysis and increased tegmental brain-derived neural growth factor (BDNF) in episodically defeated rats, whereas the continuously subordinate rats show suppression of the DA and BDNF responses. These divergent neuroadaptations to social stress may represent the substrates for the intensification of cocaine "bingeing" relative to the anhedonia-like deterioration of reward processes during subordination stress.

Neurobiological Bases of Alcohol Consumption After Social Stress.

The urge to seek and consume excessive alcohol is intensified by prior experiences with social stress, and this cascade can be modeled under systematically controlled laboratory conditions in rodents and non-human primates. Adaptive coping with intermittent episodes of social defeat stress often transitions to maladaptive responses to traumatic continuous stress, and alcohol consumption may become part of coping responses. At the circuit level, the neural pathways subserving stress coping intersect with those for alcohol consumption. Increasingly discrete regions and connections within the prefrontal cortex, the ventral and dorsal striatum, thalamic and hypothalamic nuclei, tegmental areas as well as brain stem structures begin to be identified as critical for reacting to and coping with social stress while seeking and consuming alcohol. Several candidate molecules that modulate signals within these neural connections have been targeted in order to reduce excessive drinking and relapse. In spite of some early clinical failures, neuropeptides such as CRF, opioids, or oxytocin continue to be examined for their role in attenuating stress-escalated drinking. Recent work has focused on neural sites of action for peptides and steroids, most likely in neuroinflammatory processes as a result of interactive effects of episodic social stress and excessive alcohol seeking and drinking.

Excessive alcohol consumption after exposure to two types of chronic social stress: intermittent episodes vs. continuous exposure in C57BL/6J mice with a history of drinking.

RATIONALE: The attraction to alcohol can be greatly increased when it is consumed in a social context. While pro-social interactions can potentiate voluntary alcohol drinking under some conditions, aversive social experience (i.e., social stress) can similarly intensify alcohol consumption. OBJECTIVE: We sought to determine how exposure to different types of chronic social stress (i.e., intermittent episodes of social defeat or continuous social stress) influences alcohol consumption and the reinforcing effects of alcohol in mice with a history of drinking. METHODS: Separate cohorts of male C57BL/6J mice were exposed to either 10 days of continuous or intermittent social defeat stress. In experiment 1, mice were assigned to 20% w/v alcohol consumption in a two-bottle choice protocol both prior to and after exposure to social defeat stress. In a second experiment, mice engaged in an operant response sequence to gain access to alcohol wherein completion of a fixed interval (FI; 5 min) schedule was reinforced with continuous access to alcohol (fixed ratio; FR1) for up to 1.8 g/kg. Alcohol-reinforced responding and subsequent alcohol consumption were assessed daily for 4 weeks prior to the 10-day social stress exposure and for 6-week post-stress. Machine learning was implemented to standardize the analysis of defeat behaviors exhibited by the intruder mouse during confrontation with an attacking resident. RESULTS: In mice with a prior history of alcohol drinking, intermittent episodes of social defeat stress produced a significant increase in 20% EtOH consumption in preference over concurrently available water. This increased intake persisted for at least 6 weeks after the final social stress experience. Intermittently stressed mice also accelerated their anticipatory responding during the fixed interval component of the operant response chain that was reinforced by alcohol. Neither unstressed controls nor mice exposed to continuous social stress exhibited significant increases in alcohol consumption and alcohol reinforcement. DISCUSSION: Episodic social defeat stress promotes the seeking and consumption of alcohol, extending earlier work to alcohol-experienced mice. We hypothesize that intermittent access to alcohol and intermittent episodes of social stress are additive and share common sensitizing neural mechanisms that engender excessive alcohol consumption.

To fight or not to fight: activation of the mPFC during decision to engage in aggressive behavior after ethanol consumption in a novel murine model.

RATIONALE: Alcohol consumption is a common antecedent of aggressive behavior. The effects of alcohol on the decision to engage in aggression in preference over pro-social interaction are hypothesized to arise from augmented function within the medial prefrontal cortex (mPFC). OBJECTIVE: In a newly developed procedure, we studied social decision-making in male C57BL/6 J mice based on preferentially seeking access to either sociosexual interactions with a female partner or the opportunity to attack an intruder male. While deciding to engage in aggressive vs. sociosexual behavior, corresponding neural activation was assessed via c-Fos immunoreactivity in cortical, amygdaloid and tegmental regions of interest. A further objective was to investigate how self-administered alcohol impacted social choice. METHODS: During repeated confrontations with an intruder male in their home cage, experimental mice engaged in species-specific sequence of pursuit, threat, and attack behavior within < 2 min. Mice were then conditioned to respond at one of two separate illuminated operanda in an experimental chamber (octagon) attached to their home cage; completion of 10 responses (fixed ratio 10; FR10) was reinforced by access to either a female or a male intruder which were presented in the resident's home cage. Brains were harvested following choice between the concurrently available aggressive and sociosexual options and processed for c-Fos immunoreactivity across 10 brain regions. In two separate groups, mice were trained to rapidly self-administer ethanol prior to a social choice trial in order to examine the effects of alcohol on social choice, sociosexual, aggressive acts and postures, and concurrent c-Fos activity in the mPFC and limbic regions. RESULTS AND DISCUSSION: Eight out of 65 mice consistently chose to engage in aggressive behavior in preference to sociosexual contact with a female when each outcome was concurrently available. Self-administered alcohol (experiment 1: 1.2 ± 0.02 g/kg; experiment 2: 0, 1.0, 1.5, and 1.8 g/kg) increased responding for the aggressive option in mice that previously opted predominantly for access to sociosexual interactions with the female. When choosing the aggressive, but not the sociosexual option, the prelimbic area of the mPFC revealed increased c-Fos activity, guiding future detailed inquiry into the neural mechanisms for aggressive choice.

Induction of deltaFosB in the periaqueductal gray by stress promotes active coping responses.

We analyzed the influence of the transcription factor DeltaFosB on learned helplessness, an animal model of affective disorder wherein a subset of mice exposed to inescapable stress (IS) develop a deficit in escape behavior. Repeated IS induces DeltaFosB in the ventrolateral periaqueductal gray (vlPAG), and levels of the protein are highly predictive of an individual's subsequent behavorial deficit-with the strongest DeltaFosB induction observed in the most resilient animals. Induction of DeltaFosB by IS predominates in substance P-positive neurons in the vlPAG, and the substance P gene, a direct target for DeltaFosB, is downregulated upon DeltaFosB induction. Local overexpression of DeltaFosB in the vlPAG using viral-mediated gene transfer dramatically reduces depression-like behaviors and inhibits stress-induced release of substance P. These results indicate that IS-induced accumulation of DeltaFosB in the vlPAG desensitizes substance P neurons enriched in this area and opposes behavioral despair by promoting active defense responses.

Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli.

Previous work has identified alterations in histone acetylation in animal models of drug addiction and depression. However, the mechanisms which integrate drugs and stress with changes in chromatin structure remain unclear. Here, we identify the activity-dependent class II histone deacetylase, HDAC5, as a central integrator of these stimuli with changes in chromatin structure and gene expression. Chronic, but not acute, exposure to cocaine or stress decreases HDAC5 function in the nucleus accumbens (NAc), a major brain reward region, which allows for increased histone acetylation and transcription of HDAC5 target genes. This regulation is behaviorally important, as loss of HDAC5 causes hypersensitive responses to chronic, not acute, cocaine or stress. These findings suggest that proper balance of histone acetylation is a crucial factor in the saliency of a given stimulus and that disruption of this balance is involved in the transition from an acute adaptive response to a chronic psychiatric illness.

Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex.

Brain stimulation and imaging studies in humans have highlighted a key role for the prefrontal cortex in clinical depression; however, it remains unknown whether excitation or inhibition of prefrontal cortical neuronal activity is associated with antidepressant responses. Here, we examined cellular indicators of functional activity, including the immediate early genes (IEGs) zif268 (egr1), c-fos, and arc, in the prefrontal cortex of clinically depressed humans obtained postmortem. We also examined these genes in the ventral portion of the medial prefrontal cortex (mPFC) of mice after chronic social defeat stress, a mouse model of depression. In addition, we used viral vectors to overexpress channel rhodopsin 2 (a light-activated cation channel) in mouse mPFC to optogenetically drive "burst" patterns of cortical firing in vivo and examine the behavioral consequences. Prefrontal cortical tissue derived from clinically depressed humans displayed significant reductions in IEG expression, consistent with a deficit in neuronal activity within this brain region. Mice subjected to chronic social defeat stress exhibited similar reductions in levels of IEG expression in mPFC. Interestingly, some of these changes were not observed in defeated mice that escape the deleterious consequences of the stress, i.e., resilient animals. In those mice that expressed a strong depressive-like phenotype, i.e., susceptible animals, optogenetic stimulation of mPFC exerted potent antidepressant-like effects, without affecting general locomotor activity, anxiety-like behaviors, or social memory. These results indicate that the activity of the mPFC is a key determinant of depression-like behavior, as well as antidepressant responses.

Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action.

We previously reported that the activity of mesolimbic dopamine neurons of the ventral tegmental area (VTA) is a key determinant of behavioral susceptibility vs resilience to chronic social defeat stress. However, this was based solely on ex vivo measurements, and the in vivo firing properties of VTA dopamine neurons in susceptible and resilient mice, as well as the effects of antidepressant treatments, remain completely unknown. Here, we show that chronic (10 d) social defeat stress significantly increased the in vivo spontaneous firing rates and bursting events in susceptible mice but not in the resilient subgroup. Both the firing rates and bursting events were significantly negatively correlated with social avoidance behavior, a key behavioral abnormality induced by chronic social defeat stress. Moreover, the increased firing rates, bursting events, and avoidance behavior in susceptible mice were completely reversed by chronic (2 week), but not acute (single dose), treatments with the antidepressant medication fluoxetine (20 mg/kg). Chronic social defeat stress increased hyperpolarization-activated cation current (I(h)) in VTA dopamine neurons, an effect that was also normalized by chronic treatment with fluoxetine. As well, local infusion of I(h) inhibitors ZD7288 (0.1 µg) or DK-AH 269 (0.6 µg) into the VTA exerted antidepressant-like behavioral effects. Together, these data suggest that the firing patterns of mesolimbic dopamine neurons in vivo mediate an individual's responses to chronic stress and antidepressant action.

Gene expression in aminergic and peptidergic cells during aggression and defeat: relevance to violence, depression and drug abuse.

In this review, we examine how experiences in social confrontations alter gene expression in mesocorticolimbic cells. The focus is on the target of attack and threat due to the prominent role of social defeat stress in the study of coping mechanisms and victimization. The initial operational definition of the socially defeated mouse by Ginsburg and Allee (1942) enabled the characterization of key endocrine, cardiovascular, and metabolic events during the initial response to an aggressive opponent and during the ensuing adaptations. Brief episodes of social defeat stress induce an augmented response to stimulant challenge as reflected by increased locomotion and increased extracellular dopamine (DA) in the nucleus accumbens (NAC). Cells in the ventral tegmental area (VTA) that project to the NAC were more active as indicated by increased expression of c-fos and Fos-immunoreactivity and BDNF. Intermittent episodes of social defeat stress result in increased mRNA for MOR in brainstem and limbic structures. These behavioral and neurobiological indices of sensitization persist for several months after the stress experience. The episodically defeated rats also self-administered intravenous cocaine during continuous access for 24 h ("binge"). By contrast, continuous social stress, particularly in the form of social subordination stress, leads to reduced appetite, compromised endocrine activities, and cardiovascular and metabolic abnormalities, and prefer sweets less as index of anhedonia. Cocaine challenges in subordinate rats result in a blunted psychomotor stimulant response and a reduced DA release in NAC. Subordinate rats self-administer cocaine less during continuous access conditions. These contrasting patterns of social stress result from continuous vs. intermittent exposure to social stress, suggesting divergent neuroadaptations for increased vulnerability to cocaine self-administration vs. deteriorated reward mechanisms characteristic of depressive-like profiles.

Aggression: How the anterior cingulate cortex helps to ensure a fair fight.

Violent behavior is the product of a diverse network of neural structures. A new study shows that the anterior cingulate cortex is important for helping to restrain overly aggressive acts, even within a fight, to ensure animals match their behavioral intensity with the challenge posed by their opponents.

Hypoactive Thalamic Crh+ Cells in a Female Mouse Model of Alcohol Drinking After Social Trauma.

BACKGROUND: Comorbid stress-induced mood and alcohol use disorders are increasingly prevalent among female patients. Stress exposure can disrupt salience processing and goal-directed decision making, contributing to persistent maladaptive behavioral patterns; these and other stress-sensitive cognitive and behavioral processes rely on dynamic and coordinated signaling by midline and intralaminar thalamic nuclei. Considering the role of social trauma in the trajectory of these debilitating psychopathologies, identifying vulnerable thalamic cells may provide guidance for targeting persistent stress-induced symptoms. METHODS: A novel behavioral protocol traced the progression from social trauma to the development of social defensiveness and chronically escalated alcohol consumption in female mice. Recent cell activation-measured as cFos-was quantified in thalamic cells after safe social interactions, revealing stress-sensitive corticotropin-releasing hormone-expressing (Crh+) anterior central medial thalamic (aCMT) cells. These cells were optogenetically stimulated during stress-induced social defensiveness and abstinence-escalated binge drinking. RESULTS: Crh+ aCMT neurons exhibited substantial activation after social interactions in stress-naïve but not in stressed female mice. Photoactivating Crh+ aCMT cells dampened stress-induced social deficits, whereas inhibiting these cells increased social defensiveness in stress-naïve mice. Optogenetically activating Crh+ aCMT cells diminished abstinence-escalated binge alcohol drinking in female mice, regardless of stress history. CONCLUSIONS: This work uncovers a role for Crh+ aCMT neurons in maladaptive stress-induced social interactions and in binge drinking after forced abstinence in female mice. This molecularly defined thalamic cell population may serve as a critical stress-sensitive hub for social deficits caused by exposure to social trauma and for patterns of excessive alcohol drinking in female populations.

Antidepressant actions of histone deacetylase inhibitors.

Persistent symptoms of depression suggest the involvement of stable molecular adaptations in brain, which may be reflected at the level of chromatin remodeling. We find that chronic social defeat stress in mice causes a transient decrease, followed by a persistent increase, in levels of acetylated histone H3 in the nucleus accumbens, an important limbic brain region. This persistent increase in H3 acetylation is associated with decreased levels of histone deacetylase 2 (HDAC2) in the nucleus accumbens. Similar effects were observed in the nucleus accumbens of depressed humans studied postmortem. These changes in H3 acetylation and HDAC2 expression mediate long-lasting positive neuronal adaptations, since infusion of HDAC inhibitors into the nucleus accumbens, which increases histone acetylation, exerts robust antidepressant-like effects in the social defeat paradigm and other behavioral assays. HDAC inhibitor [N-(2-aminophenyl)-4-[N-(pyridine-3-ylmethoxy-carbonyl)aminomethyl]benzamide (MS-275)] infusion also reverses the effects of chronic defeat stress on global patterns of gene expression in the nucleus accumbens, as determined by microarray analysis, with striking similarities to the effects of the standard antidepressant fluoxetine. Stress-regulated genes whose expression is normalized selectively by MS-275 may provide promising targets for the future development of novel antidepressant treatments. Together, these findings provide new insight into the underlying molecular mechanisms of depression and antidepressant action, and support the antidepressant potential of HDAC inhibitors and perhaps other agents that act at the level of chromatin structure.

Delta FosB mediates epigenetic desensitization of the c-fos gene after chronic amphetamine exposure.

The molecular mechanisms underlying the transition from recreational drug use to chronic addiction remain poorly understood. One molecule implicated in this process is DeltaFosB, a transcription factor that accumulates in striatum after repeated drug exposure and mediates sensitized behavioral responses to psychostimulants and other drugs of abuse. The downstream transcriptional mechanisms by which DeltaFosB regulates drug-induced behaviors are incompletely understood. We reported previously the chromatin remodeling mechanisms by which DeltaFosB activates the expression of certain genes; however, the mechanisms underlying DeltaFosB-mediated gene repression remain unknown. Here, we identify c-fos, an immediate early gene rapidly induced in striatum after acute psychostimulant exposure, as a novel downstream target that is repressed chronically by DeltaFosB. We show that accumulation of DeltaFosB in striatum after chronic amphetamine treatment desensitizes c-fos mRNA induction to a subsequent drug dose. DeltaFosB desensitizes c-fos expression by recruiting histone deacetylase 1 (HDAC1) to the c-fos gene promoter, which, in turn, deacetylates surrounding histones and attenuates gene activity. Accordingly, local knock-out of HDAC1 in striatum abolishes amphetamine-induced desensitization of the c-fos gene. In concert, chronic amphetamine increases histone H3 methylation on the c-fos promoter, a chromatin modification also known to repress gene activity, as well as expression levels of the H3 histone methyltransferase, KMT1A (lysine methyltransferase 1A, formerly SUV39H1). This study reveals a novel epigenetic pathway through which DeltaFosB mediates distinct transcriptional programs that may ultimately alter behavioral plasticity to chronic amphetamine exposure.

Social stress, therapeutics and drug abuse: preclinical models of escalated and depressed intake.

The impact of ostensibly aversive social stresses on triggering, amplifying and prolonging intensely rewarding drug taking is an apparent contradiction in need of resolution. Social stress encompasses various types of significant life events ranging from maternal separation stress, brief episodes of social confrontations in adolescence and adulthood, to continuous subordination stress, each with its own behavioral and physiological profile. The neural circuit comprising the VTA-accumbens-PFC-amygdala is activated by brief episodes of social stress, which is critical for the DA-mediated behavioral sensitization and increased stimulant consumption. A second neural circuit comprising the raphe-PFC-hippocampus is activated by continuous subordination stress and other types of uncontrollable stress. In terms of the development of therapeutics, brief maternal separation stress has proven useful in characterizing compounds acting on subtypes of GABA, glutamate, serotonin and opioid receptors with anxiolytic potential. While large increases in alcohol and cocaine intake during adulthood have been seen after prolonged maternal separation experiences during the first two weeks of rodent life, these effects may be modulated by additional yet to be identified factors. Brief episodes of defeat stress can engender behavioral sensitization that is relevant to escalated and prolonged self-administration of stimulants and possibly opioids, whereas continuous subordination stress leads to anhedonia-like effects. Understanding the intracellular cascade of events for the transition from episodic to continuous social stress in infancy and adulthood may provide insight into the modulation of basic reward processes that are critical for addictive and affective disorders.

Translational models of adaptive and excessive fighting: an emerging role for neural circuits in pathological aggression.

Aggression is a phylogenetically stable behavior, and attacks on conspecifics are observed in most animal species. In this review, we discuss translational models as they relate to pathological forms of offensive aggression and the brain mechanisms that underlie these behaviors. Quantifiable escalations in attack or the development of an atypical sequence of attacks and threats is useful for characterizing abnormal variations in aggression across species. Aggression that serves as a reinforcer can be excessive, and certain schedules of reinforcement that allow aggression rewards also allow for examining brain and behavior during the anticipation of a fight. Ethological attempts to capture and measure offensive aggression point to two prominent hypotheses for the neural basis of violence. First, pathological aggression may be due to an exaggeration of activity in subcortical circuits that mediate adaptive aggressive behaviors as they are triggered by environmental or endogenous cues at vulnerable time points. Indeed, repeated fighting experiences occur with plasticity in brain areas once considered hardwired. Alternatively, a separate "violence network" may converge on aggression circuitry that disinhibits pathological aggression (for example, via disrupted cortical inhibition). Advancing animal models that capture the motivation to commit pathological aggression remains important to fully distinguish the neural architecture of violence as it differs from adaptive competition among conspecifics.

Persistent increase of I.V. cocaine self-administration in a subgroup of C57BL/6J male mice after social defeat stress.

RATIONALE: Stressful life experiences can persistently increase the motivation for, and consumption of, intensely rewarding stimuli, like cocaine, over time. In rodents, intermittent versus continuous exposure to social stress engenders opposing changes to reward-related behavior, as measured by consumption of sucrose and cocaine. OBJECTIVE: The present study examines if the effects of intermittent versus continuous social stress on cocaine self-administration in mice parallel those seen in rats. METHODS: Both forms of social stress involve a brief daily physical confrontation with an aggressive resident for 10 consecutive days. Continuous social stress involves constant visual and olfactory exposure to an aggressive resident via habitation in a protected portion of the resident's home cage, while exposure to an aggressive resident during intermittent social stress is limited to a single, physical encounter per day. Implementing a femoral vein catheterization method for the first time in mice, we determined divergent changes to intravenous cocaine self-administration. RESULTS: Modestly increased cocaine self-administration after intermittent social stress was confirmed. In a subset of animals, continuous social stress in mice substantially increased cocaine self-administration and sucrose intake. By stark contrast, another subpopulation had substantial attenuation of cocaine self-administration and sucrose intake after continuous social stress. CONCLUSIONS: Bimodal divergence in responding for rewarding stimuli including cocaine after social stress experience likely reflects two opposing forms of coping to continuous social stress that promote either a sensitization or attenuation of reward-seeking.

Fighting Females: Neural and Behavioral Consequences of Social Defeat Stress in Female Mice.

BACKGROUND: Despite the twofold higher prevalence of major depressive and posttraumatic stress disorders in women compared with men, most clinical and preclinical studies have focused on male subjects. We used an ethological murine model to study several cardinal symptoms of affective disorders in the female targets of female aggression. METHODS: Intact Swiss Webster (CFW) female resident mice were housed with castrated male mice and tested for aggression toward female intruders. For 10 days, aggressive CFW female residents defeated C57BL/6J (B6) female intruders during 5-minute encounters. Measures of corticosterone, c-Fos activation in hypothalamic and limbic structures, and species-typical behaviors were collected from defeated and control females. Ketamine (20 mg/kg) was tested for its potential to reverse stress-induced social deficits. RESULTS: Housed with a castrated male mouse, most intact resident CFW females readily attacked unfamiliar B6 female intruders, inflicting >40 bites in a 5-minute encounter. Compared with controls, defeated B6 females exhibited elevated plasma corticosterone and increased c-Fos activation in the medial amygdala, ventral lateral septum, ventromedial hypothalamus, and hypothalamic paraventricular nucleus. Chronically defeated females also showed vigilance-like behavior and deficits in social interactions, novel object investigation, and nesting. The duration of social interactions increased 24 hours after chronically defeated female mice received a systemic dose of ketamine. CONCLUSIONS: These findings demonstrate that CFW female mice living with male conspecifics can be used as aggressive residents in an ethological model of female social defeat stress. These novel behavioral methods will encourage further studies of sex-specific neural, physiological, and behavioral adaptations to chronic stress and the biological bases for interfemale aggression.