[show abstract][hide abstract] ABSTRACT: We recently demonstrated in male wild-type Groningen rats that enhancing brain oxytocin (OXT) levels acutely produces marked pro-social explorative and anti-aggressive effects. Moreover, these pharmacologically-induced changes are moderated by the individual's aggressive phenotype, suggesting an inverse relationship between aggressiveness and tonic endogenous OXT signaling properties. Aim of the present study was to verify the hypothesis that variations in OXT expression and/or OXT receptor (OXTR) binding in selected brain regions are associated with different levels or forms of aggression. To this end, male resident wild-type Groningen rats that repeatedly contested and dominated intruder conspecifics were categorized as being low aggressive, highly aggressive or excessively aggressive. Their brains were subsequently collected and quantified for OXT mRNA expression and OXTR binding levels. Our results showed that OXT mRNA expression in the hypothalamic paraventricular nucleus (PVN), but not in the supraoptic nucleus (SON), negatively correlates with the level of offensiveness. In particular, the excessively aggressive group showed a significantly lower OXT mRNA expression in the PVN as compared to both low and highly aggressive groups. Further, the excessively aggressive animals showed the highest OXTR binding in the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST). These findings demonstrate that male rats with excessively high levels and abnormal forms of aggressive behavior have diminished OXT transcription and enhanced OXTR binding capacities in specific nodes of the social behavioral brain circuitry.
Behavioural brain research 01/2014; · 3.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: In humans, there is a documented association between anxiety disorders and cardiovascular disease. Putative underlying mechanisms may include an impairment of the autonomic nervous system control of cardiac function. The primary objective of the present study was to characterize cardiac autonomic modulation and susceptibility to arrhythmias in genetic lines of rats that differ largely in their anxiety level. To reach this goal, electrocardiographic recordings were performed in high-anxiety behavior (HAB, n = 10) and low-anxiety behavior (LAB, n = 10) rats at rest, during stressful stimuli and under autonomic pharmacological manipulations, and analyzed by means of time- and frequency-domain indexes of heart rate variability. During resting conditions, HAB rats displayed a reduced heart rate variability, mostly in terms of lower parasympathetic (vagal) modulation compared to LAB rats. In HAB rats, this relatively low cardiac vagal control was associated with smaller heart rate responsiveness to acute stressors compared to LAB counterparts. In addition, beta-adrenergic pharmacological stimulation induced a larger incidence of ventricular tachyarrhythmias in HABs compared to LABs. At sacrifice, a moderate increase in heart-body weight ratio was observed in HAB rats. We conclude that high levels of anxiety-related behavior in rats are associated with signs of i) impaired autonomic modulation of heart rate (low vagally-mediated heart rate variability), ii) poor adaptive heart rate responsiveness to stressful stimuli, iii) increased arrhythmia susceptibility, and iv) cardiac hypertrophy. These results highlight the utility of the HAB/LAB model for investigating the mechanistic basis of the comorbidity between anxiety disorders and cardiovascular disease.
[show abstract][hide abstract] ABSTRACT: The costs of violence and aggression in our society have stimulated the scientific search for the predictors and causes of aggression. The majority of studies have focused on males, which are considered to be more aggressive than females in most species. However, rates of offensive behavior in girls and young women are considerable and are currently rising in Western society. The extrapolation of scientific results from males to young, non-maternal females is a priori limited, based on the profound sex differences in brain areas and functioning of neurotransmitters involved in aggression. Therefore, we established a paradigm to assess aggressive behavior in young virgin female rats, i.e. the female intruder test (FIT). We found that approximately 40% of un-manipulated adult (10-11 weeks old) female Wistar rats attack an intruder female during the FIT, independent of their estrous phase or that of their intruder. In addition, adolescent (7-8 weeks old) female rats selected for high anxiety behavior (HABs) displayed significantly more aggression than non-selected (NAB) or low-anxiety (LAB) rats. Intracerebroventricular infusion of oxytocin (OXT, 0.1 µg/5 µl) inhibited aggressive behavior in adult NAB and LAB, but not HAB females. Adolescent NAB rats that had been aggressive towards their intruder showed increased pERK immunoreactivity (IR) in the hypothalamic attack area and reduced pERK-IR in OXT neurons in the paraventricular hypothalamic nucleus compared to non-aggressive NAB rats. Taken together, aggressive behavior in young virgin female rats is partly dependent on trait anxiety, and appears to be under considerable OXT control.
PLoS ONE 01/2014; 9(3):e91701. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Chronic psychosocial stress is a recognized risk factor for various affective and somatic disorders. In an established murine model of chronic psychosocial stress, exposure to chronic subordinate colony housing (CSC) results in an alteration of physiological, behavioral, neuroendocrine and immunological parameters, including a long-lasting increase in anxiety, adrenal hypertrophy and thymus atrophy. Based on the stress-protective and anxiolytic properties of oxytocin (OXT) after acute administration in rodents and humans, the major aims of our study were to assess whether chronic administration of OXT dose-dependently affects the behavior and physiology of male mice, as for therapeutic use in humans, mostly chronic treatment approaches will be used. Further, we studied, whether chronic administration during CSC prevents stress-induced consequences. Our results indicate that chronic intracerebroventricular (ICV) infusion of OXT (15 days) at high (10 ng/h), but not at low (1 ng/h) dose, induces an anxiogenic phenotype with a concomitant reduction of OXT receptor (OXTR) binding within the septum, the basolateral and medial amygdala, as well as the median raphe nucleus. Further, we demonstrate that chronic ICV infusion of OXT (1 ng/h) during a 19-day CSC exposure prevents the hyper-anxiety, thymus atrophy, adrenal hypertrophy, and decreased in vitro adrenal ACTH sensitivity. Thus, given both negative, but also beneficial effects seen after chronic OXT treatment, which appear to be dose-dependent, a deeper understanding of long-lasting treatment effects is required before OXT can be considered for long-term therapeutic use for the treatment of psychopathologies such as autism, schizophrenia or anxiety-disorders.
[show abstract][hide abstract] ABSTRACT: Apoptotic death of photoreceptors in hereditary retinal degenerations can be prevented by neuroprotective molecules. Here, we report that adrenal glucocorticoids (GC) released during psychosocial stress protect photoreceptors from apoptosis after light damage. Psychosocial stress is known to be the main type of stressor humans are exposed to and was induced here in mice by 10hours of chronic subordinate colony housing (CSC). Photoreceptor damage was generated by subsequent exposure to white light. Short-term psychosocial stress prior to illumination significantly reduced the number of apoptotic photoreceptors, an effect that was absent in adrenalectomized (ADX) mice. The neuroprotective effect was completely restored in ADX mice substituted with GC. Moreover, phosphorylation of retinal AKT increased following CSC or exogenous GC treatment, an effect that was again absent in ADX mice exposed to CSC. Finally, inhibition of AKT signaling with triciribine blocked the stress- and GC-mediated neuroprotective effects on photoreceptors. In summary, we provide evidence that 1) short-term psychosocial stress protects photoreceptors from light-induced damage and 2) the protective effect is most likely mediated by GC-induced activation of the AKT signaling pathway.
[show abstract][hide abstract] ABSTRACT: Chronic psychosocial stress is a risk factor for the development of affective as well as somatic disorders. However, the vulnerability to adverse stress effects varies between individuals, with previous negative life events along with the genetic predisposition playing a major role. In support, we previously showed that the consequences of chronic psychosocial stress induced by chronic subordinate colony housing (CSC, 19 days) can be amplified by pre-exposing mice to repeated maternal separation during early life. To test the significance of the genetic predisposition on the effects of CSC, mice selectively bred for high (mHAB) and low (mLAB) anxiety-related behaviour and non-selected CD1 mice (mNAB) were exposed to CSC in the present study. In confirmation of our previous results, CSC mice of both mHAB and mNAB lines displayed chronic stress-related symptoms including increased adrenal weight, decreased adrenal in vitro ACTH sensitivity, lower plasma CORT:ACTH ratio, and increased IFN-γ secretion from isolated mesenteric lymph node cells compared with single-housed controls of the respective line. However, the CSC-induced anxiogenic effect found in mNAB was not confirmed in mHAB mice, possibly due to a ceiling effect in these highly anxious mice. Interestingly, mHAB were not more vulnerable to CSC than mNAB mice, while mLAB mice were resilient to CSC as indicated by all parameters assessed.Taken together, our findings indicate that the genetic predisposition, in this case the innate anxiety of an individual, affects its vulnerability to chronic psychosocial stress, with a low-anxiety phenotype mediating resilience to both affective and somatic consequences of CSC.
[show abstract][hide abstract] ABSTRACT: Social fear and avoidance of social situations represent the main behavioral symptoms of social anxiety disorder (SAD), a highly prevalent anxiety disorder that is poorly elucidated and has rather unsatisfactory therapeutic options. Therefore, animal models are needed to study the underlying etiology and pathophysiology of SAD and to verify the efficacy of possible novel treatment approaches. In this review, we describe and discuss the most important paradigms that have been shown to induce social avoidance and fear in rodents, including foot shock exposure, restraint stress, social isolation, social instability, social defeat, conditioned defeat, social defeat/overcrowding, chronic subordinate colony housing, chronic mild stress, maternal separation and social fear conditioning. We also describe some of the behavioral paradigms used to assess social avoidance and fear in rodents, including the social interaction test, the social preference-avoidance test, the social approach-avoidance test, the three-chambered social approach test, the partition test and the modified Y-maze test. We focus on the behavioral alterations these paradigms induce, especially on social interaction, general anxiety and depressive-like behavior given that SAD is strongly comorbid with anxiety and affective disorders.
Cell and Tissue Research 06/2013; · 3.68 Impact Factor
[show abstract][hide abstract] ABSTRACT: The brain corticotropin-releasing factor (CRF) system triggers a variety of neuroendocrine and behavioural responses to stress. Whether maternal behaviour and emotionality in lactation are modulated by CRF has rarely been investigated. In the present study, we measured CRF mRNA expression within the parvocellular part of the paraventricular nucleus in virgin and lactating Wistar rats bred for high (HAB) and low (LAB) anxiety-related behaviour or non-selected for anxiety (NAB). Further, we intracerebroventricularly infused synthetic CRF or the CRF receptor (CRF-R) antagonist D-Phe to manipulate CRF-R1/2 non-specifically in lactating HAB, LAB, and NAB dams, and monitored maternal care, maternal motivation, maternal aggression, and anxiety. The CRF mRNA expression in the parvocellular part of the paraventricular nucleus was higher in HAB vs. LAB rats independent of reproductive status. The lactation-specific decrease of CRF mRNA was confirmed in LAB and NAB dams but was absent in HAB dams. Intracerebroventricular CRF decreased maternal care under basal conditions in the home cage in all breeding lines and reduced attack behaviour in HAB and LAB dams during maternal defence. In contrast, D-Phe rescued maternal care after exposure to maternal defence in the home cage without influencing maternal aggression. Furthermore, D-Phe decreased and CRF tended to increase anxiety in HAB/NAB and LAB dams, respectively, suggesting an anxiogenic effect of CRF in lactating females. In conclusion, low CRF-R activation during lactation is an essential prerequisite for the adequate occurrence of maternal behaviour.
European Journal of Neuroscience 06/2013; · 3.75 Impact Factor
[show abstract][hide abstract] ABSTRACT: The possibility to improve socio-emotional behaviors in humans by intranasal administration of synthetic oxytocin (OXT) attracts increasing attention, but its uptake into the brain has never been demonstrated so far. Here we used simultaneous microdialysis in both the dorsal hippocampus and amygdala of rats and mice in combination with concomitant blood sampling from the jugular vein to study the dynamics of the neuropeptide in brain extracellular fluid and plasma after its nasal administration. OXT was found to be increased in microdialysates from both the hippocampus and amygdala with peak levels occurring 30-60min after nasal administration. Despite a similar temporal profile of OXT concentrations in plasma, peripheral OXT is unlikely to contribute to dialysate OXT as calculated from in vitro recovery data, indicating a central route of transport. Moreover, intraperitoneal administration of synthetic OXT in identical amounts caused rapid peak levels in brain dialysates and plasma during the first 30min after treatment and a subsequent return toward baseline. While the precise route(s) of central transport remain to be elucidated, our data provide the first evidence that nasally applied OXT indeed reaches behaviorally relevant brain areas, and this uptake is paralleled by changes in plasma OXT.
[show abstract][hide abstract] ABSTRACT: In humans, there is unequivocal evidence of an association between anxiety states and altered respiratory function. Despite this, the link between anxiety and respiration has been poorly evaluated in experimental animals. The primary objective of the present study was to investigate the hypothesis that genetic lines of rats that differ largely in their anxiety level would display matching alterations in respiration. To reach this goal, respiration was recorded in high-anxiety behavior (HAB, n = 10) and low-anxiety behavior (LAB, n = 10) male rats using whole-body plethysmography. In resting state, respiratory rate was higher in HABs (85±2 cycles per minute, cpm) than LABs (67±2 cpm, p<0.05). During initial testing into the plethysmograph and during a restraint test, HAB rats spent less time at high-frequency sniffing compared to LAB rats. In addition, HAB rats did not habituate in terms of respiratory response to repetitive acoustic stressful stimuli. Finally, HAB rats exhibited a larger incidence of sighs during free exploration of the plethysmograph and under stress conditions. We conclude that: i) HAB rats showed respiratory changes (elevated resting respiratory rate, reduced sniffing in novel environment, increased incidence of sighs, and no habituation of the respiratory response to repetitive stimuli) that resemble those observed in anxious and panic patients, and ii) respiratory patterns may represent a promising way for assessing anxiety states in preclinical studies.
PLoS ONE 01/2013; 8(5):e64519. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation which may progress towards inflammation (nonalcoholic steatohepatitis (NASH)). NAFLD is regarded as a consequence of a sedentary, food-abundant lifestyle which, in the modern world, often coincides with chronically high levels of perceived psychosocial stress. Here, we aimed to characterize the effect of chronic psychosocial stress on the development of NAFLD/NASH in male mice either fed with standard chow or NASH-inducing high fat diet. Chronic psychosocial stress was induced by chronic subordinate colony housing (CSC), a pre-clinically validated paradigm relevant for human affective and somatic disorders. Single housed (SHC) mice served as controls. Under standard chow conditions CSC mice revealed lower hepatic triglyceride levels but higher hepatic TNFα, MCP-1 and HMOX mRNA expression, while serum transaminase levels did not significantly differ from SHC mice. Under the NASH-inducing high-fat diet CSC and SHC mice showed similar body weight-gain and serum levels of glucose and adiponectin. Moreover, liver histology as well as TNFα, MCP-1 and HMOX expression were similar in CSC and SHC mice fed with HFD. Surprisingly, CSC showed even significantly lower transaminase levels than SHC mice fed with the same NASH-inducing diet. Together, these data indicate that under normal dietary conditions the CSC model induces noticeable hepatic oxidative stress and inflammation without causing manifest hepatocellular injury. In contrast, CSC exhibited a protective effect on hepatocellular injury in a dietary NASH-model. Identification of the underlying mechanisms of this phenomenon may lead to novel therapeutic strategies to prevent progression of NAFLD.
International journal of clinical and experimental pathology 01/2013; 6(8):1585-93. · 2.24 Impact Factor
[show abstract][hide abstract] ABSTRACT: The neuropeptide oxytocin is involved in social cognition and interaction across species and plays a crucial role in the regulation of affiliative behaviors. Oxytocin levels in cerebrospinal fluid (CSF), but also in plasma or urine, have been shown to be negatively associated with childhood traumata, aggressive behavior, and suicide attempts. Recently, an altered activity of the oxytocin system has been discussed to play a prominent role in borderline personality disorder (BPD), which is thought to be closely related to traumatic experiences in childhood and is characterized by (para)suicidal behaviors as well as aggressive outbursts. In the present study, we compared plasma oxytocin levels of women with and without BPD in the follicular phase and assessed the relationship between oxytocin concentrations and childhood traumata. Women diagnosed with BPD had significantly reduced oxytocin concentrations, even after controlling for estrogen, progesterone, and contraceptive intake. In addition, plasma oxytocin correlated negatively with experiences of childhood traumata, in particular with emotional neglect and abuse. The results of mediation analyses do not support a model of oxytocin being a prominent mediator in the link between childhood trauma and BPD. Thus, the findings indicate dysregulations in the oxytocin system of patients diagnosed with BPD with more longitudinal research being necessary to disentangle the relationship between childhood adversities, oxytocin system, and psychopathology.
Hormones and Behavior 11/2012; · 3.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: Chronic stress is known to enhance the susceptibility for addiction disorders including alcoholism. While these findings have been recapitulated in animal models, the majority of these studies have utilized non-social rather than social stress paradigms; the latter of which are believed to be more relevant to the human situation. Therefore, the major aim of this study was to investigate, if 14 days of chronic subordinate colony housing (CSC), a pre-clinically validated psychosocial stress paradigm relevant for human psychiatric and somatic disorders, enhances ethanol (EtOH) consumption in male mice. To assess this, we employed the well-established two-bottle free-choice paradigm where mice were given access to water and 2, 4, 6 and 8% EtOH solutions (with the concentrations increasing each fourth day) following termination of the stress procedure. After 14 days of CSC, stressed mice consumed significantly more EtOH at all concentrations tested and displayed increased EtOH preference at concentrations of 6 and 8%. This effect was not due to an altered taste preference in CSC mice as assessed by saccharine- and quinine-preference tests, but was accompanied by increased anxiety-related behavior. Systemic administration of baclofen (2.5 mg/kg) or oxytocin (OXT; 10 mg/kg) reduced the EtOH intake in single housed control (baclofen, OXT) and CSC (baclofen) mice, whereas intracerebroventricular OXT (0.5 μg/2 μl) was ineffective in both groups. Taken together, these results suggest that (i) chronic psychosocial stress enhances EtOH consumption, and (ii) baclofen and OXT differentially affect EtOH intake in mice.
[show abstract][hide abstract] ABSTRACT: Brain oxytocin (OXT) plays an important role in short-term social memory in laboratory rodents. Here we monitored local release of OXT and its functional involvement in the maintenance and retrieval of social memory during the social discrimination test. We further assessed, if the local effects of OXT within the medial amygdala (MeA) and lateral septum (LS) on social discrimination abilities were dependent on the biological relevance of the social stimulus, thus comparing male juvenile versus adult female conspecifics. OXT release was increased in the LS of male rats during the retrieval, but not during the acquisition or maintenance, of social memory for male juvenile stimuli. Blockade of OXT activity by intracerebroventricular (ICV) administration of a specific OXT receptor antagonist (OXTR-A, rats: 0.75μg/5μl, mice: 2μg/2μl) immediately after acquisition of social memory impaired the maintenance of social memory, and consequently discrimination abilities during retrieval of social memory. In contrast, ICV OXTR-A was without effect when administered 20min prior to retrieval of social memory in both species. Non-social memory measured in the object discrimination test was not affected by ICV OXTR-A in male mice, indicating that brain OXT is mainly required for memory formation in a social context. The biological relevance of the social stimulus seems to importantly determine social memory abilities, as male rats recognized a previously encountered female adult stimulus for at least 2h (versus 60min for male juveniles), with a region-dependent contribution of endogenous OXT; while bilateral administration of OXTR-A into the MeA (0.1μg/1μl) impaired social memory for adult females only, administration of OXTR-A into the LS via retrodialysis (10μg/ml, 1.0μl/min) impaired social memory for both male juveniles and female adults. Overall, these results indicate that brain OXT is a critical mediator of social memory in male rodents and that, depending on the biological relevance of the social stimulus, distinct brain regions are recruited to mediate its effects.
[show abstract][hide abstract] ABSTRACT: Oxytocin and vasopressin are regulators of anxiety, stress-coping, and sociality. They are released within hypothalamic and limbic areas from dendrites, axons, and perikarya independently of, or coordinated with, secretion from neurohypophysial terminals. Central oxytocin exerts anxiolytic and antidepressive effects, whereas vasopressin tends to show anxiogenic and depressive actions. Evidence from pharmacological and genetic association studies confirms their involvement in individual variation of emotional traits extending to psychopathology. Based on their opposing effects on emotional behaviors, we propose that a balanced activity of both brain neuropeptide systems is important for appropriate emotional behaviors. Shifting the balance between the neuropeptide systems towards oxytocin, by positive social stimuli and/or psychopharmacotherapy, may help to improve emotional behaviors and reinstate mental health.
Trends in Neurosciences 09/2012; 35(11):649-59. · 13.58 Impact Factor
[show abstract][hide abstract] ABSTRACT: Autism spectrum disorders (ASD) and social anxiety disorder involve various forms of social deficits like impaired affiliative behavior, social cognition and social approach. Although the neurobiological underpinnings of these disorders are largely unknown, rodent and human studies suggest an involvement of the evolutionary highly conserved oxytocin (OXT) and vasopressin (AVP), as these neuropeptides modulate various aspects of mammalian social behaviors. In this review we summarize the current knowledge regarding the involvement of brain OXT and AVP in rodent social behaviors related to social dysfunctions in ASD. Starting with an introduction into the neurobiology of the central OXT and AVP systems (neuroanatomy, central release, receptor distribution) we describe the distinct roles OXT and AVP play in basic social behaviors in rodents, i.e. affiliative behavior (pair-bonding and maternal behavior), social cognition (social memory), and social approach (social preference or social avoidance). The regulatory capacity of OXT and AVP to modulate social behaviors in various rodent species implies a high translational potential, in particular that dys-regulations in the brain neuropeptide systems may underlie social dysfunctions in ASD. It also suggests that the brain OXT and AVP systems are promising pharmacotherapeutic targets to improve social behaviors and to reverse social deficits.
Behavioural brain research 08/2012; · 3.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: A better neurobiological understanding of high and abnormal aggression based on adequate animal models is essential for novel therapy and prevention. Selective breeding of rats for extremes in anxiety-related behavior resulted in two behavioral phenotypes with high and abnormal forms of aggression. Rats bred for low anxiety-related behavior (LAB) consistently show highest levels of aggression and little social investigation in the resident-intruder (RI) test, compared with non-selected low-aggressive (NAB) rats. High anxiety-related (HAB) rats also show higher levels of aggression than NAB rats, but to a lesser extent than LAB rats. Accordingly, extremes in inborn anxiety in both directions are linked to an increased aggression level. Further, both LAB and HAB, but not NAB males, display abnormal aggression (attacks towards vulnerable body parts, females or narcotized males), which is particularly prominent in LABs. Also, only in LAB rats, the nucleus accumbens (NAc) was found to be strongly activated in response to the RI test as reflected by increased c-fos and zif268 mRNA expression, and higher local dopamine release compared with NAB males, without differences in local dopamine receptor binding. Consequently, local pharmacological manipulation by infusion of an anesthetic (lidocaine, 20μg/μl) or a dopamine D2 (haloperidol, 10ng/μl), but not D1 (SCH-23390 10ng/μl), receptor antagonist significantly reduced high aggression in LAB rats. Thus, LAB rats are an adequate model to study high and abnormal aggression. In LAB males, this is likely to be linked to hyper-activation of the reward system, as found in psychopathic patients. Specifically, activation of the accumbal dopamine system is likely to underlie the high aggression observed in LAB rats.