The Drd2 gene, encoding the dopamine D2 receptor (D2R), was recently indicated as a potential target in the etiology of lowered sociability (i.e., social withdrawal), a symptom of several neuropsychiatric disorders such as Schizophrenia and Major Depression. Many animal species show social withdrawal in response to stimuli, including the vinegar fly Drosophila melanogaster and mice, which also share most human disease-related genes. Here we will test for causality between Drd2 and sociability and for its evolutionary conserved function in these two distant species, as well as assess its mechanism as a potential therapeutic target. During behavioral observations in groups of freely interacting D. melanogaster, Drd2 homologue mutant showed decreased social interactions and locomotor activity. After confirming Drd2’s social effects in flies, conditional transgenic mice lacking Drd2 in dopaminergic cells (autoreceptor KO) or in serotonergic cells (heteroreceptor KO) were studied in semi-natural environments, where they could freely interact. Autoreceptor KOs showed increased sociability, but reduced activity, while no overall effect of Drd2 deletion was observed in heteroreceptor KOs. To determine acute effects of D2R signaling on sociability, we also showed that a direct intervention with the D2R agonist Sumanirole decreased sociability in wild type mice, while the antagonist showed no effects. Using a computational ethological approach, this study demonstrates that Drd2 regulates sociability across evolutionary distant species, and that activation of the mammalian D2R autoreceptor, in particular, is necessary for social functioning.

In this study, apical dendritic spine density of neurons in hippocampal, amygdalar and prefrontal cortical areas was compared in rats that were repeatedly winning or losing social conflicts. Territorial male wild-type Groningen (WTG) rats were allowed multiple daily attacks (>20 times) on intruder males in the resident-intruder paradigm. Frequent winning experiences are known to facilitate uncontrolled aggressive behavior reflected in aggressive attacks on anesthetized males which was also observed in the winners in this study. Both winners and losers were socially housed during the experiments; winners with females to stimulate territorial behavior, and losers with two other losing male rats. Twenty-four hours after the last social encounter, brains from experienced residential winners and repeatedly defeated intruder rats were collected and neuronal morphology in selected brain regions was studied via Golgi-Cox staining. Results indicate that spine density in the apical dendrites of the hippocampal CA1 reduced similarly in both winners and losers. In addition, winners showed increased spine densities at the proximal segments (20-30 ?m) of the basolateral amygdala neurons and losers tended to show a decreased spine density at the more proximal segments of the infralimbic region of prefrontal cortex neurons. No effect of winning and losing was observed in the medial amygdala. The atrophic effect of repeated defeats in hippocampal and prefrontal regions was anticipated despite the fact that social housing of the repeatedly losing intruder males may have played a protective role. The reduction of hippocampal spine density in the winners seems surprising but supports previous findings in hierarchical dominant males in rat colonies. The dominants showed even greater shrinkage of the apical dendritic arbors of hippocampal CA3 pyramidal neurons compared to the stressed subordinates.

ABSTRACT Suppression of hippocampal neurogenesis is a readout for stress-induced alterations in neuroplasticity. In this study, we hypothesized that a single episode of severe social or non-social stress would differentially suppress neurogenesis in the dentate gyrus (DG) 10 days later in two rat strains. We anticipated that the suppression following social stress would be less severe in wildtype Groningen (WTG) rats, a rat strain considered relatively resilient to social stressors. Male Wistar and WTG were subjected to either social defeat or to immobilization stress. Behavioral response to social defeat and acute corticosterone response to both stressors was measured as well as anxiety behavior 10 days later on the elevated plus maze. Subsequently, brains were collected following cardiac aldehyde perfusion. The behavioral freezing response to defeat was much stronger in Wistar rats as compared to WTG rats. Acute corticosteroid response was similar in both strains although Wistar rats more rapidly resumed baseline values. There was no significant effect of both stressors on hippocampal DG cell proliferation and differentiation as well as on anxiety behavior. However, a striking strain difference appeared in anxiety behavior and both markers of neurogenesis. The WTG strain exhibiting much lower anxiety as well as reduced rate of hippocampal neurogenesis under all treatments. The results in this study suggest that both short-lasting acute stressors failed to induce lasting anxiety or decreased neurogenesis in the DG. Future studies could explore if and how rate of hippocampal neurogenesis is related with behavioral coping with stress.

There are large individual differences in the way animals, including humans, behaviorally and physiologically cope with environmental challenges and opportunities. Rodents with either a proactive or reactive coping style not only differ in their capacity to adapt successfully to environmental conditions, but also have a differential susceptibility to develop stress-related (psycho)pathologies when coping fails. In this study, we explored if there are structural neuronal differences in spine density in brain regions important for the regulation of stress coping styles. For this, the individual coping styles of wild-type Groningen (WTG) rats were determined using their level of offensive aggressiveness assessed in the resident-intruder paradigm. Subsequently, brains from proactive (high-aggressive) and reactive (low-aggressive) rats were Golgi-cox stained for spine quantification. The results reveal that dendritic spine densities in the dorsal hippocampal CA1 region and basolateral amygdala are similar in rats with proactive and reactive coping styles. Interestingly, however, dendritic spine density in the medial amygdala (MeA) is strikingly reduced in the proactive coping rats. This brain region is reported to be strongly involved in rivalry aggression which is the criterion by which the coping styles in our study are dissociated. The possibility that structural differences in spine density in the MeA are involved in other behavioral traits of distinct coping styles needs further investigation.

Social withdrawal is found across neuropsychiatric disorders and in numerous animal species under various conditions. It has substantial impact on the quality of life in patients suffering from neuropsychiatric disorders. Often it occurs prodromal to the disease, suggesting that it is either an early biomarker or central to its etiology. Healthy social functioning is supported by the social brain of which the building blocks go back millions of years, showing overlap between humans, rodents and insects. Thus, to elucidate social withdrawal, we have to approach its environmental triggers and its neural and molecular genetic determinants in an evolutionary context. Pathological social withdrawal may originate from a faulty regulation of specific neural circuits. As there is considerable heritability in social disorders, the genetic building blocks of the social decision making network might be our most relevant target to obtain an understanding of the transition of normal social interaction into social withdrawal.

It is likely that the chronic stress of social defeat or exclusion contributes to the increased psychosis risk among members of ethnic minorities. Is this idea compatible with the dopamine or neurodevelopmental hypothesis, two dominant hypotheses with regard to pathogenesis? Defeated animals show clear evidence of dopamine sensitization. As for humans, one study showed elevated striatal dopamine function in migrants and their children. Other studies have shown this in other excluded groups, namely, adults with hearing impairment and individuals with a history of childhood trauma. Of note, the perigenual anterior cingulate cortex may play a major role in the processing of social stress and regulates dopaminergic areas implicated in stress sensitization. The authors are not aware of studies in humans that examined whether (proxies for) social exclusion contribute(s) to structural brain changes present at psychosis onset. Animal studies, however, reported that long-term isolation may lead to reductions in brain volume and that social defeat can reduce neurogenesis.

Social withdrawal is associated with a variety of neuropsychiatric disorders, including neurodevelopmental disorders. Rodent studies provide the opportunity to study neurobiological mechanisms underlying social withdrawal, however, homologous paradigms to increase translatability of social behaviour between human and animal observation are needed. Standard behavioural rodent assays have limited ethological validity in terms of number of interaction partners, type of behaviour, duration of observation and environmental conditions. In addition, reproducibility of behavioural findings in rodents is further limited by manual and subjective behavioural scoring. Using a newly developed automated tracking tool for longitudinal monitoring of freely moving mice, we assessed social behaviours (approach, sniff, follow and leave) over seven consecutive days in colonies of BTBR and of C57BL/6J mice in two independent laboratories. Results from both laboratories confirmed previous findings of reduced social interaction in BTBR mice revealing a high level of reproducibility for this mouse phenotype using longitudinal colony assessments. In addition, we showed that detector settings contribute to laboratory specific findings as part of the behavioural data analysis procedure. Our cross-site study demonstrates reproducibility and robustness of reduced social interaction in BTBR mice using automated analysis in an ethologically relevant context.

The increased incidence of depression in women going through peri-menopause suggests that fluctuations in estrogen levels may increase the risk of developing depression. Nonetheless, this psychiatric disorder is likely to be multifactorial and consequently an additional trigger may be needed to induce depression in this population. Stress could be such a trigger. We therefore investigated the effect of ovarian estrogen depletion and chronic mild stress (CMS) on depressive-like behavior and brain metabolism in female rats. Approximately 2 and 9 weeks after estrogen depletion by ovariectomy, behavioral changes were assessed in the open-field test and the forced swim test, and brain metabolism was measured with [18F]FDG PET imaging. A subset of animals was subjected to a 6-weeks CMS protocol starting 17 days after ovariectomy. Short-term estrogen depletion had a significant effect on brain metabolism in subcortical areas, but not on behavior. Differences in depressive-like behavior were only found after prolonged estrogen depletion, leading to an increased immobility time in the forced swim test. Prolonged estrogen depletion also resulted in an increase in glucose metabolism in frontal cortical areas and hippocampus, whereas a decrease glucose metabolism was found in temporal cortical areas, hypothalamus and brainstem. Neither short-term nor prolonged estrogen depletion caused anxiety-like behavior. Changes in body weight, behavior and brain glucose metabolism were not significantly affected by CMS. In conclusion, ovarian estrogen depletion resulted in changes in brain metabolism and depressive-like behavior, but these changes were not enhanced by CMS.

Exposure to severe or persistent social stress may lead to the development of psychiatric disorders such as anxiety and depression. These mood disorders are associated with structural alterations of neural architecture in limbic brain regions that control emotion, mood and cognition. Structural remodeling may either be a sign of successful adaptation, or of failure to do so. In neuropsychiatric disorders like depression structural remodeling involves apoptosis, reduced neurogenesis, and structural remodeling of neuronal dendrites which most likely reflects the latter. Here we review key findings from animal models of psychosocial stress that have been used to gain insights into the relation between stress-related behavioral disorders like depression and structural plasticity. Specifically, we focus on models having a high face validity like social defeat stress in the resident-intruder paradigm and chronic stress of social subordination in social housing conditions. Moderate to severe social stress appears to stimulate plasticity and neuronal growth in regions of the amygdala, whereas the effects in the hippocampus and prefrontal cortex tend to be opposite. A major focus of the current review is to characterize social stress induced structural changes in these brain regions, aiming to provide insight in pathways and factors that underlie behavioral effects of stress and depression.

One of the missions of the Spanish Society of Rheumatology is to provide the necessary tools for excellence in health care. Currently, there is no reference point to quantify medical actions in this specialty, and this is imperative.A list of actions was drawn up and a hierarchical classification system was established by developing a complexity index, calculated based on the completion time and difficulty level of each action.The results of the Delphi method tended to the consensus opinion within a group (mean σ2 − σ1 = 0.75–1.43 = −0.68, mean IQR2–IQR1 = 0.8–1.9 = −1.1). The values of the complexity index ranged between 48 and 465 points. Among consultation actions, those reaching the highest scores were the first inpatient visit (366) and visits to the patient's home (369). Among diagnostic techniques, biopsies were prominent, those with the highest score were: bone biopsy (465), sural nerve biopsy (416) and synovial biopsy (380). Ultrasound scan scored 204, capillaroscopy 113 and densitometry 112. Among therapeutic techniques, infiltration/arthrocentesis/articular injection in children reached the highest difficulty (388). The score for ultrasound-guided articular injection was 163. The score for clinical report on disability was 323 and expert report 370.A nomenclature of 54 actions in Rheumatology was compiled. Biopsies (bone, sural nerve, synovial), inpatient visits, visits to the patient's home, infiltrations in children, and the preparation of the expert report were identified as the most complex actions. Musculoskeletal ultrasound is twice as complex as subsequent visits, capillaroscopy or bone densitometry.Una misión de la Sociedad Española de Reumatología es aportar las herramientas necesarias para alcanzar la excelencia asistencial. En la actualidad no existe una referencia que cuantifique la complejidad de los actos médicos de esta especialidad.Se elaboró una relación de los actos propios del reumatólogo y se estableció un sistema de clasificación jerárquica a partir de la construcción de un índice de complejidad, calculado mediante el tiempo de realización y el grado de dificultad de cada acto.Los resultados del método Delphi tendieron a una opinión grupal consensuada (media σ2 - σ1 = 0,75-1,43 = -0,68, media IQR2 - IQR1 = 0,8-1,9 = -1,1). El rango de valores del índice de complejidad osciló de 48 a 465 puntos. Entre las consultas, las que alcanzaron mayor gradación fueron la primera visita al paciente hospitalizado (366) y la visita a domicilio (369). Entre las técnicas diagnósticas, destacaron las biopsias. Las que puntuaron más alto fueron: biopsia ósea (465), de nervio sural (416) y sinovial (380). La ecografía tuvo una puntuación de 204, la capilaroscopia de 113 y la densitometría de 112. Entre las técnicas terapéuticas, la máxima dificultad (388), la alcanzó la infiltración/artrocentesis/inyección articular infantil. La puntuación de la inyección articular con control ecográfico fue de 163. El informe clínico de minusvalía, 323 y el informe pericial, 370.Este trabajo ha permitido elaborar un nomenclátor de 54 actos en reumatología donde se identifican como actos más complejos la realización de biopsias (ósea, nervio sural, sinovial), la visita a paciente hospitalizado, la visita a domicilio, la infiltración infantil bajo sedación y la elaboración de un informe pericial. La ecografía osteomuscular es considerada el doble de compleja de una visita sucesiva, la capilaroscopia o la densitometría ósea.

Disrupted sociability and consequent social withdrawal are (early) symptoms of a wide variety of neuropsychiatric diseases, such as schizophrenia, autism spectrum disorders, depressive disorders and Alzheimer's disease. The paucity of objective measures to translationally assess social withdrawal characteristics has been an important limitation to study this behavioral phenotype, both in human and rodents. The aim of the present study was to investigate sociability and social withdrawal in rodents using an ethologically valid behavioral paradigm, the Visible Burrow System (VBS). The VBS mimics a natural environment, with male and female rodents housed together in an enclosure where a large open arena is connected to a continuously dark burrow system that includes 4 nest boxes. In this study, mixed-sex colonies of C57BL/6J and of BTBR mice have been investigated (n = 8 mice per colony). Results showed marked differences between the two strains, in terms of sociability as well as social withdrawal behaviors. In particular, BTBR mice performed less social behaviors and have a preference for non-social behaviors compared to C57BL/6J mice. Neurobiologically, the decreased sociability of BTBR was accompanied by reduced GABA and increased glutamate concentrations in brain prefrontal cortex (PFC) and amygdala regions. In conclusion, our study validated the use of the VBS as an ethologically relevant behavioral paradigm in group-housed mice to investigate individual sociability and social withdrawal features and their underlying neurobiology. This paradigm may provide new insights to develop new therapeutic treatments for behavioral dysfunctions that may be relevant across neuropsychiatric diseases.

Previous studies have demonstrated that repeated immobilization and restraint stress cause contrasting patterns of dendritic reorganization as well as alterations in spine density in amygdalar and hippocampal neurons. Whether social and ethologically relevant stressors can induce similar patterns of morphological plasticity remains largely unexplored. Hence, we assessed the effects of repeated social defeat stress on neuronal morphology in basolateral amygdala (BLA), hippocampal CA1 and infralimbic medial prefrontal cortex (mPFC). Male Wistar rats experienced social defeat stress on 5 consecutive days during confrontation in the resident-intruder paradigm with larger and aggressive Wild-type Groningen rats. This resulted in clear social avoidance behavior one day after the last confrontation. To assess the morphological consequences of repeated social defeat, 2 weeks after the last defeat, animals were sacrificed and brains were stained using a Golgi-Cox procedure. Morphometric analyses revealed that, compared to controls, defeated Wistar rats showed apical dendritic decrease in spine density on CA1 but not BLA. Sholl analysis demonstrated a significant dendritic atrophy of CA1 basal dendrites in defeated animals. In contrast, basal dendrites of BLA pyramidal neurons exhibited enhanced dendritic arborization in defeated animals. Social stress failed to induce lasting structural changes in mPFC neurons. Our findings demonstrate for the first time that social defeat stress elicits divergent patterns of structural plasticity in the hippocampus versus amygdala, similar to what has previously been reported with repeated physical stressors. Therefore, brain region specific variations may be a universal feature of stress-induced plasticity that is shared by both physical and social stressors.

Introduction In the present study we report the effect of corticosterone in the regulation Glucocorticosteroid hormones, corticosterone (in rat) or cortisol (in of hippocampal muscarinic acetylcholine receptor immunoreactivity (mAChRhuman), are known to influence brain processes such as mood, behaviour and ir) expression in rats. Adrenalectomy (ADX) or a single injection of a memory (McEwen et al. 1986; de Kloet 1991; Bohus 1994; Korte et al. 1996). mineralocorticoid antagonist RU-28318 (1.0 mg/100 g b.w.) in adrenally intact These actions of circulating corticosteroid hormones are mediated via rats 24 hrs prior to sacrifice revealed an increased mAChR-ir in hippocampal intracellular corticosteroid receptors. At present, two different corticosterone CA1 and CA3 areas. Corticosterone replacement (100μg/ 100g b.w.) prevented receptor types are known in the brain: the mineralocorticoid receptor (MR) and the increase in mAChR-ir of ADX animals. However, glucocorticoid receptor the glucocorticoid receptor (GR) (de Kloet 1991). The high density of MRs antagonist (RU38486) treatment in adrenally intact rats failed to affect the and GRs in hippocampal neurons suggest that corticosteroids are important mAChR immunolabelling. These results point to a modulation of muscarinic regulators of the function of this structure (McEwen et al. 1986; de Kloet 1991; receptors by corticosterone that is predominantly mediated by the mineralovan Steensel et al. 1996). Several biochemical (Gilad 1987; Takayama et al. corticoid receptor. 1987; Biegon et al. 1985) and electrophysiological studies (Hesen and Joëls 1993, 1996) have proposed a role for corticosterone in cholinergic neurotransmission in the hippocampus. The hippocampal formation and in particular the cholinergic septohippocampal system have been implicated in the neural substrate for spatial learning, predominantly through the action of acetylcholine on muscarinic acetylcholine receptors (mAChR) (Hagan et al. 1987; van der Zee et al. 1995). It has been also shown that altering levels of plasma corticosterone affect memory functions. For example, depletion of circulating corticosteroids by removal of the adrenal glands (ADX) impairs place navigation in the water maze (Oitzl and de Kloet 1992). Selective blockade of central MRs and GRs by specific antagonists disturbs different aspects of spatial learning in a conventional water maze (Oitzl and de Kloet 1992). Recently, we found that repeated blockade of MRs impaired reference memory in the hole board test, which is a free-choice food rewarded spatial learning paradigm (Douma et al. 1998b). Accordingly, both types of corticosterone receptors seem to be involved in the hormonal modulation of the process of spatial learning. Previous results from our laboratory revealed that successful training performance in the hole board spatial discrimination task causes an increase and subcellular redistribution of mAChR immunoreactivity (mAChR-ir) in hippocampal pyramidal cells (van der Zee et al. 1995; Douma et al. 1997; Beldhuis et al. 1992). In view of the putative effects of corticosteroids on cholinergic neurotransmission and spatial memory processes, we examined cholinoceptive muscarinic receptors of the hippocampal pyramidal cholinergic target cells by means of mAChR immunocytochemistry in relation to experimental manipulations of corticosteroids and their receptors. The impact 104 Chapter 5 Corticosterone and muscarinic receptor immunoreactivity 105 of adrenalectomy and differential MR and GR blockade in adrenally intact and perfused with 300 ml of a fixative consisting of 3% paraformaldehyde, animals on mAChR-ir was studied in the CA1, CA3 and the dentate gyrus 0.05% glutaraldehyde and 0.2% picric acid in 0.1 M phosphate buffer (PB) at region of the hippocampus. pH 7.4. Fixation was preceded by a prerinse with 50 ml saline solution. The Materials and Methods The experiments were approved by the Committee on Animal Bio-Ethics of the University of Groningen. 42 Male Wistar rats, weighing 290-340 g at the beginning of the experiments, were used. The rats were housed in groups of 6 animals per cage and kept on a 12 h lights on-lights off cycle, lights on from 7.00-19.00 h. Food and water were available ad libitum. The experiments were carried out between 9.00h and 12.00h. ADX and antagonist treatment Six animals were sham-adrenalectomized (Sham) and twelve animals were bilaterally adrenalectomized (ADX) under ether anesthesia. Six animals of the latter group received a single subcutaneous injection (S.C.) of corticosterone in a dose of 100 μg/ 100g body weight (cortADX) producing physiological serum levels of corticosterone (de Kloet et al. 1994), whereas the other animals were injected (S.C.) with the vehicle control solution immediately after the surgical procedure. For antagonist treatment 24 intact rats were divided into four groups of six each: Control (vehicle treated), aMR (anti-mineralocorticoid treated), aGR (anti-glucocorticoid treated), and aMR/aGR (treated with both antagonists). The MR antagonist ( RU28318; 3,3-oxo-7-propyl-17hydroxy-androstan-4-en17yl-propionic acid-lactone) (Perroteau et al. 1984) and the GR antagonist (RU38486; 17 -hydroxy-11 -(4-dimethyl amino-phenyl)17 -(1-propynyl) estra-4,9-diene-3-one) (Gaillard et al. 1984; Moguilewski et al. 1984) were kindly provided by Roussel-UCLAF, Romainville, France. Both steroids were first dissolved in ethanol and subsequently diluted in polyethylene glycol 400 (PEG; BDH chemicals Ltd., Poole England) until a final ethanol concentration of 2%. The vehicle control contained the same PEG/ethanol concentration. RU28318 was injected (S.C.) with a dose of 1.0 mg/100 g body weight, whereas RU38486 was given in a dose of 2.5 mg/100 g body weight. Injections (0.2 ml) were given at 10.30h . The effects of various treatments on mAChR’s were studied 24 hours later. Prior to transcardial perfusion the rats were deeply anaesthetized with ether brains were removed, stored overnight in 30 % buffered sucrose at 4°C for cryoprotection, and coronally sectioned on a cryostat microtome at a thickness of 20 μm. Immediately before perfusion, 0.5 ml aterial blood was taken from the left atrium to determine plasma corticosterone levels. The blood samples were immediately transferred to centrifuge tubes containing 10 μl heparin solution (500U/ml) and centrifuged for 20 min. at 3,500 G. The supernatant was stored at -20°C for the corticosterone assay. Corticosterone was extracted from 75 μl plasma and determined by HPLC with UV detection at 254 nm according to Dawson et al. (1984) with minor changes. Briefly, plasma samples were deproteïnized with methanol and centrifuged. The supernatant was further cleaned by extraction on a C8 Solid Phase Extraction Column (J.T. Baker, Deventer. The Netherlands). Corticosterone was eluted with acetone and this extract was aspirated and redissolved in 25% acetonitrile/water for subsequent injection onto the column (Nucleosil, length 10 cm, i.d. 3 mm, particle size 5 μm; Chrompack International, Middelburg, The Netherlands). The mobile phase was made by mixing 340 ml Acetonitrile to a total volume of 1 liter with water and was pumped at a rate of 0.5 ml/min. Dexamethasone was used as the internal standard. The absolute detection threshold for corticosterone in plasma was 8 ng/ml. The intraand interassay coefficients were 3% and 8%, respectively. For muscarinic receptor protein immunocytochemistry free floating brain sections were incubated 24 h at 4°C with phosphate buffered saline (PBS) containing mouse anti-mAChR IgM (M35; Chemunex, Paris, 1:200). Next the sections were incubated in biotinylated rabbit anti mouse IgM for 2 h at room temperature (RT) and after subsequent rinsing in PBS to streptavidin-HRP (Zymed, 1:200 2h at RT). The tissue-bound peroxidase was visualized using the diaminobenzidine (DAB) reaction (30 mg DAB in 100 ml Tris Buffer and 0.01% H O ). 2 2 The distribution of M35-immunoreactivity was quantified by measuring the relative optical density (OD) by way of an image analysis system (Quantimet 600, Leica). The OD was measured in the CA1 and CA3 pyramidal cell layer and associated apical dendrites, and in the DG molecular cell layer at the anterior-posterior level I.A. 4.7 (Paxinos and Watson 1982). The OD values of the corpus callosum served as a measure for non-specific background staining. Specific staining was calculated by subtraction of the OD of the 106 Chapter 5 Corticosterone and muscarinic receptor immunoreactivity 107 background from the total OD values. ADX-induced increment, however, was reduced to control level by application For quantification 3 adjacent sections per animal containing the of corticosterone immediately after ADX (Fig 1A). The labeling-intensity in hippocampus were analysed unilaterally. The data were averaged and the molecular layer of the dentate gyrus was less pronounced and noncalculated per group. The OD of the ADX, cortADX, aMR, aGR, and significantly affected by ADX or cort/ADX. aMR/aGR groups were compared with the OD of the control groups and statistically analysed using the Kruskal-Wallis ANOVA followed by the MannWhitney U-test. A probability level of P<0.05 was taken as statistical significance for all tests. All data are presented as means with their standard errors (SEM).

You might find this additional info useful...This article cites€17 articles, 3 of which you can access for free at: http://ajpheart.physiology.org/content/275/2/H460.full#ref-list-1This article has been cited by€3 other HighWire-hosted articles: http://ajpheart.physiology.org/content/275/2/H460#cited-by Updated information and services including high resolution figures, can be found at: http://ajpheart.physiology.org/content/275/2/H460.fullPhysiology can be found at: Additional material and information about American Journal of Physiology - Heart and Circulatoryhttp://www.the-aps.org/publications/ajpheartThis information is current as of November 21, 2012.

The interaction between the serotonin transporter (SERT) linked polymorphic region (5-HTTLPR) and adverse early life stressing (ELS) events is associated with enhanced stress susceptibility and risk to develop mental disorders like major depression, anxiety, and aggressiveness. In particular, human short allele carriers are at increased risk. This 5-HTTLPR polymorphism is absent in the rodent SERT gene, but heterozygous SERT knockout rodents (SERT+/-) show several similarities to the human S-allele carrier, therefore creating an animal model of the human situation. Many rodent studies investigated ELS interactions in SERT knockout rodents combined with ELS. However, underlying neuromolecular mechanisms of the (mal) adaptive responses to adversity displayed by SERT rodents remain to be elucidated. Here, we provide a comprehensive review including studies describing mechanisms underlying SERT variation x ELS interactions in rodents. Alterations at the level of translation and transcription but also epigenetic alterations considerably contribute to underlying mechanisms of SERT variation x ELS interactions. In particular, SERT+/-rodents exposed to adverse early rearing environment may be of high translational and predictive value to the more stress sensitive human short-allele carrier, considering the similarity in neurochemical alterations. Therefore, SERT+/-rodents are highly relevant in research that aims to unravel the complex psychopathology of mental disorders. So far, most studies fail to show solid evidence for increased vulnerability to develop affective-like behavior after ELS in SERT+/-rodents. Several reasons may underlie these failures, e.g., (1) stressors used might not be optimal or severe enough to induce maladaptations, (2) effects in females are not sufficiently studied, and (3) few studies include both behavioral manifestations and molecular correlates of ELS-induced effects in SERT+/-rodents. Of course, one should not exclude the (although unlikely) possibility of SERT+/-rodents not being sensitive to ELS. In conclusion, future studies addressing ELS-induced effects in the SERT+/-rodents should extensively study both long-term behavioral and (epi) genetic aspects in both sexes. Finally, further research is warranted using more severe stressors in animalmodels. Fromthere on, we should be able to draw solid conclusions whether the SERT+/-exposed to ELS is a suitable translational animal model for studying 5-HTTLPR polymorphism and stress interactions.

Understanding the role of the social environment in the development of stress related diseases requires a more fundamental understanding of stress. Stress includes not only the stimulus and the response but also the individual appraisal of the situation. The social environment is not only essential for survival it is at the same time an important source of stressors. This review discusses the social stress concept, how it has been studied in rodents in the course of time and some more recent insights into the appraisal process. In addition to the factors controllability and predictability, outcome expectancy and feedback of the victim's own actions during the social stress are suggested to be important factors in the development of stress related disease. It is hypothesized that individual differences in the way in which these factors are used in the appraisal of everyday life situations may explain individual vulnerability.

The purpose of this review is to examine whether a contribution of social exclusion to the pathogenesis of psychosis is compatible with the dopamine hypothesis and/or the neurodevelopmental hypothesis. Humans experience social exclusion as defeating. An animal model for defeat is the resident-intruder paradigm. The defeated animal shows evidence of an increased sensitivity to amphetamine, increased dopamine release in the nucleus accumbens and prefrontal cortex, and increased firing of dopaminergic neurons in the ventral tegmental area. As for humans, one study showed that amphetamine-induced striatal dopamine release was significantly greater among nonpsychotic young adults with severe hearing impairment than among normal hearing controls. Two other studies reported an association between childhood trauma and increased dopamine function in striatal subregions. Several studies have suggested that the perigenual anterior cingulate cortex (pgACC) may play a role in the processing of social stress. Importantly, the pgACC regulates the activity of the ventral striatum through bidirectional interconnections. We are not aware of studies in humans that examined whether (proxies for) social exclusion contributes to the structural brain changes present at psychosis onset. Animal studies, however, reported that long-term isolation may lead to reductions in volume of the total brain, hippocampus, or medial prefrontal cortex. Other animal studies reported that social defeat can reduce neurogenesis. In conclusion, the answer to the question as to whether there are plausible mechanisms whereby social exclusion can contribute to the pathogenesis of psychosis is cautiously affirmative.

Hierarchical social status greatly influences health and well-being in mammals, including humans. The social rank of an individual is established during competitive encounters with conspecifics. Intuitively, therefore, social dominance and aggressiveness may seem intimately linked. Yet, whether an aggressive personality trait may predispose individuals to a particular rank in a social colony setting remains largely unclear. Here we tested the hypothesis that high trait aggressiveness in Wildtype Groningen (WTG) rats, as assessed in a classic resident-intruder offensive aggression paradigm predicts social dominance in a mixed-sex colony housing using the Visible Burrow System (VBS). We also hypothesized that hierarchical steepness, as reflected in the number and intensity of the social conflicts, positively correlates with the average level of trait aggressiveness of the male subjects in the VBS. Clear and stable hierarchical ranking was formed within a few days in VBS colonies as indicated and reflected by a rapid loss of body weight in subordinates which stabilized after 2-3days. Social conflicts, that occurred mainly during these first few days, also resulted in bite wounds in predominantly subordinate males. Data clearly showed that trait aggressiveness does not predict dominance status. The most aggressive male in a mixed sex group of conspecifics living in a closed VBS environment does not always become the dominant male. In addition, data did not convincingly indicate that in colonies with only highly aggressive males, agonistic interactions were more intense. Number of bite wounds and body weight loss did not positively correlate with trait-aggressiveness of subordinates. In this study, rats from this wild-derived rat strain behave differently from Long-Evans laboratory rats that have been studied up till now in many experiments using the VBS. Strain dependent differences in the capacity to display appropriate social behavior fitting an adaptive strategy to a high or low social ranking position probably play an important role in the level of perceived stress in mixed sex social colonies like the VBS.

The interaction between the serotonin transporter (SERT) linked polymorphic region (5-HTTLPR) and adverse early life stressing (ELS) events is associated with enhanced stress susceptibility and risk to develop mental disorders like major depression, anxiety, and aggressiveness. In particular, human short allele carriers are at increased risk. This 5-HTTLPR polymorphism is absent in the rodent SERT gene, but heterozygous SERT knockout rodents (SERT+/−) show several similarities to the human S-allele carrier, therefore creating an animal model of the human situation. Many rodent studies investigated ELS interactions in SERT knockout rodents combined with ELS. However, underlying neuromolecular mechanisms of the (mal)adaptive responses to adversity displayed by SERT rodents remain to be elucidated. Here, we provide a comprehensive review including studies describing mechanisms underlying SERT variation × ELS interactions in rodents. Alterations at the level of translation and transcription but also epigenetic alterations considerably contribute to underlying mechanisms of SERT variation × ELS interactions. In particular, SERT+/− rodents exposed to adverse early rearing environment may be of high translational and predictive value to the more stress sensitive human short-allele carrier, considering the similarity in neurochemical alterations. Therefore, SERT+/− rodents are highly relevant in research that aims to unravel the complex psychopathology of mental disorders. So far, most studies fail to show solid evidence for increased vulnerability to develop affective-like behavior after ELS in SERT+/− rodents. Several reasons may underlie these failures, e.g., (1) stressors used might not be optimal or severe enough to induce maladaptations, (2) effects in females are not sufficiently studied, and (3) few studies include both behavioral manifestations and molecular correlates of ELS-induced effects in SERT+/− rodents. Of course, one should not exclude the (although unlikely) possibility of SERT+/− rodents not being sensitive to ELS. In conclusion, future studies addressing ELS-induced effects in the SERT+/− rodents should extensively study both long-term behavioral and (epi)genetic aspects in both sexes. Finally, further research is warranted using more severe stressors in animal models. From there on, we should be able to draw solid conclusions whether the SERT+/− exposed to ELS is a suitable translational animal model for studying 5-HTTLPR polymorphism and stress interactions.