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BACKGROUND: The mechanical properties of present-day percutaneous repairs of Achilles tendon ruptures are not known. MATERIAL AND METHODS: Artificially-created ruptures in 24 human cadaveric Achilles tendons were repaired with an open Bunnell repair, a percutaneous calcaneal tunnel or a percutaneous bone-anchor repair. In the open technique no.1 PDS-II absorbable suture material was used, and in the percutaneous techniques either no.1 PDS-II or no.1 Panacryl absorbable suture material was used. The specimens were tested in a materials testing machine until failure occurred. RESULTS: The common mode of failure was suture breakage in non-anchor repairs, and anchor pullout in anchor repairs. The average strength of the repairs varied from 166 N (SD 60) to 211 N (SD 30), with no differences between the techniques (p = 0.5). INTERPRETATION: Taking costs into account, the percutaneous calcaneal tunnel technique and the open technique are the methods of choice. [ABSTRACT FROM AUTHOR]

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., (© 2023. The Author(s).)

Although exercise is usually associated with beneficial effects on physical and mental health, patients recovering from surgery may be hampered to perform active exercise. Whole body vibration (WBV) is suggested a passive alternative for physical training. Aim of the present study was to explore the therapeutic potential of WBV compared to physical exercise during early post-surgery recovery. Male three months old Wistar rats underwent major abdominal surgery. Starting the day after surgery, rats were subjected to either daily WBV or exercise (treadmill running) for 15 consecutive days. Control rats underwent pseudo treatment. During the first week after surgery, effects of interventions were obtained from continuous recording of hemodynamic parameters, body temperature and activity (via an implanted transducer). Behavioral tests were performed during the second post-surgical week to evaluate anxiety-like behavior, short and long-term memory functions, cognitive flexibility and motor performance. Animals were sacrificed 15 days after surgery and brain tissue was collected for analysis of hippocampal neuroinflammation and neurogenesis. Surgery significantly impacted all parameters measured during the first post-surgery week, irrespective of the type of surgery. Effect on cognitive performance was limited to cognitive flexibility; both WBV and exercise prevented the surgery-induced decline. Exercise, but not WBV increased anxiety-like behavior and grip strength. WBV as well as exercise prevented the surgery-induced declined neurogenesis, but surgery-associated hippocampal neuroinflammation was not affected. Our results indicated that active exercise and WBV share similar therapeutic potentials in the prevention of surgery induced decline in cognitive flexibility and hippocampal neurogenesis. In contrast to exercise, WBV did not increase anxiety-like behavior. Since neither intervention affected hippocampal neuroinflammation, other mechanisms and/or brain areas may be involved in the behavioral effects. Taken together, we conclude that WBV may provide a relevant alternative to active exercise during the early stage of post-operative recovery., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Food availability modulates survival, reproduction and thereby population size. In addition to direct effects, food availability has indirect effects through density of conspecifics and predators. We tested the prediction that food availability in isolation affects reproductive success by experimentally manipulating food availability continuously for 3 years in zebra finches (Taeniopygia guttata) housed in outdoor aviaries. To this end, we applied a technique that mimics natural variation in food availability: increasing the effort required per food reward without affecting diet. Lower food availability resulted in a slight delay of start of laying and fewer clutches per season, but did not affect clutch size or number of offspring reared per annum. However, increasing foraging costs substantially reduced offspring growth. Thus, food availability in isolation did not impact the quantity of offspring reared, at the expense of offspring quality. Growth declined strongly with brood size, and we interpret the lack of response with respect to offspring number as an adaptation to environments with low predictability, at the time of egg laying, of food availability during the period of peak food demand, typically weeks later. Manipulated natal brood size of the parents did not affect reproductive success. Individuals that were more successful reproducers were more likely to survive to the next breeding season, as frequently found in natural populations. We conclude that the causal mechanisms underlying associations between food availability and reproductive success in natural conditions may be more complex than usually assumed. Experiments in semi-natural meso-populations can contribute to further unravelling these mechanisms., (© 2022. The Author(s).)

Predictive models are essential for advancing knowledge of brain disorders. High variation in study outcomes hampers progress. To address the validity of predictive models, we performed a systematic review and meta-analysis on behavioural phenotypes of the knock-out rodent model for Fragile X syndrome according to the PRISMA reporting guidelines. In addition, factors accountable for the heterogeneity between findings were analyzed. The knock-out model showed good translational validity and replicability for hyperactivity, cognitive and seizure phenotypes. Despite low replicability, translational validity was also found for social behaviour and sensory sensitivity, but not for attention, aggression and cognitive flexibility. Anxiety, acoustic startle and prepulse inhibition phenotypes, despite low replicability, were opposite to patient symptomatology. Subgroup analyses for experimental factors moderately explain the low replicability, these analyses were hindered by under-reporting of methodologies and environmental conditions. Together, the model has translational validity for most clinical phenotypes, but caution must be taken due to low effect sizes and high inter-study variability. These findings should be considered in view of other rodent models in preclinical research., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Whole body vibration (WBV) is a form of passive exercise by the stimulation of mechanical vibration platform. WBV has been extensively investigated through clinical studies with main focus on the musculoskeletal system. However, pre-clinical data in the context of behavior, memory and motor functions with aged rodents are limited. The aim of this experiment was to investigate the dose dependent effects of a five weeks long WBV intervention with an aged animal model including anxiety-related behavior, memory and motor functions, as well as markers of (neuro)inflammation. Male Wistar rats (18 months) underwent 5 or 20 min daily vibration exposure or pseudo-treatment (i.e.: being subjected to the same environmental stimuli for 5 or 20 min, but without exposure to vibrations) 5 times per week. After 5 weeks treatment, cognitive functions, anxiety-like behavior and motor performance were evaluated. Finally, brain tissue was collected for immunohistological purposes to evaluate hippocampal (neuro)inflammation. Animals with 20 min daily session of WBV showed a decrease in their anxiety-like behavior and improvement in their spatial memory. Muscle strength in the grip hanging test was only significantly improved by 5 min daily WBV treatments, whereas motor coordination in the balance beam test was not significantly altered. Microglia activation showed a significant decrease in the CA1 and Dentate gyrus subregions by both dose of WBV. In contrast, these effects were less pronounced in the CA3 and Hilus subregions, where only 5 min dose showed a significant effect on microglia activation. Our results indicate, that WBV seems to be a comparable strategy on age-related anxiety, cognitive and motor decline, as well as alleviating age-related (neuro)inflammation., (© 2022. The Author(s).)

Aging is a progressive process leading to functional decline in many domains. Recent studies have shown that physical exercise (PE) has a positive influence on the progression of age-related functional decline, including motor and brain functions. Whole body vibration (WBV) is a form of passive stimulation by mechanical vibration platforms, which offers an alternative for PE interventions, especially for aged individuals. WBV has been demonstrated to mimic the beneficial effects of PE on the musculoskeletal system, as well on the central nervous system. However, preclinical data with aged rodents are very limited. Hence, the purpose of this experiment was to investigate the effects of a 5-week WBV intervention with an aged animal model on memory functions, anxiety-related behavior, and motor performance. The 18-month old male ( N = 14) and female ( N = 14) Wistar rats were divided into two groups, namely, vibration and pseudo-vibration. Animals underwent a 5-week WBV intervention protocol with low intensity (frequency of 30 Hz and amplitude of 50-200 μm) stimulation. After 5 weeks, the following cognitive and motor tests were administered: open-field, novel and spatial object recognition, grip-hanging, and balance-beam. WBV-treated rats showed a decrease in their anxiety level in the open field test compared with those in the pseudo-treated controls. In addition, WBV-treated male animals showed significantly increased rearing in the open-field test compared to their pseudo controls. Spatial memory was significantly improved by WBV treatment, whereas WBV had no effect on object memory. Regarding motor performance, both grip strength and motor coordination were improved by WBV treatment. Our results indicate that WBV seems to have comparable beneficial effects on age-related emotional, cognitive, and motor decline as what has been reported for active PE. No striking differences were found between the sexes. As such, these findings further support the idea that WBV could be considered as a useful alternative for PE in case active PE cannot be performed due to physical or mental issues., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Oroszi, Geerts, de Boer, Schoemaker, van der Zee and Nyakas.)

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 μm) 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., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Rationale: Many depressed women continue antidepressant treatment during pregnancy. Selective serotonin reuptake inhibitor (SSRI) treatment during pregnancy increases the risk for abnormal social development of the child, including increased aggressive or defiant behavior, with unknown effects on sexual behavior., Objectives: Our aim was to investigate the effects of perinatal SSRI treatment and maternal depression, both separately and combined, on aggressive and sexual behavior in male rat offspring., Methods: Heterozygous serotonin transporter (SERT ±  ) knockout dams exposed to early life stress (ELSD) were used as an animal model of maternal depression. Early life stress consisted of separating litters from their mother for 6 h a day on postnatal day (PND)2-15, resulting in a depressive-like phenotype in adulthood. Depressive-like dams were treated with fluoxetine (FLX, 10 mg/kg) or vehicle throughout pregnancy and lactation (gestational day 1 until PND 21). Male offspring were tested for aggressive and sexual behavior in adulthood. As lifelong reductions in SERT expression are known to alter behavioral outcome, offspring with normal (SERT +/+ ) and reduced (SERT ±  ) SERT expression were assessed., Results: Perinatal FLX treatment reduced offensive behavior and the number of animals attacking and increased the latency to attack, especially in SERT +/+ offspring. Perinatal FLX treatment reduced the mounting frequency in SERT +/+ offspring. ELSD increased offensive behavior, without affecting sexual behavior in SERT ± offspring., Conclusions: Overall, our research demonstrates that perinatal FLX treatment and ELSD have opposite effects on aggressive behavior, with little impact on sexual behavior of male offspring.

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., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Rationale: Selective serotonin reuptake inhibitor (SSRI) antidepressants are increasingly prescribed during pregnancy. Changes in serotonergic signaling during human fetal development have been associated with changes in brain development and with changes in affective behavior in adulthood. The suprachiasmatic nucleus (SCN) is known to be modulated by serotonin and it is therefore assumed that SSRIs may affect circadian rhythms. However, effects of perinatal SSRI treatment on circadian system functioning in the offspring are largely unknown., Objective: Our aim was to investigate the effects of perinatal exposure to the SSRI fluoxetine (FLX) on circadian behavior, affective behavior, and 5-HT 1A receptor sensitivity in female rats. In addition, we studied the expression of clock genes and the 5-HT 1A receptor in the SCN, as they are potentially involved in underlying mechanisms contributing to changes in circadian rhythms., Results: Perinatal FLX exposure shortened the free-running tau in response to the 5-HT 1A/7 agonist 8-OH-DPAT. However, FLX exposure did not alter anxiety, stress coping, and 5-HT 1A receptor sensitivity. No differences were found in 5-HT 1A receptor and clock genes Per1, Per2, Cry1, and Cry2 SCN gene expression., Conclusions: Perinatal FLX exposure altered the response to a phase-shifting challenge in female rats, whether this may pose health risks remains to be investigated.

Certain models of cone beam computed tomography (CBCT) image-guided radiotherapy (IGRT) systems require manually placing the appropriate bowtie filter according to the relevant imaging protocol. Inadvertently using a wrong bowtie filter or no bowtie filter could cause unexpected image artifacts. In this work, CBCT image artifact patterns caused by different bowtie filter placement were evaluated. CBCT images of CT phantoms, that is, a Body Norm phantom, a Catphan® phantom and an anthropomorphic RANDO® phantom, were acquired at a Varian Trilogy® unit with an On-Board Imager® (OBI) system. Three image acquisition protocols were evaluated. For Standard Head protocol, half-fan bowtie and no bowtie filter were studied for comparison with the correct full-fan bowtie acquisition. For Pelvis and Low-Dose Thorax protocols, full-fan bowtie and no bowtie were studied for comparison with the correct half-fan bowtie acquisition. In addition, the possibility of reversed direction half-fan bowtie was also discussed. All possible scenarios of bowtie filter misplacement caused distinct artifacts regardless of protocols. These artifact patterns are different from the characteristic crescent artifact when correct bowtie filter was placed. Based on the artifact patterns described in this study we recommend reviewing image artifacts at time of image acquisition. If unexpected artifacts appear in the CBCT images, one should verify the correct placement of the bowtie filter and retake the image if necessary. However, it should also be stressed that using a wrong bowtie filter or forgetting to place the bowtie filter can cause increased patient dose. It is always a good practice to verify the bowtie filter placement before acquiring CBCT images for image-guided radiotherapy., (© 2020 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Brain serotonin (5-HT) neurotransmission plays an important role in male sexual behavior and it is well established that activating 5-HT 1 A receptors in rats facilitate ejaculatory behavior. However, the relative contribution of 5-HT 1 A somatodendritic autoreceptors and heteroreceptors in this pro-sexual behavior is unclear. Moreover, it is unclear whether the contribution of somatodendritic 5-HT 1 A autoreceptors and postsynaptic 5-HT 1 A heteroreceptors alter when extracellular 5-HT levels are chronically increased. Serotonin transporter knockout (SERT -/- ) rats exhibit enhanced extracellular 5-HT levels and desensitized 5-HT 1 A receptors. These rats model neurochemical changes underlying chronic SSRI-induced sexual dysfunction. We want to determine the role of presynaptic versus postsynaptic 5-HT 1 A receptors in the pro-sexual effects of 5-HT 1 A receptor agonists in SERT +/+ and in SERT -/- rats. Therefore, acute effects of the biased 5-HT 1 A receptor agonists F-13714, a preferential 5-HT 1 A autoreceptor agonist, or F-15599, a preferential 5-HT 1 A heteroreceptor agonist, and S15535 a mixed 5-HT 1 A autoreceptor agonist/heteroreceptor antagonist, on male sexual behavior were assessed. A clear and stable genotype effect was found after training where SERT +/+ performed sexual behavior at a higher level than SERT -/- rats. Both F-15599 and F-13714 induced pro-sexual activity in SERT +/+ and SERT -/- animals. Compared to SERT +/+ , the F13714-dose-response curve in SERT -/- rats was shifted to the right. SERT +/+ and SERT -/- rats responded similar to F15599. Within both SERT +/+ and SERT -/- rats the potency of F-13714 was much stronger compared to F-15599. S15535 had no effect on sexual behavior in either genotype. In SERT +/+ and SERT -/- rats that were selected on comparable low sexual activity (SERT +/+ 3 or less ejaculations and SERT -/- 5 or less ejaculations in 10 weeks) S15535 also did not influence sexual behavior. The two biased compounds with differential effects on 5-HT 1 A auto- and hetero-receptors, exerted pro-sexual activity in both SERT +/+ and SERT -/- rats. Applying these specific pharmacological tools has not solved whether pre- or post-synaptic 5-HT 1 A receptors are involved in pro-sexual activity. Moreover, the inactivity of S15535 in male sexual behavior in either genotype was unexpected. The question is whether the in vivo pharmacological profile of the different 5-HT 1 A receptor ligands used, is sufficient to differentiate pre- and/or post-synaptic 5-HT 1 A receptor contributions in male rat sexual behavior., (Copyright © 2020 Esquivel-Franco, de Boer, Waldinger, Olivier and Olivier.)

Inconsistent findings between laboratories are hampering scientific progress and are of increasing public concern. Differences in laboratory environment is a known factor contributing to poor reproducibility of findings between research sites, and well-controlled multisite efforts are an important next step to identify the relevant factors needed to reduce variation in study outcome between laboratories. Through harmonization of apparatus, test protocol, and aligned and non-aligned environmental variables, the present study shows that behavioral pharmacological responses in Shank2 knockout (KO) rats, a model of synaptic dysfunction relevant to autism spectrum disorders, were highly replicable across three research centers. All three sites reliably observed a hyperactive and repetitive behavioral phenotype in KO rats compared to their wild-type littermates as well as a dose-dependent phenotype attenuation following acute injections of a selective mGluR1 antagonist. These results show that reproducibility in preclinical studies can be obtained and emphasizes the need for high quality and rigorous methodologies in scientific research. Considering the observed external validity, the present study also suggests mGluR1 as potential target for the treatment of autism spectrum disorders.

Brain serotonin (5-HT) plays a key role in aggressive behaviours and related psychopathologies, but its precise mechanism of action remains elusive. Genetic animal models may provide a tool to elucidate the relationship between aggression and serotonin. The present study showed that tryptophan hydroxylase 2 (Tph2) knockout (KO) rats, which exhibit profoundly diminished extracellular serotonin levels, display increased aggressiveness compared to their Tph2 wildtype (WT) counterparts. However, the level of aggression in Tph2 KO rats did not equal that of feral wild type Groningen (WTG) rats. To investigate whether enhanced 5-HT 1A receptor functionality may be present in Tph2 KO rats, we tested the acute anti-aggressive potency of the highly selective 5-HT 1A receptor full agonist NLX-112 (a.k.a. befiradol or F13640). Data show that compared to Tph2 WT and WTG rats, the NLX-112 dose-effect curve was shifted to the right in Tph2 KO animals. These results suggest that, unlike previous reports in Tph2 KO mice, Tph2 KO rats have a decreased 5-HT 1A receptor sensitivity compared to both Tph2 WT and WTG animals., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Recently, the putative association between selective serotonin reuptake inhibitor (SSRI) exposure during pregnancy and the development of social disorders in children has gained increased attention. However, clinical studies struggle with the confounding effects of maternal depression typically co-occurring with antidepressant treatment. Furthermore, preclinical studies using an animal model of maternal depression to study effects of perinatal SSRI exposure on offspring social behavior are limited. Therefore, the aim of this study was to investigate effects of perinatal fluoxetine exposure on juvenile and adult social behavior in male and female rat offspring, using an animal model of maternal vulnerability. We exposed heterozygous serotonin transporter (SERT) deficient female rats to early life maternal separation stress, and used this as a model for maternal vulnerability. Control and early life stressed heterozygous serotonin transporter knockout (SERT) dams were treated with the SSRI fluoxetine or vehicle throughout gestation and lactation. Subsequently, both male and female wildtype (SERT +/+ ) and heterozygous (SERT +/- ) rat offspring were tested for pup ultrasonic vocalizations (USVs), juvenile social play behavior and adult social interaction. Fluoxetine treatment of the dams resulted in a reduced total USV duration in pups at postnatal day 6, especially in SERT +/+ males. Perinatal fluoxetine exposure lowered social play behavior in male offspring from both control and early life stressed dams. However, in females a fluoxetine-induced reduction in juvenile play behavior was only present in offspring from control dams. Offspring genotype did not affect juvenile play behavior. Despite fluoxetine-induced behavioral effects at juvenile age, fluoxetine reduced male adult social behavior in offspring from control dams only. Effects of fluoxetine on female adult social behavior were virtually absent. Interestingly, early life stress in dams increased adult social exploration in vehicle exposed SERT +/+ female offspring and total social behavior in fluoxetine exposed adult SERT +/- male offspring. Furthermore, SERT +/- males appeared less social during adulthood compared to SERT +/+ males. Overall, the present study shows that chronic blockade of the serotonin transporter by fluoxetine during early development has a considerable impact on pup USVs, juvenile social play behavior in both male and female offspring, and to a lesser extent on male social interaction in adulthood.

Rationale: Only a subset of impulsive aggressive patients benefits from selective serotonin reuptake inhibitor (SSRI) treatment, confirming contradictory results about the association between serotonin (5-hydroxytryptamine, 5-HT) and aggression. This shows the need to define behavioral characteristics within this subgroup to move towards individualized pharmacological treatment of impulsive aggression., Methods: Here we submitted an outbred strain of Long Evans rats to a crossover design treatment regimen with the SSRI citalopram, to test its anti-aggressive effect. Behavioral characteristics were baseline aggression, anxiety parameters as measured in the elevated plus maze and open field and cue responsivity as indicated by sign vs. goal tracking behavior. 5-HT 1A receptor densities as measured by ex vivo [ 18 F]MPPF binding were determined in the dorsal raphe nucleus, dentate gyrus, orbitofrontal cortex, infralimbic cortex and prelimbic cortex, because of the receptors' involvement in the therapeutic delay of SSRIs and aggression., Results: We found statistically significant increased variance in aggressive behavior after citalopram treatment. However, none of the selected parameters predicted the citalopram treatment effect., Conclusion: Since aggression after citalopram treatment decreased in a subgroup of animals and increased in the other, future research should focus on other possible predictors to support treatment strategies in aggressive patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The American Association of Physicists in Medicine (AAPM) is a nonprofit professional society whose primary purposes are to advance the science, education, and professional practice of medical physics. The AAPM has more than 8000 members and is the principal organization of medical physicists in the United States. The AAPM will periodically define new practice guidelines for medical physics practice to help advance the science of medical physics and to improve the quality of service to patients throughout the United States. Existing medical physics practice guidelines will be reviewed for the purpose of revision or renewal, as appropriate, on their fifth anniversary or sooner. Each medical physics practice guideline (MPPG) represents a policy statement by the AAPM, has undergone a thorough consensus process in which it has been subjected to extensive review, and requires the approval of the Professional Council. The medical physics practice guidelines recognize that the safe and effective use of diagnostic and therapeutic radiation requires specific training, skills, and techniques as described in each document. As the review of the previous version of AAPM Professional Policy (PP)-17 (Scope of Practice) progressed, the writing group focused on one of the main goals: to have this document accepted by regulatory and accrediting bodies. After much discussion, it was decided that this goal would be better served through a MPPG. To further advance this goal, the text was updated to reflect the rationale and processes by which the activities in the scope of practice were identified and categorized. Lastly, the AAPM Professional Council believes that this document has benefitted from public comment which is part of the MPPG process but not the AAPM Professional Policy approval process. The following terms are used in the AAPM's MPPGs: Must and Must Not: Used to indicate that adherence to the recommendation is considered necessary to conform to this practice guideline. Should and Should Not: Used to indicate a prudent practice to which exceptions may occasionally be made in appropriate circumstances., (© 2018 American Association of Physicists in Medicine. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

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., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Escalated interpersonal aggression and violence are common symptoms of multiple psychiatric disorders and represent a significant global health issue. Current therapeutic strategies are limited due to a lack of understanding about the neural and molecular mechanisms underlying the 'vicious' shift of normal adaptive aggression into violence, and the environmental triggers that cause it. Development of novel animal models that validly capture the salient features of human violent actions combined with newly emerging technologies for mapping, measuring, and manipulating neuronal activity in the brain significantly advance our understanding of the etiology, neuromolecular mechanisms, and potential therapeutic interventions of excessive aggressive behaviors in humans., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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.

Considerable individual differences exist in trait-like patterns of behavioral and physiological responses to salient environmental challenges. This individual variation in stress coping styles has an important functional role in terms of health and fitness. Hence, understanding the neural embedding of coping style variation is fundamental for biobehavioral neurosciences in probing individual disease susceptibility. This review outlines individual differences in trait-aggressiveness as an adaptive component of the natural sociobiology of rats and mice, and highlights that these reflect the general style of coping that varies from proactive (aggressive) to reactive (docile). We propose that this qualitative coping style can be disentangled into multiple quantitative behavioral domains, e.g., flexibility/impulse control, emotional reactivity and harm avoidance/reward processing, that each are encoded into selective neural circuitries. Since functioning of all these brain circuitries rely on fine-tuned serotonin signaling, autoinhibitory control mechanisms of serotonergic neuron (re)activity are crucial in orchestrating general coping style. Untangling the precise neuromolecular mechanisms of different coping styles will provide a roadmap for developing better therapeutic strategies of stress-related diseases., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Sleep deprivation has profound effects on cognitive performance, and some of these effects may be mediated by impaired prefrontal cortex function. In search of an animal model to investigate this relationship we studied the influence of restricted sleep on operant conditioning in rats, particularly the performance in a differential reinforcement of low rate responding (DRL) task, which is highly dependent upon an intact prefrontal cortex. Animals were trained to withhold a lever press until an imposed delay of 30 s after the last press had passed in order to achieve a food reward. Once the animals had mastered the task, they were sleep-restricted for 7 days with 20 h of sleep deprivation per day. At the end of each daily sleep deprivation session, performance on the DRL task was assessed. The results show that sleep-restricted animals were less able to time their responses correctly, started pressing the lever more randomly and showed signs of behavioural disinhibition, the latter possibly reflecting enhanced impulsivity. Our data support the hypothesis that a sleep debt has disruptive consequences for the functioning of the prefrontal cortex. This model offers possibilities for future studies investigating the underlying biochemical and molecular mechanisms of this relationship., (© 2016 European Sleep Research Society.)

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.

Despite moderate heritability estimates, the molecular architecture of aggressive behavior remains poorly characterized. This study compared gene expression profiles from a genetic mouse model of aggression with zebrafish, an animal model traditionally used to study aggression. A meta-analytic, cross-species approach was used to identify genomic variants associated with aggressive behavior. The Rankprod algorithm was used to evaluated mRNA differences from prefrontal cortex tissues of three sets of mouse lines (N = 18) selectively bred for low and high aggressive behavior (SAL/LAL, TA/TNA, and NC900/NC100). The same approach was used to evaluate mRNA differences in zebrafish (N = 12) exposed to aggressive or non-aggressive social encounters. Results were compared to uncover genes consistently implicated in aggression across both studies. Seventy-six genes were differentially expressed (PFP < 0.05) in aggressive compared to non-aggressive mice. Seventy genes were differentially expressed in zebrafish exposed to a fight encounter compared to isolated zebrafish. Seven genes (Fos, Dusp1, Hdac4, Ier2, Bdnf, Btg2, and Nr4a1) were differentially expressed across both species 5 of which belonging to a gene-network centred on the c-Fos gene hub. Network analysis revealed an association with the MAPK signaling cascade. In human studies HDAC4 haploinsufficiency is a key genetic mechanism associated with brachydactyly mental retardation syndrome (BDMR), which is associated with aggressive behaviors. Moreover, the HDAC4 receptor is a drug target for valproic acid, which is being employed as an effective pharmacological treatment for aggressive behavior in geriatric, psychiatric, and brain-injury patients. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: The serotonin (5-HT) deficiency hypothesis of aggression is being seriously challenged by pharmacological data showing robust anti-aggressive effects of 5-HT1A receptor agonists in dose ranges that concomitantly inhibit 5-HT neurotransmission. Hence, an adequate interpretation of the role of 5-HT activity in regulating aggression depends on elucidating the predominant site of action, i.e., raphe presynaptic autoreceptors versus forebrain postsynaptic heteroreceptors, of these 5-HT1A receptor agonists., Objectives: The present experiments investigated the anti-aggressive properties of the selective 5-HT1A receptor agonists F15599 that preferentially target postsynaptic 5-HT1A heteroreceptors in the frontal cortex and F13714 that more preferentially activates raphe somatodendritic 5-HT1A autoreceptors., Methods: Both 'biased' agonists were acutely administered intraperitoneally in aggressive resident male WTG rats confronting an intruder., Results: Systemic administration of F15599 and F13714 exerted very potent (ID50 = 0.095 and 0.0059 mg/kg, respectively) anti-aggressive effects. At 4.5-fold higher dose ranges, the anti-aggressive effects were accompanied by concomitant motor inactivity and/or reduction of social engagement. Pretreatment with WAY-100635 counteracted the behavioural effects of both agonists., Conclusions: Overall, the qualitatively similar but quantitatively different anti-aggressive profiles of F15599 and F13714 largely correspond to their distinct 5-HT1A receptor binding/activation potencies. Moreover, the marked anti-aggressive potency of F13714 adds additional support for a critical role of raphe somatodendritic 5-HT1A autoreceptors, and hence phasic 5-HT neuron activity, in the initiation/execution of aggressive actions.

Experimental studies aimed at understanding the neurobiology of aggression started in the early 20th century, and by employing increasingly sophisticated tools of functional neuroanatomy (i.e., from electric/chemical lesion and stimulation techniques to neurochemical mapping and manipulations) have provided the important framework for the functional brain circuit organization of aggressive behaviors. Recently, newly emerging technologies for mapping,measuring and manipulating neural circuitry at the level of molecular and genetically defined neuronal subtypes promise to further delineate the precise neural microcircuits mediating the initiation and termination of aggressive behavior, and characterize its dynamic neuromolecular functioning. This paper will review some of the behavioral, neuroanatomical and neurochemical evidence in support of a modular view of the neurobiology of offensive aggressive behavior. Although aggressive behavior likely arises from a specific concerted activity within a distributed neural network across multiple brain regions, emerging opto- and pharmacogenetic neuronal manipulation studies make it clear that manipulation of molecularly-defined neurons within a single node of this global interconnected network seems to be both necessary and sufficient to evoke aggressive attacks. However, the evidence so far also indicates that in addition to behavior-specific neurons there are neuronal systems that should be considered as more general behavioral control modules. The answer to the question of behavioral specificity of brain structures at the level of individual neurons requires a change of the traditional experimental setup. Studies using c-fos expression mapping usually compare the activation patterns induced by for example aggression with a home cage control. However, to reveal the behavioral specificity of this neuronal activation pattern, a comparison with other social and non-social related behaviors such as mating, defensive burying or running might be more appropriate. In addition, the correlations between aggressive behavior and other behaviors in different environmental contexts might give an indication of these more general behavioral control functions. Elucidating how neural circuits that modulate social-aggressive behavior also mediate other complex emotional behaviors or states will lead to a better understanding of the molecular mechanisms by which social deficits are expressed in various neuropsychiatric disorders. This likely will lead to more efficacious pharmacological or circuit-based therapeutics to curb excessive/abnormal aggressive behavior and improve social function.

Background: Human hip morphology is variable, and some variations (or hip morphotypes) such as coxa profunda and coxa recta (cam-type hip) are associated with femoroacetabular impingement and the development of osteoarthrosis. Currently, however, this variability is unexplained. A broader perspective with background information on the morphology of the proximal femur of nonhuman apes is lacking. Specifically, no studies exist of nonhuman ape femora that quantify concavity and its variability., Questions/purposes: We hypothesized that, when compared with modern humans, the nonhuman apes would show (1) greater proximal femoral concavity; (2) less variability in concavity; and (3) less sexual dimorphism in proximal femoral morphology., Methods: Using identical methods, we compared 10 morphological parameters in 375 human femora that are part of the Hamann-Todd collection at the Cleveland Museum of Natural History with 210 nonhuman ape femora that are part of the collection of the Royal Museum for Central Africa, Tervuren, Belgium, and the Muséum National d'Histoire Naturelle, Paris, France., Results: The nonhuman apes have larger proximal femoral concavity than modern humans. This morphology is almost uniform without large variability or large differences neither between species nor between sexes., Conclusions: Variability is seen in human but not in nonhuman ape proximal femoral morphology. An evolutionary explanation can be that proximal femoral concavity is more important for the nonhuman apes, for example for climbing, than for modern humans, where a lack of concavity may be related to high loading of the hip, for example in running.

Individual differences in coping style emerge as a function of underlying variability in the activation of a mesocorticolimbic brain circuitry. Particularly serotonin seems to play an important role. For this reason, we assessed serotonin-2A receptor (5-HT2A R) binding in the brain of rats with different coping styles. We compared proactive and reactive males of two rat strains, Wild-type Groningen (WTG) and Roman high- and low avoidance (RHA, RLA). 5-HT2A R binding in (pre)frontal cortex (FC) and hippocampus was investigated using a radiolabeled antagonist ([(3) H]MDL-100907) and agonist ([(3) H]Cimbi-36) in binding assays. No differences in 5-HT2A R binding were observed in male animals with different coping styles. [(3) H]MDL-100907 displayed a higher specific-to-nonspecific binding ratio than [(3) H]Cimbi-36. Our findings suggest that in these particular rat strains, 5-HT2A R binding is not an important molecular marker for coping style. Because neither an antagonist nor an agonist tracer showed any binding differences, it is unlikely that the affinity state of the 5-HT2A R is co-varying with levels of aggression or active avoidance in WTG, RHA and RLA., (© 2015 Wiley Periodicals, Inc.)

We recently demonstrated that acute and chronic intracerebroventricular enhancement of brain OXT levels induces potent anti-aggressive and pro-social explorative effects during social challenges. However, the exact anatomical location in the brain where OXT exerts its action is still elusive. In the present study, we targeted two critical brain areas, i.e. the central amygdala (CeA) and the dorsal raphe (DR), both containing high levels of OXT receptors (OXTRs) and constituting important nodes of the neural circuitry related to aggression. Behavioral effects of local micro-infusion of OXT and OXTR antagonist, L368.899, (alone and combined) were evaluated in resident male rats during confrontations with an unfamiliar male intruder. Our results show that OXT microinjected into the CeA markedly reduced resident's offensive behavior and facilitated social exploration, without affecting other non-aggressive behaviors. The receptor specificity of the behavioral effects was verified when a micro-infusion of a selective OXTR antagonist nullified the changes. Pharmacological blockade of CeA OXTRs per se was without clear behavioral effects suggesting that endogenous OXT within the CeA does not play a major inhibitory role on offensiveness. Anatomical specificity was also supported by the absence of relevant behavioral effects when OXT was microinjected into more medial sub-regions of the amygdala. Likewise, within the DR neither OXT nor OXTR exerted significant effects on offensive aggression, while microinjection of the 5-HT1A autoreceptor agonist in this region significantly suppressed aggression. In conclusion, our results point at the CeA as an important brain site of action for the anti-aggressive and pro-social explorative effects induced by exogenous enhancement of brain OXT levels., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Socio-emotional deficits and impulsive/aggressive outbursts are prevalent symptoms of many neuropsychiatric disorders, and intranasal administration of oxytocin (OXT) is emerging as a putative novel therapeutic approach to curb these problems. Recently, we demonstrated potent anti-aggressive and pro-social effects of intracerebroventricular (icv) OXT administration in male rats. The present study tested whether similar behavioral effects are induced when OXT is delivered intranasally. Heart-rate and blood-pressure responses were telemetrically monitored to investigate whether peripheral physiological effects were provoked after intranasal OXT administration. Intranasal OXT administration in resident animals reduced offensive aggression and increased social exploration toward an unfamiliar male intruder. Using a partner-preference test, intranasal OXT also strengthened the bonding between the male resident and its female partner. No changes in cardiovascular (re)activity were found, indicating an absence of direct peripheral physiological effects after intranasal OXT treatment. In conclusion, although the precise route and mechanisms of nose-to-brain transport/communication remain to be elucidated, our data demonstrated intranasal OXT to be an effective application method for suppressing intermale aggression and enhancing social affiliation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Adolescence is generally considered as a developmental period during which adverse social experiences may have lasting consequences in terms of an increased vulnerability to affective disorders. This study aimed at determining the individual susceptibility to adolescent social stress using a rat model. We used rats of the Wild-type Groningen strain, which are characterized by a broad variation in adult levels of aggression and impulsivity. We hypothesized that experience of social defeat in adolescence results in heightened aggression and impulsivity levels in adulthood. In contrast to our expectation, adolescent social defeat did not lead to a difference in the average adult level of aggression and impulsivity, but the significant correlation between offensive aggression and impulsivity found in control animals was not present in animals defeated during adolescence., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Aggression is closely related to impulsive behavior both in humans and in animals. To avoid potential negative consequences, aggressive behavior is kept in control by strong inhibitory mechanisms. Failure of these inhibitory mechanisms results in violent behavior. In the present experiments, we investigated whether aggressive behavior is related to impulsive behavior. Furthermore, we investigated if violent behavior can be distinguished from "normal" aggressive behavior in terms of impulsivity levels. We used rats of the wild-type Groningen strain, rats of this strain differ widely in their level of offensive aggression expressed toward an unfamiliar intruder male, ranging from no aggression at all to very high levels of intense and sometimes violent behavior. Violent behavior was displayed by some of the animals that were given repeated winning experience. We used behavioral performance in an unpredictable operant conditioning paradigm for food reinforcement (variable interval 15) and performance in a differential-reinforcement of low rate (DRL-60s) responding as determinants for impulsivity. We predicted that offensive aggression is correlated with behavioral flexibility measured by the VI-15 procedure and that aggressive behavior is characterized by low behavioral inhibition on the DRL task. In addition we expected that violent animals would be characterized by extremely low levels of behavioral inhibition on the DRL task. We showed that the level of offensive aggression indeed positively correlated with VI-15 performance. In addition, we showed that behavioral performance on the DRL procedure is similar in low and high aggressive rats. However, violent animals can be dissociated by a lower efficiency of lever pressing on a DRL-60s schedule of reinforcement., (© 2014 Wiley Periodicals, Inc.)

Oxytocin (OXT) has been implicated in the regulation of social behaviors, including intermale offensive aggression. Recently, we showed that acute enhancement of brain OXT levels markedly suppressed offensive aggression and increased social exploration in resident rats confronted with an intruder in their home territory. Moreover, a different responsivity to the exogenous OXTergic manipulation was observed among individuals based on their baseline aggression. In this study we aimed at evaluating the behavioral response to chronically enhancing or attenuating central OXT levels, and at scrutinizing whether the trait-aggression moderates the treatment-induced behavioral changes. To this end, resident male wild-type Groningen rats were continuously (via osmotic minipumps) intracerebroventricularly infused with synthetic OXT or a selective OXT receptor (OXTR) antagonist for 7days. Changes in behavior were assessed performing a resident-intruder test before and at the end of the treatment period, as well as after 7days of withdrawal. Chronic infusion of OXT was found to selectively suppress aggression and enhance social exploration. Chronic blockage of OXTRs instead increased introductory aggressive behavior (i.e. lateral threat), yet without affecting the total duration of the aggression. The magnitude of the anti-aggressive changes correlated positively with the level of baseline aggression. Interestingly, OXT-induced behavioral changes persisted 7days after cessation of the treatment. In conclusion, these findings provide further evidence that enhanced functional activity of the central OXTergic system decreases social offensive aggression while it increases social explorative behavior. The data also indicate that chronically enhancing brain OXT levels may cause enduring anti-aggressive and pro-social explorative behavioral effects., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Rationale: A substantial body of research suggests that the neuropeptide oxytocin promotes social affiliative behaviors in a wide range of animals including humans. However, its antiaggressive action has not been unequivocally demonstrated in male laboratory rodents., Objective: Our primary goal was to examine the putative serenic effect of oxytocin in a feral strain (wild type Groningen, WTG) of rats that generally show a much broader variation and higher levels of intermale aggression than commonly used laboratory strains of rats., Methods: Resident animals were intracerebroventricularly (icv) administered with different doses of synthetic oxytocin and oxytocin receptor antagonist, alone and in combination, in order to manipulate brain oxytocin functioning and to assess their behavioral response to an intruder., Results: Our data clearly demonstrate that acute icv administered oxytocin produces dose-dependent and receptor-selective changes in social behavior, reducing aggression and potentiating social exploration. These antiaggressive effects are stronger in the more offensive rats. On the other hand, administration of an oxytocin receptor antagonist tends to increase (nonsignificantly) aggression only in low-medium aggressive animals., Conclusions: These results suggest that transiently enhancing brain oxytocin function has potent antiaggressive effects, whereas its attenuation tends to enhance aggressiveness. In addition, a possible inverse relationship between trait aggression and endogenous oxytocinergic signaling is revealed. Overall, this study emphasizes the importance of brain oxytocinergic signaling for regulating intermale offensive aggression. This study supports the suggestion that oxytocin receptor agonists could clinically be useful for curbing heightened aggression seen in a range of neuropsychiatric disorders like antisocial personality disorder, autism, and addiction.

Aggression is a major component of territorial behaviour. However, different mechanisms evolved to fulfil the defence function while reducing the cost derived from agonistic interactions, as a differential response to the same stimulus, depending on the outcome of past conflicts - priming, which makes the aggressive response adaptable. Aggressive behaviour is facilitated by the stress response, so, we tested the effect of a single injection of a mineralocorticoid antagonist (spironolactone) on the escalation of territorial aggression in a resident-intruder paradigm, and its modulation by social stimulus. We used naïve Wild Type Groningen - WTG - rats as residents, and naïve and previously defeated Wistar rats as intruders. The first encounter was 1h after the injection, and then repeated in 3 consecutive days. When WTG rats were confronted with naïve Wistar rats, single injections of spironolactone completely abolished the attack behaviour in the short term while enhancing it in the long term. When we used defeated Wistar rats, the spironolactone effect was not as great. The short-term reduction in aggressive behaviour was attributable to the blockade of mineralocorticoid receptors during the first encounters, while the enhancement in aggressive behaviour in the long term was suggested to be related to the imbalance between mineralocorticoid and glucocorticoid receptors during the stress response associated to the encounters., (Copyright © 2013 Elsevier B.V. All rights reserved.)

This video publication explains in detail the experimental protocol of the resident-intruder paradigm in rats. This test is a standardized method to measure offensive aggression and defensive behavior in a semi natural setting. The most important behavioral elements performed by the resident and the intruder are demonstrated in the video and illustrated using artistic drawings. The use of the resident intruder paradigm for acute and chronic social stress experiments is explained as well. Finally, some brief tests and criteria are presented to distinguish aggression from its more violent and pathological forms.

Personality characteristics, e.g. aggressiveness, have long been associated with an increased risk of cardiac disease. However, the underlying mechanisms remain unclear. In this study we used a rodent model for characterizing cardiac autonomic modulation in rats that differ widely in their level of aggressive behavior. To reach this goal, high-aggressive (HA, n = 10) and non-aggressive (NA, n = 10) rats were selected from a population (n = 121) of adult male Wild-type Groningen rats on the basis of their latency time to attack (ALT, s) a male intruder in a resident-intruder test lasting 600 s. In order to obtain information on their cardiac autonomic modulation, ECG recordings were subsequently obtained via radiotelemetry 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, HA rats (ALT<90 s) displayed reduced heart rate variability, mostly in terms of lower vagal modulation compared to NA rats (ALT>600 s). Exposure to stressful stimuli (i.e. restraint and psychosocial stress) provoked similar tachycardic responses between the two groups. However, under stress conditions HA rats displayed a reduced vagal antagonism and an increased incidence of tachyarrhythmias compared to NA rats. In addition, beta-adrenergic pharmacological stimulation induced a much larger incidence of ventricular tachyarrhythmias in HA rats compared to NA counterparts. These findings are consistent with the view that high levels of aggressive behavior in rats are associated to signs of cardiac autonomic impairment and increased arrhythmogenic susceptibility that may predict vulnerability to cardiac morbidity and mortality.

Morphology variants of the hip such as coxa recta (aspherical femoral head and/or reduced head-neck concavity) or coxa profunda (overcoverage, or "deep" socket) are associated with cam and pincer impingement respectively, and may ultimately lead to coxarthrosis. Several population studies have documented the prevalence of hip morphotypes, but few studies have examined this prevalence in total hip arthroplasty (THA) patients, or persons without hip symptoms or signs.
We reviewed whether coxa recta and profunda morphotypes were more prevalent in THA patients compared to normal controls. Further, we explored differences in hip abductor mechanism related to hip morphology.
We examined 113 THA patients and 83 normal controls with anteroposterior pelvic and lateral hip 
radiographs. Coxa recta and profunda were classified with alpha and lateral CE-angle, respectively. The abductor ratio (AR) was measured on AP pelvic radiographs.
Both coxa recta and profunda were more prevalent in THA patients than normal controls (coxa recta: male 42% vs 8%, female 15% vs 5%, respectively and coxa profunda: male 20% vs 1%, female 19% vs 6% respectively). AR was higher in females than males, both in THA patients (1.66 vs 1.47) and normal controls (1.68 vs 1.57). Coxa profunda was associated with a lower AR (1.54 vs 1.61).
The higher prevalence of coxa recta and profunda in arthroplasty patients supports the theory of a role of these morphotypes in the development of coxarthrosis. The higher AR in females signifies the need for increased abductor work. Coxa profunda may be an adaptation to lower the AR.

The current theories of animal personality are based on the observation that individual variation in behavior and physiology appears to be consistent across contexts. Rats of the Roman selection lines have been originally selected for differences in shuttle-box behavior. Besides differences in active avoidance, these animals differ more generally in coping style. Roman high avoidance (RHA) rats show high levels of active avoidance, whereas Roman low avoidance (RLA) rats tend to respond with a more passive (i.e. freezing) response. Based on the two tier model of coping styles, we hypothesized that RHA rats would show high levels of offensive behavior and are more impulsive compared to RLA rats. We characterized animals in a two-way active avoidance task on five consecutive days. Thereafter animals were tested for their level of offensive aggression and impulsive behavior. The level of offensive aggression was examined in a standard resident-intruder paradigm. Furthermore, we tested aspects of impulsivity in an unpredictable operant conditioning paradigm (variable interval-15 schedule) for food reinforcement and during extinction of lever press behavior. We show that RHA rats are indeed characterized by high levels of two-way active avoidance in a shuttle-box paradigm. Surprisingly, the level of offensive aggression was higher in RLA compared to RHA rats. Consistent with the coping style interpretation, the number of lever presses in the VI-15 schedule for food reinforcement was higher in RHA rats compared to RLA rats. During a session of frustrating non-reward, RHA rats were more persistent. Taken together, results of the two-way active avoidance task and VI-15 performance in rats of the Roman selection lines fit with the two tier model of coping styles. Unexpectedly, the level of offensive aggression does not match with this model.

Anxiety disorders in humans reduce both the heart rate variability (HRV) and the sensitivity of the cardiac baroreflex (BRS). Both may contribute to sudden death. To elucidate the mechanisms underlying these alterations, male rats were subjected to social defeat sessions on four consecutive days. Five days later, the rats were found to be in an anxiety-like state. At this time point, we analysed HRV and BRS in the defeated rats, with or without treatment with the anxiolytic chlordiazepoxide (CDZ). HRV was reduced after social defeat, due to changes in the autonomic balance favouring the sympathetic over the parasympathetic component. Spontaneous and pharmacological baroreflex gains were also reduced. CDZ abolished anxiety-like symptoms as well as HRV and BRS alterations. Inhibition of the dorsomedial hypothalamus (DMH) with muscimol reversed all cardiovascular alterations, whereas blockade of the nucleus tractus solitarii (NTS) 5-HT3 receptor by the local or systemic administration of granisetron restored only baroreflex gains and the parasympathetic component of HRV. In conclusion, repeated social defeat in the rat lead to an anxiety-like state that was associated with lasting reduction in HRV and baroreflex gains. The DMH and the NTS were responsible for these chronic cardiovascular alterations. These regions may therefore constitute new therapeutic targets for reducing cardiac dysfunction and fibrillation in anxiety disorders.

Rationale: Preclinical experimental models of pathological aggressive behavior are a sorely understudied and difficult research area., Objectives: How valid, reliable, productive, and informative are the most frequently used animal models of excessive aggressive behavior?, Methods: The rationale, key methodological features, supporting data, and arguments as well as their disadvantages and limitations of the most frequently used animal models for excessive aggressive behavior are summarized and their validity and reliability are evaluated., Results: Excessive aggressive behavior is validly and reliably seen in (1) a proportion of feral-derived rats and selectively bred mice; (2) rats with compromised adrenal function resulting in a hypoglucocorticoid state; (3) a significant minority of mice, rats, and monkeys after consumption of a moderate dose of alcohol; and (4) resident animals of various species after social instigation. Limitations of these procedures include restrictive animal research regulations, the requirement of expertise in surgical, pharmacological, and behavioral techniques, and the behaviorally impoverished mouse strains that are used in molecular genetics research. Promising recent initiatives for novel experimental models include aggressive behaviors that are evoked by optogenetic stimulation and induced by the manipulation of early social experiences such as isolation rearing or social stress., Conclusions: One of the most significant challenges for animal models of excessive, potentially abnormal aggressive behavior is the characterization of distinctive neurobiological mechanisms that differ from those governing species-typical aggressive behavior. Identifying novel targets for effective intervention requires increased understanding of the distinctive molecular, cellular, and circuit mechanisms for each type of abnormal aggressive behavior.

Using 15 parameters, we provide a systematic description of mammal proximal femoral morphology. We established two types of proximal femoral morphology, termed coxa recta and coxa rotunda, characterized by low versus high concavity of the head-neck junction. Concavity is a measure of the sphericity of the femoral head as it meets the femoral neck that can be quantified by angular measurements. We asked whether the parameter of concavity corresponds with the classification of mammal proximal femoral morphology based on coalesced versus separate ossification patterns and locomotor patterns. Statistical analysis demonstrated a distinction between coxa recta and coxa rotunda with significant differences between the two groups in all but 3 of the 15 parameters examined. We found the most discriminating measurement between mammal hips to be the concavity of the posterior head-neck junction (beta angle). Coxa recta (small concavity) and coxa rotunda (large concavity) relate to the ossification pattern seen in proximal femoral development, and species-specific patterns of locomotion. We interpret the two hip types to reflect optimization for strength (recta) versus mobility (rotunda). Conceptually, both hip types can be recognized in humans, where coxa recta can be related to the development of osteoarthritis., (Copyright © 2012 Wiley Periodicals, Inc.)

Intensity-modulated radiation therapy (IMRT) is a powerful technique in planning the delivery of dose. The most common IMRT delivery requires the use of moving multileaf collimators (MLCs) to deliver the requested fluence pattern. A dynamic delivery IMRT field file will contain several control points that are defined MLC shapes at a marked fraction of the delivered monitor units. The size of this file and the fidelity of the deliverable fluence are proportional to the number of control points defined. This study investigates the effect of reducing the number of control points has on the resultant dose distribution quality in complex IMRT in efforts to reduce transfer times, loading times, check sum times and file storage. Analysis was performed with 6 head and neck patients on an Eclipse version 8.5 treatment planning system (Varian, Palo Alto, CA). To ensure the quality of all treatments, Eclipse defines a minimum of 64 and a maximum of 320 control points per subfield (Eclipse Algorithms Reference guide). All 6 patients' plans were calculated with fixed 64, 166, and 320 control points using the sliding window technique. In addition, each plan was calculated in variable mode (Normal mode) in which the planning system determined the required number of control points. Each of the 4 plans for each patient was renormalized to provide the same mean planning target volume (PTV) 70 dose. Dose values for critical and target structures were examined for each patient. When examining the minimum, maximum, and mean doses to all target structures, it was noted that the greatest reduction in target dose coverage caused by reduced number of control points was 0.5%, which occurred for the minimum dose to the PTV56 structure in one plan." Dose analysis for critical structures showed no clinically significant increase in dose when compared with the 320 control point plan., (Copyright © 2012 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Adverse and stressful experiences during adolescence are often of a social nature. The social defeat model in rats is used as an animal model for bullying in humans. Usually large individual differences in response to social defeat are found. The personality type that is mostly affected and the underlying mechanisms are unknown. We used male rats of the Roman selection lines to test whether social defeat (between postnatal days 45 and 57) followed by social isolation has a different impact in animals with divergent levels of emotional reactivity and coping style. The level of offensive aggression, impulsivity and performance during frustrating non-reward (extinction) were used as measures for the adult coping style of animals. Impulsivity was measured by performance on an unpredictable operant conditioning schedule (variable interval-15, VI-15) for food reinforcement. This study demonstrates that the adult, baseline level of impulsivity is higher in Roman high avoidance (RHA) rats. RHA rats showed a higher number of lever presses compared to Roman low avoidance (RLA) rats on a VI-15 schedule. The level of offensive aggression did not differ between the two lines. Surprisingly, a tendency towards more offensive aggression in RLA rats was found. Social stress during adolescence disturbed the normal development of adult personality, mostly in RHA rats. RHA rats that were defeated during adolescence reduced the number of lever presses on the VI-15 schedule of reinforcement and were more persistent during a session of frustrating non-reward. However, we did not find an effect of social defeat on performance during extinction. A tendency towards increased attack latencies after social defeat in adolescence was found. The time spent on offensive aggression was unaffected by social defeat., (Copyright © 2011 Elsevier Inc. All rights reserved.)