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Photographs depicting animals in the defensive burying test. ( A ) Some time after receiving a shock, animal begins spraying bedding toward the prod. ( B ) Typical of the F344, animal engages in extensive burying behavior such that bedding completely covers prod. ( C ) Unlike the F344, the WKY buries very little and after a series of prod approaches, remains immobile in a corner of the test chamber.
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Coping-or how one routinely deals with stress-is a complex behavioral trait with bearing on chronic disease and susceptibility to psychiatric disorders. This complexity is a result of not only underlying multigenic factors, but also important non-genetic ones. The defensive burying (DB) test, although originally developed as a test of anxiety, can...
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Context 1
... shocked, animals typically approach the prod a certain number of times [in a stretch-attend posture likely indicative of risk assessment (Rodgers 1997)], and at some point begin spraying bedding toward the prod (Fig. 1A), at times completely cov- ering the prod (Fig. 1B). Behaviors measured include latency to begin burying, duration of burying, the number of times an animal approaches the prod, and the number of times a rat gets shocked. Animals engaged in active coping will have a shorter latency to bury, a longer duration of burying, and fewer prod ...
Context 2
... shocked, animals typically approach the prod a certain number of times [in a stretch-attend posture likely indicative of risk assessment (Rodgers 1997)], and at some point begin spraying bedding toward the prod (Fig. 1A), at times completely cov- ering the prod (Fig. 1B). Behaviors measured include latency to begin burying, duration of burying, the number of times an animal approaches the prod, and the number of times a rat gets shocked. Animals engaged in active coping will have a shorter latency to bury, a longer duration of burying, and fewer prod approaches. Animals employing passive coping tend to ...
Context 3
... latency to bury, a longer duration of burying, and fewer prod approaches. Animals employing passive coping tend to approach the prod more frequently, while having a longer latency to bury and a shorter duration of burying. After a period of prod approaches, these passive copers will typically remain immobile in a corner of the test chamber (Fig. 1C). For further de- tails on the defensive burying test, see Neuroscience Protocols (Treit D ...
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Citations
... Quantitative genetic analyses were carried out as described [137,150,153]. Genome scans were carried out using sex and lineage and a sex-by-lineage interaction as additive covariates. ...
... Here we summarize only the significant QTL for all the phenotypes. The QTL analyses of the different traits and specific findings were reported in detail previously [34,36,137,146,[151][152][153]. What can be seen from the table above is that multiple traits across tests can map to the same locus. ...
... During our QTL study, we observed that WKYs show greater variation in the FST than F344 and even some outbred strains such as SD [152,153]. Based on this observation and that the WKYs may not have been completely inbred at distribution to breeders, we began their selective breeding based on immobility behavior in the FST [156]. The bidirectional selective breeding resulted in the WKY More Immobile (WMI) and the WKY Less Immobile (WLI) strains. ...
There is an ongoing debate about the value of animal research in psychiatry with valid lines of reasoning stating the limits of individual animal models compared to human psychiatric illnesses. Human depression is not a homogenous disorder; therefore, one cannot expect a single animal model to reflect depression heterogeneity. This limited review presents arguments that the Wistar Kyoto (WKY) rats show intrinsic depression traits. The phenotypes of WKY do not completely mirror those of human depression but clearly indicate characteristics that are common with it. WKYs present despair-like behavior, passive coping with stress, comorbid anxiety, and enhanced drug use compared to other routinely used inbred or outbred strains of rats. The commonly used tests identifying these phenotypes reflect exploratory, escape-oriented, and withdrawal-like behaviors. The WKYs consistently choose withdrawal or avoidance in novel environments and freezing behaviors in response to a challenge in these tests. The physiological response to a stressful environment is exaggerated in WKYs. Selective breeding generated two WKY substrains that are nearly isogenic but show clear behavioral differences, including that of depression-like behavior. WKY and its substrains may compare characteristics of subgroups of depressed individuals with social withdrawal, low energy, weight loss, sleep disturbances, and specific cognitive dysfunction. The genomes of the WKY and WKY substrains contain variations that impact the function of many genes identified in recent human genetic studies of depression. Thus, these strains of rats share characteristics of human depression at both phenotypic and genetic levels, making them a model of depression traits.
... We have studied the genetic components of behavioral responsiveness to acute stress in the reciprocally crossed F 2 generation of Wistar Kyoto (WKY) and Fischer 344 (F344) rat strains using the defensive burying (DB) and open field tests (OFT) [15][16][17][18][19]. The parental WKY strain consistently exhibits hypoactive and avoidant behavior compared to that of the F344 [19]. ...
... Defensive burying. Three weeks after the OFT, the defensive burying test was carried out on the same animals as previously described in the QTL studies [15,16,19]. Briefly, male rats of the three strains were habituated to a Plexiglas chamber (40 cm square, 60 cm high) with bedding (wood shaving) (7 cm deep, 1 cm below the hole for the prod) for 15 min each day, for three consecutive days, between 10:00 AM and 2:00 PM. ...
... To investigate the generalizability of the findings to a different acute stress phenotype, we measured the acute stress response differences between the two strains in the conditioning part (day 1) of the CFC (Fig 1). Similar to behaviors in the DB and OFT [15,16,19], WKY rats exhibited significantly more freezing in response to the stress of the footshock (t(30) = 4.066; P < 0.01), which is a clear indication of a more passive stress response (Fig 1A). Furthermore, WKYs also exhibited a significantly lower frequency of rearing (t(29) = 4.00; P < 0.01), which is an avoidance response [19,35]. ...
Acute stress responsiveness is a quantitative trait that varies in severity from one individual to another; however, the genetic component underlying the individual variation is largely unknown. Fischer 344 (F344) and Wistar Kyoto (WKY) rat strains show large differences in behavioral responsiveness to acute stress, such as freezing behavior in response to footshock during the conditioning phase of contextual fear conditioning (CFC). Quantitative trait loci (QTL) have been identified for behavioral responsiveness to acute stress in the defensive burying (DB) and open field test (OFT) from a reciprocal F2 cross of F344 and WKY rat strains. These included a significant QTL on chromosome 6 (Stresp10). Here, we hypothesized that the Stresp10 region harbors genes with sequence variation(s) that contribute to differences in multiple behavioral response phenotypes between the F344 and WKY rat strains. To test this hypothesis, first we identified differentially expressed genes within the Stresp10 QTL in the hippocampus, amygdala, and frontal cortex of F344 and WKY male rats using genome-wide microarray analyses. Genes with both expression differences and non-synonymous sequence variations in their coding regions were considered candidate quantitative trait genes (QTGs). As a proof-of-concept, the F344.WKY-Stresp10 congenic strain was generated with the Stresp10 WKY donor region into the F344 recipient strain. This congenic strain showed behavioral phenotypes similar to those of WKYs. Expression patterns of Gpatch11 (G-patch domain containing 11), Cdkl4 (Cyclin dependent kinase like 4), and Drc1 (Dynein regulatory complex subunit 1) paralleled that of WKY in the F344.WKY-Stresp10 strain matching the behavioral profiles of WKY as opposed to F344 parental strains. We propose that these genes are candidate QTGs for behavioral responsiveness to acute stress.
... Animals with high levels of immobility in the FST are said to exhibit high levels of despair. The WKY rat is a recognized animal model of depression, with high FST immobility (Armario et al. 1995;Lahmame & Armario 1996;Lopez-Rubalcava & Lucki 2000;Rittenhouse et al. 2002;Solberg et al. 2003;Solberg et al. 2004), altered sucrose preference (D'Souza & Sadananda 2016), increased response to stress (Courvoisier et al. 1996;Gilad & Shiller 1989;Solberg et al. 2006), altered sleep and circadian patterns (Dugovic et al. 2000;Solberg et al. 2001), and passive coping in multiple other tests including defensive burying (Pare 1989;Pare 1994;Ahmadiyeh et al. 2003). Because WKY rats demonstrate despair-like behavior at an early age, they are regarded as a model for juvenile depression (Malkesman & Weller 2009). ...
Major depressive disorder (MDD) is a complex illness caused by both genetic and environmental factors. Antidepressant resistance also has a genetic component. To date, however, very few genes have been identified for major depression or antidepressant resistance. In the current study, we investigated whether outbred heterogeneous stock (HS) rats would be a suitable model to uncover the genetics of depression and its connection to antidepressant resistance. The Wistar Kyoto (WKY) rat, one of the eight founders of the HS, is a recognized animal model of juvenile depression and is resistant to fluoxetine antidepressant treatment. We therefore hypothesized that adolescent HS rats would exhibit variation in both despair-like behavior and response to fluoxetine treatment. We assessed heritability of despair-like behavior and response to sub-acute fluoxetine using a modified forced swim test (FST) in four-week old HS rats. We also tested whether blood transcript levels previously identified as depression biomarkers in adolescent human subjects are differentially expressed in HS rats with high versus low FST immobility. We demonstrate heritability of despair-like behavior in four-week old HS rats and show that many HS rats are resistant to fluoxetine treatment. In addition, blood transcript levels of Amfr, Cdr2, and Kiaa1539, genes previously identified in human adolescents with MDD, are differentially expressed between HS rats with high vs low immobility. These data demonstrate that FST despair-like behavior will be amenable to genetic fine-mapping in adolescent HS rats. The overlap between human and HS blood biomarkers suggest that these studies may translate to depression in humans.
... sympathoexcitatory α2B-adrenergic receptors, leading to a hyperadrenergic hypertensive state (47). Earlier, the same region of Chr.X was characterized by three loci (Stresp1, Stresp2, Stresp3) for behavioral response to a stressful stimulus measured with the defensive burying test for stress response in F 2 (WKY Â F344) rats (48). So, the locus on Chr.X defined here as the locus for the elevation of BP, adrenal weight, and the elevation of corticosterone level in 3-to 4-month-old F 2 (ISIAH Â WAG) rats may contain genes, contributing to the regulation of BP through the stress-related modulation of the HPA axis. ...
The genetic basis of the stress-sensitive arterial hypertension was investigated using the quantitative trait loci (QTL) approach. Two groups of F(2) (inherited stress-induced arterial hypertension [ISIAH] × Wistar albino Glaxo [WAG]) hybrid males of different age (3-4 months old and 6 months old) were tested for blood pressure at rest and stressed conditions and for body composition traits. Several novel loci for the traits were determined. Some loci for blood pressure and organ weight were mapped to the same genetic region in rats of different age. The dynamic change of QTL effects in two rat groups of different age might reflect the process of stress-sensitive hypertension development.
... Prenatal thyroid function abnormalities can alter fetal brain development (Auso et al. 2004;Zoeller et al. 2004) leading to impairments in neuropsychological development and cognitive function of the adult offspring (Haddow et al. 1999;Obregon et al. 2007). The Wistar Kyoto (WKY) rat strain exhibits hypothyroidism and behavioral abnormalities including depressive behavior in the forced swim test (FST), and increased anxiety and passive coping in the defensive burying (DB) test (Ahmadiyeh et al. 2003;Ahmadiyeh et al. 2005;Ahmadiyeh et al. 2004;Baum et al. 2005;Nosek et al. 2008;Solberg et al. 2004). These physiological and behavioral phenotypes are determined by genetic and environmental influences, of which the genetic contribution has been explored extensively (Ahmadiyeh et al. 2003;Ahmadiyeh et al. 2005;Ahmadiyeh et al. 2004;Baum et al. 2005;Nosek et al. 2008;Solberg et al. 2004). ...
... The Wistar Kyoto (WKY) rat strain exhibits hypothyroidism and behavioral abnormalities including depressive behavior in the forced swim test (FST), and increased anxiety and passive coping in the defensive burying (DB) test (Ahmadiyeh et al. 2003;Ahmadiyeh et al. 2005;Ahmadiyeh et al. 2004;Baum et al. 2005;Nosek et al. 2008;Solberg et al. 2004). These physiological and behavioral phenotypes are determined by genetic and environmental influences, of which the genetic contribution has been explored extensively (Ahmadiyeh et al. 2003;Ahmadiyeh et al. 2005;Ahmadiyeh et al. 2004;Baum et al. 2005;Nosek et al. 2008;Solberg et al. 2004). In the current study we used the WKY to investigate the contribution of the hypothyroid milieu during prenatal development to adult behaviors. ...
A prenatal hypothyroid state is associated with behavioral abnormalities in adulthood. Wistar Kyoto (WKY) rats exhibit hypothyroidism and increased depressive and anxiety-like behaviors. Thus, the WKY could illuminate the mechanisms by which the reversal of developmental hypothyroidism in humans and animals results in adult behavioral improvement. We examined the outcome of maternal thyroxine (T4) treatment on thyroid hormone-regulated functions and adult behavior of the WKY offspring. Pregnant WKY dams completed gestation with and without T4 administration and their adult male offspring were tested. Measures included depressive and anxiety-like behaviors, and thyroid hormone (TH) concentrations in both plasma and specific brain regions. In addition, the expression of two proteins affecting thyroid hormone trafficking and metabolism, monocarboxylate transporter 8 (MCT-8) and iodothyronine deiodinase type III (Dio3), and of several behavior-altering molecules, glucocorticoid receptor (GR), prepro-thyrotropin releasing hormone (prepro-TRH) and corticotrophin releasing hormone (CRH), were determined in the hippocampus and amygdala of the offspring. Prenatal T4 treatment of WKYs did not affect adult depressive behavior but increased anxiety-like behavior and decreased plasma levels of THs. In the hippocampus of males treated with T4 in utero, Dio3 and MCT-8 protein levels were increased, while in the amygdala, there were increases of free T4, MCT-8, GR, prepro-TRH protein and CRH mRNA levels. These results show that T4 administration in utero programs adult peripheral and amygdalar thyroid hormone levels divergently, and that the resulting upregulation of anxiety-related genes in the amygdala could be responsible for the exacerbated anxiety-like behavior seen in WKYs after prenatal T4 treatment.
... Indeed, WKY rats exhibit increased and prolonged activation of the hypothalamic-pituitary-adrenal axis in response to swim stress (Rittenhouse et al. 2002) and acute immobilization following chronic cold stress (Pardon et al. 2003) compared to Sprague Dawley (SD) rats. A number of studies have identified potential neurobiological and genetic correlates associated with the behavioral phenotype of the WKY rat (Ahmadiyeh et al. 2003;De La Garza and Mahoney 2004;Jiao et al. 2003;Solberg et al. 2004), but the factors responsible for the increased stress sensitivity of the strain are still unknown. ...
Recent evidence suggests a role for the dynorphin/kappa-opioid receptor (KOR) system in the expression of stress-induced behaviors. Wistar Kyoto (WKY) rats exhibit increased depression-like and anxiety-like responses in behavioral tests compared to other strains and may be a model of comorbid depression and anxiety characterized by increased activity within the dynorphin/KOR system. Though KOR antagonists produce antidepressant-like effects in WKY rats, their effects in tests of anxiety-like behavior have not been examined in the WKY strain.
The aim of the current study was to investigate the effects of the KOR antagonist 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide hydrochloride (DIPPA) on the behavior of WKY rats and Sprague Dawley (SD) rats in tests of anxiety-like behavior.
The novelty-induced hypophagia and defensive burying tests were used to measure anxiety-like behavior in WKY and SD rats and determine the effects of DIPPA on anxiety-like behavior in both strains.
WKY rats displayed greater amounts of anxiety-like behavior compared to SD rats. DIPPA produced anxiolytic-like effects in both tests in both strains.
WKY rats display more anxiety-like behavior at baseline compared to SD rats, and DIPPA produced anxiolytic-like effects in both WKY and SD rats. These findings support previous research suggesting that KOR antagonists possess anxiolytic-like properties and may potentially represent a novel class of treatments for mood disorders.
... Given the potential utility of the WKY strain as a unique model of psychiatric dysfunction, the neurobiology of its phenotype could provide important understanding of the basis for depression or leads to novel targets for treatment. Quantitative trait loci and microarray analyses have been used to identify genes that are differentially expressed in WKY rats that could contribute to their behavioral phenotype (Ahmadiyeh et al, 2003(Ahmadiyeh et al, , 2005Solberg et al, 2004Solberg et al, , 2006Pearson et al, 2006). A key finding was the increased expression of the k-opioid receptor (KOR) in the locus coeruleus of WKY rats compared to Sprague-Dawley (SD) rats, a result confirmed by real-time PCR (Pearson et al, 2006). ...
The Wistar Kyoto (WKY) rat strain is a putative genetic model of comorbid depression and anxiety. Previous research showing increased kappa-opioid receptor (KOR) gene expression in the brains of WKY rats, combined with studies implicating the KOR in animal models of depression and anxiety, suggests that alterations in the KOR system could have a role in the WKY behavioral phenotype. Here, the effects of KOR antagonists in the forced swim test (FST) were compared with the WKY and the Sprague-Dawley (SD) rat strains. As previously reported, WKY rats showed more immobility behavior than SD rats. The KOR antagonists selectively produced antidepressant-like effects in the WKY rats. By contrast, the antidepressant desipramine reduced immobility in both strains. Brain regions potentially underlying the strain-specific effects of KOR antagonists in the FST were identified using c-fos expression as a marker of neuronal activity. The KOR antagonist nor-binaltorphimine produced differential effects on the number of c-fos-positive profiles in the piriform cortex and nucleus accumbens shell between SD and WKY rats. The piriform cortex and nucleus accumbens also contained higher levels of KOR protein and dynorphin A peptide, respectively, in the WKY strain. In addition, local administration of nor-binaltorphimine directly into the piriform cortex produced antidepressant-like effects in WKY rats further implicating this region in the antidepressant-like response to KOR antagonists. These results support the use of the WKY rat as a model of affective disorders potentially involving KOR overactivity and provide more evidence that KOR antagonists could potentially be used as novel antidepressants.
... Human moodincongruent psychotic features in bipolar disorder are linkage to 2p11-q14, which is syntenic to QTL region of SSC15 (Goes et al. 2007). Ahmadiyeh et al. (2003) mapped three QTL associated with coping behaviors to the X chromosome in rats. The region is also syntenic to the porcine QTL region in this study. ...
Maternal behavior around parturition is important to piglet survival. An extreme form of failure of maternal behavior, also called maternal infanticide, often occurs in some sows. This is defined as an active attack to piglets using the jaws, resulting in serious or fatal bite wounds within 24 h of birth. It leads to considerable economic losses to the pig industry and severe problems in pig welfare. In this study, maternal behaviors from 5 h before to 24 h after parturition were recorded in detail on 288 White Duroc x Erhualian intercross F(2) sows over their three continuous farrowings. In the F(2) population 12.8% gilts showed maternal infanticide in their first litter, while the incidences of maternal infanticide at their second and third farrowing reduced to 7.5% and 4.5%, respectively. All F(2) sows were genotyped for 194 microsatellite markers spanning the whole pig genome. A whole genome linkage analysis was performed using the non-parametric linkage test by SimWalk2 software. The results identified that seven chromosome regions on SSC2, SSC6, SSC14, SSC15 and SSCX were significantly linked with maternal infanticide (P < 0.05). The quantitative trait loci (QTL) on SSC2 and SSCX achieved P < 0.01 significance level. The most promising QTLs, however, were detected on X chromosome where three peaks of negative logarithm of P-value located at marker SW980, SW2456 and SW1608. QTLs on SSC2 and SSCX from this experiment were consistent with published results from the Western commercial lines.
... This decrease in activity was more pronounced in WKYs. These observations confirm the active coping style previously reported in F344s [31] and the passive coping style previously reported in WKYs303132. Repeated testing resulted in an increase in anxiety in both tests and for both strains. ...
... This decrease in activity was more pronounced in WKYs. These observations confirm the active coping style previously reported in F344s [31] and the passive coping style previously reported in WKYs303132. Repeated testing resulted in an increase in anxiety in both tests and for both strains. ...
This study posed the question whether strain differences in stress-reactivity lead to differential behavioral responses in two different tests of anxiety. Strain differences in anxiety-measures are known, but strain differences in the behavioral responses to acute prior stress are not well characterized.
We studied male Fisher 344 (F344) and Wistar Kyoto (WKY) rats basally and immediately after one hour restraint stress. To distinguish between the effects of novelty and prior stress, we also investigated behavior after repeated exposure to the test chamber. Two behavioral tests were explored; the elevated plus maze (EPM) and the open field (OFT), both of which are thought to measure activity, exploration and anxiety-like behaviors. Additionally, rearing, a voluntary behavior, and grooming, a relatively automatic, stress-responsive stereotyped behavior were measured in both tests.
Prior exposure to the test environment increased anxiety-related measures regardless of prior stress, reflecting context-dependent learning process in both tests and strains. Activity decreased in response to repeated testing in both tests and both strains, but prior stress decreased activity only in the OFT which was reversed by repeated testing. Prior stress decreased anxiety-related measures in the EPM, only in F344s, while in the OFT, stress led to increased freezing mainly in WKYs.
Data suggest that differences in stressfulness of these tests predict the behavior of the two strains of animals according to their stress-reactivity and coping style, but that repeated testing can overcome some of these differences.
... Human moodincongruent psychotic features in bipolar disorder are linkage to 2p11-q14, which is syntenic to QTL region of SSC15 (Goes et al. 2007). Ahmadiyeh et al. (2003) mapped three QTL associated with coping behaviors to the X chromosome in rats. The region is also syntenic to the porcine QTL region in this study. ...
Aggressive behaviour by newly farrowed sows towards their own offspring, known as savaging, occurs commonly in the domestic pig, with a significant impact upon both the agricultural economy and animal welfare. The aims of this study were to investigate the incidence and nature of this behaviour and to compare other behaviours between savaging and non-savaging sows around parturition in 226 F2 sows that were produced by two highly divergent pig breeds of Chinese Erhualian and western Duroc with significantly genetic difference on maternal behaviours and were raised at three different pig farms. Each of these sows was housed in individual 2m×2.5m pens with concrete floors. Three kilograms of fresh straw was provided to sows before parturition. Behaviour observations were made from 5h before parturition to 24h afterward using real time 1:0 sampling. Savaging sow was defined as an apparently deliberate attack on one or more piglets that resulted in the death, by biting, of at least one piglet. The incidence of savaging was: farm 1, 10.7% in gilts (n=103) and 5.3% at the second farrowing (n=94); farm 2, 14.6% (n=48) and 6.25% (n=16), respectively; farm 3, 6.8% (n=44) at the second farrowing and 3.2% (n=31) at the third farrowing. The incidence of savaging tended to be higher in gilts (P=0.058) although some savaging gilts were killed before their second litters. There was no effect of the different farms on incidence of savaging. Prepartum nest building behaviours were not a predictor for savaging, but savage sows had a greater frequency of posture change from before parturition through the expulsive phase. This restlessness included an increase in rearing behaviour and a reduced ability to lie down carefully without endangering piglets. We suggest that savaging is part of a more generalized behavioural pathology that includes increased excitability and is not specifically piglet directed.
