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John F Cryan - One of the best experts on this subject based on the ideXlab platform.
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differential visceral nociceptive behavioural and neurochemical responses to an immune challenge in the stress sensitive Wistar Kyoto Rat strain
Behavioural Brain Research, 2013Co-Authors: Siobhain M O Mahony, Timothy G Dinan, Gerard Clarke, Declan P Mckernan, Javier A Bravo, John F CryanAbstract:A highly regulated crosstalk exists between the immune and neuroendocrine systems with the altered immune responses in stress-related disorders being a valid example of this interaction. The Wister Kyoto (WKY) Rat is an animal model with a genetic predisposition towards an exaggeRated stress response and is used to study disorders such as depression and irritable bowel syndrome (IBS), where stress plays a substantial role. The impact of a lipopolysaccride (LPS) immune challenge has not yet been investigated in this animal model to date. Hence our aim was to assess if the stress susceptible genetic background of the WKY Rat was associated with a differential response to an acute immune challenge. Central and peripheral parameters previously shown to be altered by LPS administRation were assessed. Under baseline conditions, WKY Rats displayed visceral hypersensitivity compared to Sprague Dawley (SD) control Rats. However, only SD Rats showed an increase in visceral sensitivity following endotoxin administRation. The peripheral immune response to the LPS was similar in both strains whilst the central neurochemistry was blunted in the WKY Rats. Sickness behaviour was also abrogated in the WKY Rats. Taken together, these data indicate that the genetic background of the WKY Rat mitigates the response to infection centrally, but not peripherally. This implies that heightened stress-susceptibility in vulnerable populations may compromise the coordinated CNS response to peripheral immune activation.
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interleukin 6 modulates colonic transepithelial ion transport in the stress sensitive Wistar Kyoto Rat
Frontiers in Pharmacology, 2012Co-Authors: Dervla Omalley, Timothy G Dinan, John F CryanAbstract:Immunological challenge stimulates secretion of the pro-inflammatory cytokine interleukin (IL)-6, resulting in variety of biological responses. In the gastrointestinal (GI) tract, IL-6 modulates the excitability of sub-mucosal neurons and stimulates secretion into the colonic lumen. When considered in the context of the functional bowel disorder, irritable bowel syndrome (IBS), where plasma levels of IL-6 are elevated, this may reflect an important molecular mechanism contributing to symptom flares, particularly in the diarrhoea-predominant phenotype. In these studies, colonic ion transport, an indicator of absorption and secretion, was assessed in the stress-sensitive Wistar Kyoto (WKY) Rat model of IBS. Mucosa-submucosal colonic prepaRations from WKY and control Sprague Dawley (SD) Rats were mounted in Ussing chambers and the basal short circuit current (ISC) was electrophysiologically recorded and compared between the strains. Exposure to IL-6 (1nM) stimulated a secretory current of greater amplitude in WKY as compared to SD samples. Furthermore, the observed IL-6-mediated potentiation of secretory currents evoked by veRatridine and capsaicin in SD Rats was blunted in WKY Rats. Exposure to IL-6 also stimulated an increase in trans-epithelial resistance in both SD and WKY colonic tissue. These studies demonstRate that the neuroexcitatory effects of IL-6 on submucosal plexi have functional consequences with alteRations in both colonic secretory activity and permeability. The IL-6-induced increase in colonic secretory activity appears to neurally-mediated. Thus, local increases in IL-6 levels and subsequent activation of enteric neurons may underlie alteRations in absorpto-secretory function in the WKY model of IBS.
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differential stress induced alteRations of colonic corticotropin releasing factor receptors in the Wistar Kyoto Rat
Neurogastroenterology and Motility, 2010Co-Authors: Dervla Omalley, Timothy G Dinan, Marcela Juliopieper, Sinead M Gibney, Romaindaniel Gosselin, John F CryanAbstract:Background A growing body of data implicates increased life stresses with the initiation, persistence and severity of symptoms associated with functional gut disorders such as irritable bowel syndrome (IBS). Activation of central and peripheral corticotropin-releasing factor (CRF) receptors is key to stress-induced changes in gastrointestinal (GI) function. Methods This study utilised immunofluorescent and Western blotting techniques to investigate colonic expression of CRF receptors in stress-sensitive Wistar Kyoto (WKY) and control Sprague Dawley (SD) Rats. Key Results No intra-strain differences were observed in the numbers of colonic CRFR1 and CRFR2 positive cells. Protein expression of functional CRFR1 was found to be comparable in control proximal and distal colon samples. Sham levels of CRFR1 were also similar in the proximal colon but significantly higher in WKY distal colons (SD: 0.38 ± 0.14, WKY: 2.06 ± 0.52, P < 0.01). Control levels of functional CRFR2 were similar between strains but sham WKYs samples had increased CRFR2 in both the proximal (SD: 0.88 ± 0.21, WKY: 1.8 ± 0.18, P < 0.001) and distal (SD: 0.18 ± 0.08, WKY: 0.94 ± 0.32, P < 0.05) regions. Exposure to open field (OF) and colorectal distension (CRD) stressors induced decreased protein expression of CRFR1 in SD proximal colons, an effect that was blunted in WKYs. CRD stimulated decreased expression of CRFR2 in WKY Rats alone. Distally, CRFR1 is decreased in WKY Rats following CRD but not OF stress without any apparent changes in SD Rats. Conclusions & Inferences This study demonstRates that psychological and physical stressors alter colonic CRF receptor expression and further support a role for local colonic CRF signalling in stress-induced changes in GI function.
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colorectal distension induced prefrontal cortex activation in the Wistar Kyoto Rat implications for irritable bowel syndrome
Neuroscience, 2010Co-Authors: Sinead M Gibney, Timothy G Dinan, Romaindaniel Gosselin, John F CryanAbstract:The prefrontal cortex plays a key role in the perception of painful stimuli, including those emerging from the viscera. Colorectal distension is a non-invasive stimulus used to study visceral pain processing in the nervous system. Visceral hypersensitivity is one of the main characteristics of the functional bowel disorder irritable bowel syndrome (IBS). Moreover, recent human neuroimaging studies have emphasized the importance of altered brain activity and circuitry in the manifestation of IBS symptom severity and reaction to visceral stimuli. It is unclear whether animal models of visceral hypersensitivity display a similar response. Therefore, in the present study, we have used c-Fos protein immunoreactivity as an indicator of cell activation, to compare the response of the viscerally hypersensitive Wistar-Kyoto (WKY) Rat and control Sprague-Dawley (SD) Rat strains to colorectal distension (CRD), a noxious visceral stimulus. Several corticolimbic structures were analysed including the prelimbic cortex, infralimbic cortex and the rostral and caudal anterior cingulate cortices. Moreover, visceral hypersensitivity was also assessed behaviourally in both strains. As previously described WKY Rats had a lower pain threshold than SD controls in response to CRD. In all brain regions analysed, exposure to CRD induced an increase in c-Fos activation in both the WKY and SD Rats. However, an exaggeRated cell activation was found in the prelimbic, infralimbic and rostral anterior cingulate cortices of the WKY Rat compared to SD animals. No significant difference was found in caudal anterior cingulate cortex activation when the strains were compared. These results demonstRate, to our knowledge, for the first time an augmented colorectal distension-induced prefrontal cortex activity in WKY Rats similar to that seen in IBS patients, further supporting the use of this strain as a model in which to study brain-gut axis dysregulation observed in IBS.
Eva E Redei - One of the best experts on this subject based on the ideXlab platform.
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Quantitative Trait Loci Associated with Elevated Thyroid-Stimulating Hormone in the Wistar-Kyoto Rat
2015Co-Authors: Amber E. Baum, Leah C Solberg, Nasim Ahmadiyeh, Gary Churchill, Joseph S. Takahashi, Larry J. Jameson, Eva E RedeiAbstract:Thyroid hormones are essential for the regulation of devel-opmental and physiological processes. The genetic factors un-derlying naturally occurring variability in mammalian thy-roid functionare, however, onlypartiallyunderstood.Genetic control of thyroid function can be studiedwith animalmodels such as the inbred Wistar-Kyoto (WKY) Rat strain. Previous studies established that WKY Rats have elevated TSH, slightly elevated total T3, and normal total T4 levels compared with Wistar controls. Thepresent studyconfirmedapersistent 24-h elevation of TSH in WKY Rats compared with the Fisher 344 (F344) Rat, another inbred strain. Acute T3 challenge (25 g/ 100 g body weight ip) suppressed serum TSH and T4 levels in both strains. Quantitative trait locus analysis of elevated TSH in a reciprocally bred WKY F344 F2 population identified one highly significant locus on chromosome 6 (LOD 11.7
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nuclear orphan receptor nor 1 contributes to depressive behavior in the Wistar Kyoto Rat model of depression
Brain Research, 2010Co-Authors: Daniel J Schaffer, Elif Tuncozcan, Pradeep Kumar Shukla, Andreja Volenec, Eva E RedeiAbstract:The current study explored the effects of prolonged antidepressant treatment on mRNA levels of two nuclear receptors in specific brain regions of an animal model of depression, the Wistar-Kyoto (WKY) Rat. Both nuclear receptors have been implicated in the development or treatment of depression. The expression of nuclear orphan receptor-1 (Nor-1), a member of the NR4A nuclear orphan receptor family, is induced by electroconvulsive shock, an effective treatment for depression. Deficit in the levels or function of the glucocorticoid receptor (GR) found in depressed patients has been causally implicated in depression, as this deficit is normalized by antidepressant treatments. Baseline levels of amygdalar Nor-1 and GR mRNA were higher in the WKYs compared to the comparison control Sprague-Dawley Rats (SD). Prolonged treatment with the antidepressant desipramine (DMI) decreased the expression of both transcripts in the WKY strain concomitantly with decreased immobility in the forced swim test (FST) of depressive behavior. Using short hairpin RNA (shRNA) targeted against Nor-1, we investigated the direct contribution of elevated Nor-1 expression in the amygdala of WKY to their exaggeRated depressive behavior in the FST. After validating the shRNA targeting of Nor-1 in vitro, Nor-1 shRNA containing vector was infused intracerebroventricularly, using a linear polyethylenimine (PEI)-containing in vivo gene delivery system. Repeated administRation of Nor-1 shRNA amelioRated the depressive behavior of WKYs in the FST and decreased amygdalar Nor-1 mRNA levels without affecting GR mRNA levels. These data demonstRate that brain region-specific changes in GR expression in response to DMI are strain dependent and that elevated amygdalar Nor-1 expression can contribute to depressive behavior in the WKY model of depression.
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quantitative trait loci associated with elevated thyroid stimulating hormone in the Wistar Kyoto Rat
Endocrinology, 2005Co-Authors: Amber E. Baum, Leah C Solberg, Nasim Ahmadiyeh, Joseph S. Takahashi, Larry J. Jameson, Peter Kopp, Gary A Churchill, Eva E RedeiAbstract:Thyroid hormones are essential for the regulation of developmental and physiological processes. The genetic factors underlying naturally occurring variability in mammalian thyroid function are, however, only partially understood. Genetic control of thyroid function can be studied with animal models such as the inbred Wistar-Kyoto (WKY) Rat strain. Previous studies established that WKY Rats have elevated TSH, slightly elevated total T3, and normal total T4 levels compared with Wistar controls. The present study confirmed a persistent 24-h elevation of TSH in WKY Rats compared with the Fisher 344 (F344) Rat, another inbred strain. Acute T3 challenge (25 μg/100 g body weight ip) suppressed serum TSH and T4 levels in both strains. Quantitative trait locus analysis of elevated TSH in a reciprocally bred WKY × F344 F2 population identified one highly significant locus on chromosome 6 (LOD = 11.7, TSH-1) and one suggestive locus on chromosome 5 (LOD = 2.3, TSH-2). The confidence interval of TSH-1 contains the TS...
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paradoxical hormonal and behavioral responses to hypothyroid and hyperthyroid states in the Wistar Kyoto Rat
Neuropsychopharmacology, 2001Co-Authors: Eva E Redei, Leah C Solberg, Joseph M Kluczynski, William P PareAbstract:Wistar–Kyoto (WKY) Rats show endogenous depressive behavior that can be reversed by antidepressants. Given that WKYs exhibit decreased sensitivity to some antidepressants and treatment-resistant depressed patients often show hypothalamic-pituitary-thyroid (HPT) dysregulation, we examined the behavioral and HPT hormonal responses of WKYs to altered thyroid status. “Euthyroid” WKYs had elevated basal plasma TSH and T3 levels as compared to Wistars. Hypothyroidism increased TSH levels more in WKYs than in Wistars and increased response latency in the open field test (OFT) of WKYs only. AdministRation of T4 and T3 suppressed plasma TSH equally in both strains. Wistars responded to increased T3 levels with decreased response latency and increased activity in the OFT, but increased immobility in the forced swim test. In contrast, WKYs responded only to the high T3 levels with decreased response latency in the OFT. These results suggest the existence of a decreased central nervous system sensitivity to thyroid hormones in WKYs that could be related to their depressive behavior.
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sleep in the Wistar Kyoto Rat a putative genetic animal model for depression
Neuroreport, 2000Co-Authors: Christine Dugovic, Leah C Solberg, Eva E Redei, Olivier Van Reeth, Fred W TurekAbstract:The Wistar-Kyoto (WKY) Rat exhibits several behavioral and hormonal abnormalities often associated with depression. One of the hallmarks of depression consists of alteRations in the sleep-wake cycle, particularly in rapid eye movement (REM) sleep. If the WKY Rat is indeed an animal model for depression, we hypothesized that it should also show sleep abnormalities relative to the control strain, the Wistar (WIS) Rat Under baseline conditions, WKY Rats showed a 50% increase in total REM sleep time during the 12 h light phase and an increase in sleep fragmentation during both the light and dark phase. The WKY Rats also exhibited lower EEG power densities over the entire frequency range (0.2-25.0 Hz) during REM sleep. After a 6 h sleep deprivation, the REM sleep rebound was more pronounced during the dark but not the light phase in the WKY Rats. Since the WKY Rat represents a genetic model for depression with altered EEG sleep patterns, this strain may be particularly useful for investigating the relationship between depression and sleep abnormalities.
Shanaz Tejanibutt - One of the best experts on this subject based on the ideXlab platform.
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n methyl d aspartic acid receptors are altered by stress and alcohol in Wistar Kyoto Rat brain
Neuroscience, 2010Co-Authors: Yanlin Lei, Shanaz TejanibuttAbstract:Previous studies have shown that the Wistar-Kyoto (WKY) Rat strain is more sensitive to stressors and consumes significant quantities of alcohol under basal as well as stressful conditions when compared to other strains. Given that the glutamate neurotransmitter system has been implicated in depression and addiction, the goals of the present study were to investigate the effects of stress and stress-alcohol interactions on N-methyl-d-aspartate (NMDA) receptors in the Rat brain. Thus this study measured the binding of [(3)H] MK-801 to NMDA receptors in the prefrontal cortex (PFC), caudate putamen (CPu), nucleus accumbens (NAc), hippocampus (HIP) and basolateral amygdala (BLA) in WKY Rats in comparison to the Wistar (WIS) Rat strain. Our results suggested that while voluntary alcohol consumption did not alter NMDA receptors in the PFC, CPu or NAc in either Rat strain, it increased NMDA receptors in the HIP and BLA in both strains. In contrast, chronic stress increased NMDA receptors in the PFC, CPu, NAc in WKY Rats but not in WIS Rats. Chronic stress also decreased NMDA receptors in the HIP and increased NMDA receptors in the BLA in both strains. Alcohol co-treatment with stress increased NMDA receptors in the PFC, CPu and NAc in WKY Rats but not in WIS Rats. Interestingly, while alcohol co-treatment did not reverse stress induced decreases in NMDA receptors in the HIP, it reduced the binding of NMDA receptors in the BLA to control levels in both strains. Thus it appears that NMDA receptors in the PFC, CPu and NAc may be more sensitive to the effects of stress and could be implicated in the stress-induced alcohol consumption behavior seen in WKY Rats. In contrast, NMDA receptors in the HIP and BLA may reflect an adaptive response and may not be responsible for the stress susceptible phenotype of the WKY Rat strain.
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voluntary alcohol consumption alters stress induced changes in dopamine 2 receptor binding in Wistar Kyoto Rat brain
Pharmacology Biochemistry and Behavior, 2010Co-Authors: Irene Yaroslavsky, Shanaz TejanibuttAbstract:Abstract The Wistar–Kyoto (WKY) Rat has been proposed as an animal model of depressive behavior and exhibits hyper-responsiveness to stressful stimulation when compared to other Rat strains. We have demonstRated that WKY Rats consume 200% more alcohol under naive conditions as compared to their outbred counterparts, Wistar (WIS) Rats. The present study was designed to understand the influence of stress and alcohol consumption on central dopamine type-2 (D2) receptor sites in these two behaviorally distinct Rat strains. The first part of this study examined the effects of chronic stress on alcohol consumption, while the second part examined the binding of [125I]-Iodosulpiride to D2 receptors in control, stressed or stress and alcohol co-treated WKY compared to WIS Rats. Exposure to chronic stress led to an increase in the amount of alcohol consumed by both Rat strains, with WKY Rats consuming significantly more alcohol than WIS Rats with or without stress exposure. Quantitative autoradiography experiments showed that chronic stress increased D2 receptor binding in the caudate putamen (CPu), nucleus accumbens (NAc), substantia nigra (SN) and ventral tegmental area (VTA) of WKY Rats, and reduced receptor binding in the CPu and SN of WIS Rats. Compared to the stressed animals, WKY Rats co-treated with stress and alcohol demonstRated a reduction in D2 receptor sites in the cell body regions (SN and VTA), while WIS Rats showed no changes in receptor binding. The observed changes in D2 receptor sites may indicate altered DA neurotransmission following stress and alcohol exposure. Since stressed WKY Rats consumed more alcohol, it is possible that consumption of alcohol reverses the stress-induced D2 receptor alteRations in the cell body regions, suggestive of a self medicating phenotype.
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alcohol consumption alters dopamine transporter sites in Wistar Kyoto Rat brain
Brain Research, 2006Co-Authors: Xilu Jiao, W P Pare, Shanaz TejanibuttAbstract:Abstract Even though animal and human studies show alteRations in dopamine transporter (DAT) sites after alcohol withdrawal, the role of DAT in influencing either alcoholic or depressive behavior has not been examined extensively. Given that the Wistar–Kyoto (WKY) Rat is a putative animal model of depressive behavior, the present study examined the effects of chronic alcohol consumption on DAT sites in WKY versus Wistar (WIS) Rats. Brains from both strains were sectioned for autoradiographic analysis of [3H]-GBR12935 binding to DAT sites after 24 days of alcohol exposure. The results indicated that WKY Rats consumed a greater amount of alcohol (P
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antidepressant drug induced alteRations in binding to central dopamine transporter sites in the Wistar Kyoto Rat strain
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2006Co-Authors: Xilu Jiao, William P Pare, Shanaz TejanibuttAbstract:The Wistar Kyoto (WKY) Rat has been proposed as an animal model of depressive behavior. Exposing WKY Rats to stress stimulation produces symptoms such as anhedonia, psychomotor retardation, ambivalence and negative memory bias. Given the role of the mesolimbic dopamine (DA) system in cognitive, emotional and motivational behaviors, we previously examined the distribution of DA transporter (DAT) sites in the brains of WKY compared to Wistar (WIS) and Sprague-Dawley (S-D) Rats. WKY Rats exhibited significant differences in DAT binding sites in the cell body as well as mesolimbic areas compared to the other strains. It was reasoned that these differences may lead to altered synaptic levels of DA in specific brain regions thus contributing to the behavioral differences observed in this Rat strain. Thus, the present study examined whether repeated treatment with antidepressant drugs that block the uptake of DA (nomifensine and bupropion) would modify [3H]-GBR12935 binding to DAT sites in WKY Rats compared to WIS and S-D Rats. The results indicate that while nomifensine and bupropion increased the binding of [3H]-GBR12935 to DAT sites in the mesocorticolimbic regions in WKY Rats, these drugs increased the binding of [3H]-GBR12935 to DAT sites in the cell body areas in WIS Rats but not in S-D and WKY Rats. The data from this study suggest that antidepressant induced alteRations in DAT sites in the mesocorticolimbic brain regions may play a role in the behavioral improvement seen in WKY Rats, as measured by the Open Field Test (OFT) and the Porsolt Forced Swim Test (FST).
Monika Sadananda - One of the best experts on this subject based on the ideXlab platform.
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estrous cycle phase dependent changes in anxiety and depression like profiles in the late adolescent Wistar Kyoto Rat
Annals of Neurosciences, 2017Co-Authors: Deepthi Dsouza, Monika SadanandaAbstract:BACKGROUND Depression often manifests during adolescence when the development and networking of social and emotional brain areas is being influenced by hormones. The Wistar Kyoto (WKY) Rat has been proposed as an animal model of adolescent depression with various face, construct, and predictive validities for clinical depression having been established. PURPOSE The influence of the estrous cycle on anxiety- and depression-like behaviors in female adolescents may be tested out further using this model. METHODS Female adolescent WKY Rats were tested for anxiety- and depression-like behaviors in the elevated plus maze and forced swim test (FST) during different phases of the estrous cycle with inbred, age-, and phase-matched Wistar Rats as controls. RESULTS Wistars in proestrus-estrus demonstRated reduced anxiety levels. WKY also demonstRated increased open arm time and entries and closed arm time, but less than Wistars, and as closed arm entries remained unaffected, it did not translate into a lowering of the anxiety levels. Risk taking and risk assessment behaviors were not affected by estrous phases in WKY, though exploRatory behavior was reduced in proestrus-estrus. In Wistars, increased risk taking and decreased risk assessment behaviors were observed during proestrus-estrus. Increased immobility in the FST, indicative of learned helplessness was not influenced by phase in the WKY, which was at variance with Wistars that demonstRated phase-specific differences. CONCLUSION Results indicate a masking effect of indicative hormones in this putative model of adolescent depression, with implications for an unravelling of the steroid milieu in predisposed adolescent depression and for taking phase-specific time windows into account for therapeutic interventions.
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immediate and delayed anxiety and depression like profiles in the adolescent Wistar Kyoto Rat model of endogenous depression following postweaning social isolation
Behavioural Brain Research, 2017Co-Authors: Reshma A Shetty, Monika SadanandaAbstract:In order to understand links that exist between inherited risk or predisposition, brain and behavioural development, endocrine regulation and social/environmental stimuli, animal models are crucial. The Wistar-Kyoto (WKY) Rat has been shown to have validity as a model of adult and adolescent depression. While sex- and age-specific differences in some of the face, predictive and construct validities of the model such as depression-like behaviours have been established, anhedonia and anxiety using other induced anxiety paradigms such as elevated plus maze remain equivocal. First, post-weaning social isolation effects on inherent and induced anxiety behaviours were tested during two critical time periods, early- and mid-adolescence. Isolation induced immediate effects on novel environment-induced hyperactivity and anxiety-related behaviours. Adolescent WKYs demonstRated reduced 50-kHz ultrasonic vocalizations suggesting agoraphobia-like behaviours. Second, isolated Rats, despite being subsequently social-/group-housed demonstRated longer lasting effects on social interaction measures and anhedonia. This establishes that the depression-like profile observed during early- and mid-adolescence persists into late adolescence and early adulthood in WKY. Further, that interventions at a later stage during adolescence may not be able to reverse early adolescent effects in the context of pre-disposition, thus highlighting the irreversibility of being double-hit during critical time periods of brain and behavioural development and matuRation.
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brief social isolation in the adolescent Wistar Kyoto Rat model of endogenous depression alters corticosterone and regional monoamine concentRations
Neurochemical Research, 2017Co-Authors: Reshma A Shetty, Monika SadanandaAbstract:The Wistar-Kyoto Rat (WKY) model has been suggested as a model of adult and adolescent depression though face, predictive and construct validities of the model to depression remain equivocal. The suitability of the WKY as a diathesis model that tests the double-hit hypothesis, particularly during critical periods of brain and behavioural development remains to be established. Here, effects of post-weaning social isolation were assessed during early adolescence (~30pnd) on behavioural despair and learned helplessness in the forced swim test (FST), plasma corticosterone levels and tissue monoamine concentRations in brain areas critically involved in depression, such as prefrontal cortex, nucleus accumbens, striatum and hippocampus. Significantly increased immobility in the FST was observed in socially-isolated, adolescent WKY with a concomitant increase in corticosterone levels over and above the FST-induced stress. WKY also demonstRated a significantly increased release and utilization of dopamine, as manifested by levels of metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid in nucleus accumbens, indicating that the large dopamine storage pool evident during adolescence induces greater dopamine release when stimulated. The serotonin metabolite 5-hydroxy-indoleacetic acid was also significantly increased in nucleus accumbens, indicating increased utilization of serotonin, along with norepinephrine levels which were also signficantly elevated in socially-isolated adolescent WKY. Differences in neurochemistry suggest that social or environmental stimuli during critical periods of brain and behavioural development can determine the developmental trajectories of implicated pathways.
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anxiety and depressive like profiles during early and mid adolescence in the female Wistar Kyoto Rat
International Journal of Developmental Neuroscience, 2017Co-Authors: Deepthi Dsouza, Monika SadanandaAbstract:Approaches for the development of preclinical models of depression extensively use adult and male animals owing to the discrepancies arising out of the hormonal flux in adult females and adolescents during attainment of puberty. Thus the increased vulnerability of females towards clinical depression and anxiety-related disorders remains incompletely understood. Development of clinical models of depression in adolescent females is essential in order to evolve effective treatment stRategies for adolescent depression. In the present study, we have examined the anxiety and depressive-like profiles in a putative animal model of childhood depression, the Wistar Kyoto (WKY) Rat, during early adolescence (∼postnatal day 30) and mid-adolescence (∼postnatal day 40). Female adolescent WKY Rats, tested on a series of behavioural tests modelling anxiety- and depressive-like behaviours with age-matched Wistars as controls, demonstRated marked differences during early adolescence in a strain- and age-specific manner. Anxiety indices were obtained from exposure to the elevated plus maze, where social communication vide 50-kHz ultrasonic vocalizations was also assessed, while immobility and other parameters in the forced swim test were screened for depressive-like profiles. Sucrose preference, used as a measure of anhedonia in animals, was lower in WKYs at both ages tested and decreased with age. Anxiety-related behaviours were prominent in WKY Rats only during early adolescence. WKY female Rats are anxious during early adolescence and exhibit anhedonia as a core symptom of depression during early- and mid-adolescence, thus indicating that inclusion of female animals in preclinical trials is essential and will contribute to gender-based approaches to diagnosis and treatment of adolescent depression in females.
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strain and context based 50 khz ultrasonic vocalizations and anxiety behaviour in the Wistar Kyoto Rat
Journal of Biosciences, 2015Co-Authors: Rashmi Madhava Rao, Monika SadanandaAbstract:Rodent ultrasonic vocalizations (USVs) are influenced by immediate, prior contexts and have emerged as important indicators that monitor an individual’s ‘state’. They also index direct reflections of inherent ‘trait’ and are suggested to constitute non-invasive read-outs of pathological conditions. Analysis of USVs emitted under particular contexts could help discern strain-specific differences and existence of individual USV profiles. USVs of the Wistar-Kyoto (WKY) strain, a putative model of depression, could indicate social communication deficits. In the cage, USV emission was significantly reduced in WKYs. An elevated plus maze exposure led to no change in USV emission in WKYs, while it significantly reduced USVs in Wistars. Re-exposure induced strain-specific differences in behaviour and total calling time. Sonographic patterns indicated that the predominant USV subtype were flat 50 kHz USVs. EPM exposure induced a reduction in peak amplitude in WKY USVs and in USV length in both strains. USV peak frequency and amplitude, genetically determined spectral features, were strain-specific, while bandwidth and temporal features such as total calling time and USV duRation were context-dependent. WKY USVs demonstRated characteristic spectral structures such as increased call length and reduced peak frequency while other parameters were not quantitatively different, reflecting the shared phylogeny between Wistars and WKYs.
Anthony G Phillips - One of the best experts on this subject based on the ideXlab platform.
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ketamine and its metabolite 2r 6r hnk restore hippocampal ltp and long term spatial memory in the Wistar Kyoto Rat model of depression
Molecular Brain, 2020Co-Authors: Lily R Aleksandrova, Yu Tian Wang, Anthony G PhillipsAbstract:Accumulating evidence implicates dysregulation of hippocampal synaptic plasticity in the pathophysiology of depression. However, the effects of ketamine on synaptic plasticity and their contribution to its mechanism of action as an antidepressant, are still unclear. We investigated ketamine’s effects on in vivo dorsal hippocampal (dHPC) synaptic plasticity and their role in mediating aspects of antidepressant activity in the Wistar-Kyoto (WKY) model of depression. dHPC long-term potentiation (LTP) was significantly impaired in WKY Rats compared to Wistar controls. Importantly, a single low dose (5 mg/kg, ip) of ketamine or its metabolite, (2R,6R)-HNK, rescued the LTP deficit in WKY Rats at 3.5 h but not 30 min following injection, with residual effects at 24 h, indicating a delayed, sustained facilitatory effect on dHPC synaptic plasticity. Consistent with the observed dHPC LTP deficit, WKY Rats exhibited impaired hippocampal-dependent long-term spatial memory as measured by the novel object location recognition test (NOLRT), which was effectively restored by pre-treatment with both ketamine or (2R,6R)-HNK. In contrast, in WKYs, which display abnormal stress coping, ketamine, but not (2R,6R)-HNK, had rapid and sustained effects in the forced swim test (FST), a commonly used preclinical screen for antidepressant-like activity. The differential effects of (2R,6R)-HNK observed here reveal a dissociation between drug effects on FST immobility and dHPC synaptic plasticity. Therefore, in the WKY Rat model, restoring dHPC LTP was not correlated with ketamine’s effects in FST, but importantly, may have contributed to the reversal of hippocampal-dependent cognitive deficits, which are critical features of clinical depression. Our findings support the theory that ketamine may reverse the stress-induced loss of connectivity in key neural circuits by engaging synaptic plasticity processes to “reset the system”.
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evaluation of the Wistar Kyoto Rat model of depression and the role of synaptic plasticity in depression and antidepressant response
Neuroscience & Biobehavioral Reviews, 2019Co-Authors: Lily R Aleksandrova, Yu Tian Wang, Anthony G PhillipsAbstract:Abstract In order to expand the prospects of developing novel antidepressants for treatment-resistant populations, animal models should incorpoRate not only various stress-induced behavioural, neurochemical and endocrine parallels to major depressive disorder (MDD), but also aspects of heightened stress susceptibility and resistance to conventional drugs. This review focuses on the available liteRature supporting the Wistar-Kyoto (WKY) Rat as a model of endogenous stress susceptibility and depression, and the role of synaptic plasticity in depression and antidepressant response in the context of this model. Accumulating evidence implicates a dysregulation of synaptic plasticity in the etiology of depression, leading to synaptic weakening and neuronal atrophy in vulnerable brain regions (hippocampus, prefrontal cortex). Furthermore, novel antidepressant treatments, particularly ketamine, may reverse the stress-induced loss of connectivity in these key neural circuits by engaging synaptic plasticity processes to “reset the system”. IncorpoRating synaptic plasticity into the current framework of antidepressant action may serve to bridge understanding of an antidepressant’s molecular and cellular effects with those related to regional structural plasticity and neural circuit functioning.
