Ketamine promptly normalizes excess norepinephrine and enhances dopamine neuronal activity in Wistar Kyoto rats
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PROVIDER: S-EPMC10644068 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description: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 share 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.
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Project description:Activation of autonomic neural pathways by chronic hypertensive stimuli plays a significant role in pathogenesis of hypertension. Here, we proposed that even a single acute hypertensive stimulus will activate neural and immune pathways that may be important in initiation of memory imprinting seen in chronic hypertension. We investigated the effects of acute angiotensin II (Ang II) administration on blood pressure, neural activation in cardioregulatory brain regions, and central and systemic immune responses, at 1 and 24 h post-injection. Administration of a single bolus intra-peritoneal (I.P.) injection of Ang II (36 μg/kg) resulted in a transient increase in the mean arterial pressure (MAP) (by 22 ± 4 mmHg vs saline), which returned to baseline within 1 h. However, in contrast to MAP, neuronal activity, as measured by manganese-enhanced magnetic resonance (MEMRI), remained elevated in several cardioregulatory brain regions over 24 h. The increase was predominant in autonomic regions, such as the subfornical organ (SFO; ~20%), paraventricular nucleus of the hypothalamus (PVN; ~20%) and rostral ventrolateral medulla (RVLM; ~900%), among others. Similarly, systemic and central immune responses, as evidenced by circulating levels of CD4+/IL17+ T cells, and increased IL17 levels and activation of microglia in the PVN, respectively, remained elevated at 24 h following Ang II challenge. Elevated Fos expression in the PVN was also present at 24 h (by 73 ± 11%) following Ang II compared to control saline injections, confirming persistent activation of PVN. Thus, even a single Ang II hypertensive stimulus will initiate changes in neuronal and immune cells that play a role in the developing hypertensive phenotype.
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Project description: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".
| S-EPMC7296711 | biostudies-literature
Project description:Altered gastric accommodation and intestinal morphology suggest impaired gastrointestinal (GI) transit may occur in the Wistar-Kyoto (WKY) rat strain, as common in stress-associated functional GI disorders. Because changes in GI transit can alter microbiota composition, we investigated whether these are altered in WKY rats compared with the resilient Sprague-Dawley (SD) rats under basal conditions and characterized plasma lipid and metabolite differences. Bead transit was tracked by X-ray imaging to monitor gastric emptying (4 h), small intestine (SI) transit (9 h), and large intestine transit (12 h). Plasma extracts were analyzed by lipid and hydrophilic interaction liquid chromatography (HILIC) and liquid chromatography-mass spectrometry (LC-MS). Cecal microbial composition was determined by Illumina MiSeq 16S rRNA amplicon sequencing and analysis using the QIIME pipeline. Stomach retention of beads was 77% for WKY compared with 35% for SD rats. GI transit was decreased by 34% (9 h) and 21% (12 h) in WKY compared with SD rats. Excluding stomach retention, transiting beads moved 29% further along the SI over 4-9 h for WKY compared with SD rats. Cecal Ruminococcus, Roseburia, and unclassified Lachnospiraceae genera were less abundant in WKY rats, whereas the minor taxa Dorea, Turicibacter, and Lactobacillus were higher. Diglycerides, triglycerides, phosphatidyl-ethanolamines, and phosphatidylserine were lower in WKY rats, whereas cholesterol esters and taurocholic acids were higher. The unexpected WKY rat phenotype of delayed gastric emptying, yet rapid SI transit, was associated with altered lipid and metabolite profiles. The delayed gastric emptying of the WKY phenotype suggests this rat strain may be useful as a model for gastroparesis.NEW & NOTEWORTHY This study reveals that the stress-prone Wistar-Kyoto rat strain has a baseline physiology of gastroparesis and rapid small intestine transit, together with metabolic changes consistent with lipid metabolism-associated dysbiosis, compared with nonstress-prone rats. This suggests that the Wistar-Kyoto rat strain may be an appropriate animal model for gastroparesis.
| S-EPMC5538835 | biostudies-literature
Project description:Acute acrolein inhalation in male rats resulted in multi-tissue transcriptomic alterations that were observed through Illumina mRNA sequencing. Specifically, site-specific respiratory expression profile differences were noted between air- and acrolein-exposed groups. Nasal epithelial tissue demonstrated 452 differentially expressed genes (DEGs) (310 up-regulated and 142 down-regulated)and lung tissue demonstrated 95 DEGs (80 up-regulated and 15 down-regulated). Notable transcriptomic alterations were also observed in liver tissue of acrolein-exposed rats, with 1699 identified DEGs (788 up-regulated and 911 down-regulated). A variety of mRNA expression profile differences resulting from acute acrolein inhalation was observed in other peripheral tissues, including adipose, muscle, adrenals, hippocamus, and hypothalamus. Gene changes were largely representative of oxidative and inflammatory response in the nose, as well as xenobiotic metabolism changes in the lung. Liver changes, which were most numerous, included alterated metabolic signaling (Sirtuin and FXR signaling), as well as alterated oxidoreductive, GPCR, and glucocorticoid pathways. Together, these data demonstrate acrolein, a well-characterized respiratory irritant, induces systemic neuroendocrine immunological and metabolic stress.
2023-11-16 | GSE247698 | GEO
Project description:MBD-seq in stressreactive Wistar Kyoto rats exposed to neonatal maternal separation
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Project description:Wistar Kyoto rat stellate ganglia transcriptome
| PRJNA505849 | ENA
Project description:Mounting evidence supports the rapid antidepressant efficacy of the N-methyl-D-aspartate receptor antagonist, ketamine, for treating major depressive disorder (MDD); however, its neural mechanism of action remains poorly understood. Subgenual anterior cingulate cortex (sgACC) hyper-activity during rest has been consistently implicated in the pathophysiology of MDD, potentially driven in part by excessive hippocampal gluatmatergic efferents to sgACC. Reduction of sgACC activity has been associated with successful antidepressant treatment. This study aimed to examine whether task-based sgACC activity was higher in patients with MDD compared to controls and to determine whether this activity was altered by single-dose ketamine. In Study 1, patients with MDD (N = 28) and healthy controls (N = 20) completed task-based functional magnetic resonance imaging using an established incentive-processing task. In Study 2, a second cohort of patients with MDD (N = 14) completed the same scanning protocol at baseline and following a 40 min infusion of ketamine (0.5 mg/kg). Task-based activation of sgACC was examined with a seed-driven analysis assessing group differences and changes from pre to post treatment. Patients with MDD showed higher sgACC activation to positive and negative monetary incentives compared to controls, associated with anhedonia and anxiety, respectively. In addition, patients with MDD had higher resting-state functional connectivity between hippocampus and sgACC, associated with sgACC hyper-activation to positive incentives, but not negative incentives. Finally, ketamine reduced sgACC hyper-activation to positive incentives, but not negative incentives. These findings suggest a neural mechanism by which ketamine exerts its antidepressant efficacy, via rapid blunting of aberrant sgACC hyper-reactivity to positive incentives.
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Project description:The stellate ganglia are the predominant source of sympathetic innervation to the heart. Remodeling of sympathetic nerves projecting to the heart has been observed in several cardiovascular diseases, and sympathetic dysfunction contributes to cardiac pathology. Wistar Kyoto rats are a common model for the study of cardiovascular diseases, but we lack a profile of the baseline transcriptomic and neurochemical characteristics of their cardiac sympathetic neurons. Most studies of cardiovascular disease have used male animals only, but in the future both male and female animals will be used for these types of studies; therefore, we sought to characterize the transcriptome of male and female stellate ganglia and to correlate that with catecholamine and acetylcholine content in the heart. We have generated a dataset of baseline RNA expression in male and female Wistar Kyoto rat stellate ganglia using RNA-seq, and have measured neurotransmitter levels in heart and stellate ganglia using HPLC and mass spectrometry. We identified numerous gene expression differences between male and female stellates, including genes encoding important developmental factors, receptors and neuropeptides. Female hearts had significantly higher neurotransmitter content than male hearts; however, no significant differences were detected in expression of the genes encoding neurotransmitter synthetic enzymes. Similarly, no statistically significant differences were identified between the sexes in cardiac tyrosine hydroxylase levels.
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Project description: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 microg/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 x 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 TSH receptor and type 2 deiodinase genes, and TSH-2 contains the type 1 deiodinase gene. The WKY alleles of each gene contain sequence alterations, but additional studies are indicated to identify the specific gene or genes responsible for altered regulation of the thyroid axis. These findings suggest that one or more genetic alterations within the TSH-1 locus significantly contribute to the altered thyroid function tests of the WKY rat.
| S-EPMC3764449 | biostudies-literature