Prepulse inhibition deficits in inbred and outbred rats and between-strain differences in startle habituation do not depend on startle reactivity levels.

The acoustic startle response and prepulse inhibition (PPI) of startle are measures related to information processing, which is impaired in schizophrenia. Some studies have provided inconclusive patterns of association between both measures in rodents. We assessed the influence of baseline startle response on PPI in large samples of Roman high-(RHA) and low-avoidance (RLA) rat strains and in genetically heterogeneous stock (HS) rats. Results show that RHAs exhibit a PPI deficit compared to RLA rats, which is present regardless of the startle response levels. HS rats were stratified in two sub-samples according to their high or low PPI (HS-highPPI or HS-lowPPI, respectively) scores, and then they were grouped by their differential baseline startle amplitude (high reactivity -HR- or low reactivity -LR-) within each sub-sample. Differences between high- and low-PPI-stratified HS rats remained regardless of their high or low startle amplitude scores. Thus, the impairments in %PPI found in both RHA and HS-LowPPI rats are present irrespective of the relatively high or low levels of startle amplitude in pulse-alone trials. Another objective of the present study was to evaluate whether habituation to the startling stimulus (i.e., pulse) depends on the initial baseline startle response. RLA rats habituated to the startling stimulus more effectively than RHAs regardless of their baseline startle responses. Conversely, there were no differences in startle habituation in the HS rats grouped by their extreme scores of baseline startle. Altogether, these findings suggest a deficit in information processing in RHA rats, which along with evidence indicating that this strain displays other attentional/cognitive impairments, strengthens the validity of the RHA strain as a putative model of schizophrenia-relevant features.

Establishing a Genetic Detection Protocol of Single Nucleotide Polymorphisms Panels in Inbred Rats Based on Multiplex PCR-LDR / 实验动物与比较医学

ObjectiveTo establish a set of single nucleotide polymorphisms (SNP) detection protocol for inbred rats based on multiplex PCR-ligase detection reaction (LDR). MethodsA total of 40 rats SNP sites were selected on chromosomes 1-20 and X of rats among 5 inbred strains of rats, and the 40 SNP sites were randomly divided into four groups. A genetic detection protocol for 4 groups of SNP in inbred rats based on multiplex PCR-LDR technology was constructed. 9 commonly used rat strains from two other domestic rat suppliers were detected by this protocol. Finally, the feasibility of this protocol was verified by comparing the amplification effects of different DNA polymerases by a third-party laboratory. ResultsWhen using the constructed SNP detection protocol for inbred rats to test 5 rat strains, all sites in each sample obtained good amplification results. The 9 commonly used rat strains from two other rat suppliers in china were also well amplified by this SNP detection protocol, and 40 SNPs were homozygous in each Inbred strain. The results of detection of the same rat DNA samples with three different DNA polymerases showed that the Multiplex PCR Kit, AmpliTaq Gold 360 DNA polymerase and Platinum II Taq hot start DNA polymerase had electrophoretic peaks of amplification products at all SNP sites in groups 1 to 3, and Platinum II Taq hot start DNA polymerase had one less electrophoretic peak of the amplification products at the SNP sites in group 4. In addition, inter-laboratory comparisons showed consistent results for the same amplification system. ConclusionBased on multiplex PCR-LDR technology, this study successfully established a SNP detection protocol for rats covering all autosomes and X chromosomes with the excellent stability and repeatability.

Identification of a nutrient-sensing transcriptional network in monocytes by using inbred rat models on a cafeteria diet.

Obesity has reached pandemic levels worldwide. The current models of diet-induced obesity in rodents use predominantly high-fat based diets that do not take into account the consumption of variety of highly palatable, energy-dense foods that are prevalent in Western society. We and others have shown that the cafeteria (CAF) diet is a robust and reproducible model of human metabolic syndrome with tissue inflammation in the rat. We have previously shown that inbred rat strains such as Wistar Kyoto (WKY) and Lewis (LEW) show different susceptibilities to CAF diets with distinct metabolic and morphometric profiles. Here, we show a difference in plasma MCP-1 levels and investigate the effect of the CAF diet on peripheral blood monocyte transcriptome, as powerful stress-sensing immune cells, in WKY and LEW rats. We found that 75.5% of the differentially expressed transcripts under the CAF diet were upregulated in WKY rats and were functionally related to the activation of the immune response. Using a gene co-expression network constructed from the genes differentially expressed between CAF diet-fed LEW and WKY rats, we identified acyl-CoA synthetase short-chain family member 2 (Acss2) as a hub gene for a nutrient-sensing cluster of transcripts in monocytes. The Acss2 genomic region is significantly enriched for previously established metabolism quantitative trait loci in the rat. Notably, monocyte expression levels of Acss2 significantly correlated with plasma glucose, triglyceride, leptin and non-esterified fatty acid (NEFA) levels as well as morphometric measurements such as body weight and the total fat following feeding with the CAF diet in the rat. These results show the importance of the genetic background in nutritional genomics and identify inbred rat strains as potential models for CAF-diet-induced obesity.

Leptin signal transduction underlies the differential metabolic response of LEW and WKY rats to cafeteria diet.

Although the effect of genetic background on obesity-related phenotypes is well established, the main objective of this study is to determine the phenotypic responses to cafeteria diet (CAF) of two genetically distinct inbred rat strains and give insight into the molecular mechanisms that might be underlying. Lewis (LEW) and Wistar-Kyoto (WKY) rats were fed with either a standard or a CAF diet. The effects of the diet and the strain in the body weight gain, food intake, respiratory quotient, biochemical parameters in plasma as well as in the expression of genes that regulate leptin signalling were determined. Whereas CAF diet promoted weight gain in LEW and WKY rats, as consequence of increased energy intake, metabolic management of this energy surplus was significantly affected by genetic background. LEW and WKY showed a different metabolic profile, LEW rats showed hyperglycaemia, hypertriglyceridemia and high FFA levels, ketogenesis, high adiposity index and inflammation, but WKY did not. Leptin signalling, and specifically the LepRb-mediated regulation of STAT3 activation and Socs3 gene expression in the hypothalamus were inversely modulated by the CAF diet in LEW (upregulated) and WKY rats (downregulated). In the present study, we show evidence of gene-environment interactions in obesity exerted by differential phenotypic responses to CAF diet between LEW and WKY rats. Specifically, we found the leptin-signalling pathway as a divergent point between the strain-specific adaptations to diet.

Increased renal epithelial na channel expression and activity correlate with elevation of blood pressure in spontaneously hypertensive rats.

Elevation of blood pressure with age is one of the hallmarks of hypertension in both males and females. This study examined transcriptomic profiles in the kidney of 12-, 40-, and 80-week-old spontaneously hypertensive rats and 4 recombinant inbred strains in search for functional genetic elements supporting temporal dynamics of blood pressure elevation. We found that both in males and females of spontaneously hypertensive rats and hypertensive recombinant inbred strains age-dependent blood pressure increment was accompanied by 50% heightened expression of epithelial sodium channel ß- and γ-subunits. Epithelial sodium channel subunit expression correlated positively with blood pressure but correlated negatively with renin expression. Increased epithelial sodium channel activity was observed in cultured epithelial cells isolated from the kidney medulla of 80-week-old spontaneously hypertensive rats but not in age-matched normotensive Wistar Kyoto. This difference remained evident after 24-hour treatment with aldosterone. 22Na uptake in the perfused kidney medulla was increased whereas the urinary Na/K ratio was decreased in old spontaneously hypertensive rats compared with normotensive controls. The difference was eliminated by the administration of epithelial sodium channel inhibitor benzamil. Observations in recombinant inbred strains representing various mixtures of parental hypertensive and normotensive genomes suggest that Scnn1g and Scnn1b genes themselves are not implicated in heightened expression and that the increased expression is neither secondary nor required for a partial elevation of blood pressure in contrast to spontaneously hypertensive rats. We suggest that spontaneously hypertensive rats display an intact negative feed-back between renin-angiotensin-system and epithelial Na channel activity whose upregulated expression is supported by a yet unknown mechanism.

Life or death? A physiogenomic approach to understand individual variation in responses to hemorrhagic shock.

Severe hemorrhage due to trauma is a major cause of death throughout the world. It has often been observed that some victims are able to withstand hemorrhage better than others. For decades investigators have attempted to identify physiological mechanisms that distinguish survivors from nonsurvivors for the purpose of providing more informed therapies. As an alternative approach to address this issue, we have initiated a research program to identify genes and genetic mechanisms that contribute to this phenotype of survival time after controlled hemorrhage. From physiogenomic studies using inbred rat strains, we have demonstrated that this phenotype is a heritable quantitative trait, and is therefore a complex trait regulated by multiple genes. Our work continues to identify quantitative trait loci as well as potential epigenetic mechanisms that might influence survival time after severe hemorrhage. Our ultimate goal is to improve survival to traumatic hemorrhage and attendant shock via regulation of genetic mechanisms and to provide knowledge that will lead to genetically-informed personalized treatments.