Multiple Rat Strains Research Articles

Sleep Deprivation-Induced Oxidative Stress in Rat Models: A Scoping Systematic Review.

Sleep deprivation is highly prevalent in the modern world, possibly reaching epidemic proportions. While multiple theories regarding the roles of sleep exist (inactivity, energy conservation, restoration, brain plasticity and antioxidant), multiple unknowns still remain regarding the proposed antioxidant roles of sleep. The existing experimental evidence is often contradicting, with studies pointing both toward and against the presence of oxidative stress after sleep deprivation. The main goals of this review were to analyze the existing experimental data regarding the relationship between sleep deprivation and oxidative stress, to attempt to further clarify multiple aspects surrounding this relationship and to identify current knowledge gaps. Systematic searches were conducted in three major online databases for experimental studies performed on rat models with oxidative stress measurements, published between 2015 and 2022. A total of 54 studies were included in the review. Most results seem to point to changes in oxidative stress parameters after sleep deprivation, further suggesting an antioxidant role of sleep. Alterations in these parameters were observed in both paradoxical and total sleep deprivation protocols and in multiple rat strains. Furthermore, the effects of sleep deprivation seem to extend beyond the central nervous system, affecting multiple other body sites in the periphery. Sleep recovery seems to be characterized by an increased variability, with the presence of both normalizations in some parameters and long-lasting changes after sleep deprivation. Surprisingly, most studies revealed the presence of a stress response following sleep deprivation. However, the origin and the impact of the stress response during sleep deprivation remain somewhat unclear. While a definitive exclusion of the influence of the sleep deprivation protocol on the stress response is not possible, the available data seem to suggest that the observed stress response may be determined by sleep deprivation itself as opposed to the experimental conditions. Due to this fact, the observed oxidative changes could be attributed directly to sleep deprivation.

Using liquid chromatography mass spectrometry (LC-MS) to assess the effect of age, high-fat diet, and rat strain on the liver metabolome.

The goal of this study was to use liquid chromatography mass spectrometry to assess metabolic changes of two different diets in three distinct rat strains. Sprague-Dawley, Fischer 344, and Brown-Norway male rats were maintained on a high-fat, or regular diet for 24 weeks. Liver tissue was collected at 4, 12, and 24 weeks to assess global small molecule metabolite changes using high resolution accurate mass spectrometry coupled to ultra-high-performance liquid chromatography. The results of the global metabolomics analysis revealed significant changes based on both age and diet within all three strains. Principal component analysis revealed that the influence of diet caused a greater variation in significantly changing metabolites than that of age for the Brown Norway and Fisher 344 strains, whereas diet had the greatest influence in the Sprague Dawley strain only at the 4-week time point. As expected, metabolites involved in lipid metabolism were changed in the animals maintained on a high fat diet compared to the regular diet. There were also significant changes observed in the concentration of Tri carboxylic acid cycle intermediates that were extracted from the liver of all three strains based on diet. The results of this study showed that a high fat diet caused significant liver and metabolic changes compared to a regular diet in multiple rat strains. The inbred Fisher 344 and Brown Norway rats were more metabolically sensitive to the diet changes than outbred Sprague Dawley strain. The study also showed that age, as was the case for Sprague Dawley, is an important variable to consider when assessing metabolic changes.

Recovery of sensorimotor function following sciatic nerve injury across multiple rat strains

BackgroundPeripheral nerve injury (PNI) can result in neurodegenerative changes leading to motor, sensory and autonomic dysfunction. Injury to the rat sciatic nerve is used to model pathophysiologic processes following PNI and assess the efficacy of therapeutic interventions. Frequently, temporal changes in the sciatic functional index (SFI), a measure of sensorimotor integration are measured in rats to assess functional recovery following sciatic nerve injury. However, multiple rat strains and behavioral endpoints have been employed to investigate pathophysiology of PNI and impact of therapeutic intervention on recovery, raising the possibility that rat strain may influence the outcome of such studies. New methodThe temporal course of recovery from sham, sciatic nerve crush or transection injury was assessed using SFI determined by two methods (footprint and DigiGait), and proprioceptive hind limb placement (a measure of proprioceptive integrity) of the sciatic nerve innervation, in male Sprague Dawley, Lewis, Fischer, Wistar and Long Evans rats. ResultsThe SFI profile, as assessed by both inked footprint analysis and DigiGait, following sciatic nerve injury was remarkably conserved across strains. Dramatic strain-related differences were observed in the latency to place the crush- or transection-injured hind limb following proprioceptive hind limb stimulation. Comparison with existing methodThe novelty of this study is the parallel comparison of multiple strains using existing and novel tests. ConclusionThese results suggest that some sensorimotor function tests may be sensitive to the choice of strain, as evidenced by the differences between SFI and proprioceptive function outcomes.

Autoantigen-Induced Focusing of Vβ13+ T Cells Precedes Onset of Autoimmune Diabetes in the LEW.1WR1 Rat

The earliest events leading to autoimmune type 1 diabetes (T1D) are not known in any species. A T-cell receptor (TCR)-variable region, TCR-Vβ13, is required for susceptibility to autoimmune diabetes in rats, and selective depletion of Vβ13+ T cells with an allele-specific monoclonal antibody prevents disease in multiple rat strains. To investigate the role of Vβ13 early in diabetes, we examined islet T-cell transcripts in susceptible (LEW.1WR1) and resistant (LEW.1W and Wistar Furth) strains induced with polyinosinic:polycytidylic acid. Vβ13+ T cells displayed antigenic focusing in LEW.1WR1 islets 5 days postinduction and were characterized by a substantial decrease in complementarity determining region 3 diversity. This occurred prior to significant islet T-cell accumulation (day 7) or frank diabetes (days 10–14). Vβ13+ transcripts increased in LEW.1WR1 islets during diabetes progression, but not in resistant rats. We also analyzed transcript clonality of rat TCR-Vα5, an ortholog of the dominant TCR-Vα chain found on insulin B:9-23–reactive T cells in nonobese diabetic rat islets. We observed clonal expansion of Vα5+ transcripts in prediabetic LEW.1WR1 islets, suggesting that rat Vα5 is also an important component of islet autoantigen recognition. These data provide additional evidence that genome-encoded TCR sequences are important determinants of genetic susceptibility to T1D.

Nociception and conditioned fear in rats: strains matter.

When using rats in pain research, strain-related differences in outcomes of tests for pain and nociception are acknowledged. However, very little is known about the specific characteristics of these strain differences. In this study four phylogenetically distant inbred rat strains, i.e. Wistar Kyoto (WKY), Fawn Hooded (FH), Brown Norway (BN) and Lewis (LE), were investigated in different tests related to pain and nociception. During Pavlovian fear conditioning, the LE and WKY showed a significantly longer duration of freezing behaviour than the FH and BN. Additionally, differences in c-Fos expression in subregions of the prefrontal cortex and amygdala between rat strains during retrieval and expression of conditioned fear were found. For example, the BN did not show recruitment of the basolateral amygdala, whereas the WKY, FH and LE did. During the hot plate test, the WKY and LE showed a lower thermal threshold compared to the BN and FH. In a follow-up experiment, the two most contrasting strains regarding behaviour during the hot plate test and Pavlovian fear conditioning (i.e. FH and WKY) were selected and the hot plate test, Von Frey test and somatosensory-evoked potential (SEP) were investigated. During the Von Frey test, the WKY showed a lower mechanical threshold compared to the FH. When measuring the SEP, the FH appeared to be less reactive to increasing stimulus intensities when considering both peak amplitudes and latencies. Altogether, the combined results indicate various differences between rat strains in Pavlovian fear conditioning, nociception related behaviours and nociceptive processing. These findings demonstrate the necessity of using multiple rat strains when using tests including noxious stimuli and suggest that the choice of rat strains should be considered. When selecting a strain for a particular study it should be considered how this strain behaves during the tests used in that study.

AKT is critically involved in cooperation between obesity and the dietary carcinogen amino-1-methyl-6-phenylimidazo [4,5-b] (PhIP) toward colon carcinogenesis in rats

Obesity is highly associated with colon cancer development. Whereas it is generally attributed to pro-tumorigenic effects of high fat diet (HFD), we here show that a common genetic basis for predisposition to obesity and colon cancer might also underlie the close association. Comparison across multiple rat strains revealed that strains prone to colon tumorigenesis initiated by a dietary carcinogen amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) tended to develop obesity. Through transcriptome and extensive immunoblotting analyses, we identified the basal level of activated AKT in colonic crypts as a biomarker for the common predisposition. Notably, PhIP induced activation of AKT, which could persist for several weeks under a low fat diet (LFD), but not under HFD. On the other hand, PhIP and HFD independently induced Wnt pathway activation and inhibited apoptosis, through distinct mechanisms involving GSK-3β, caspase 3 and poly-ADP ribose polymerase (PARP). Taken together, these observations provide mechanistic insights into how PhIP-induced activation of AKT might cooperate with HFD at multiple levels toward development of colon cancer.

Building better animal models of disease through integration of multiple disease phenotypes

Animal models of disease are used to test hypotheses of disease mechanisms as well as for therapeutic development. Effective animal models must sufficiently reflect human disease and should be classified carefully as disease models. Integration of genomic and phenotypic data provides the foundation to study the genetic and environmental influences on the risk, onset and progression of disease. PhenoMiner, at the Rat Genome Database (http://rgd.mcw.edu), is an interactive data‐mining tool to compare clinical measurements used as indices of disease across multiple rat strains, measured under a variety of conditions. Data are integrated through the use of four ontologies (rat strain, clinical measurement, measurement method, experimental conditions). PhenoMiner provides a solid foundation to distinguish phenotypes by strains and strains by phenotypes. Currently more than 42,000 records can be viewed graphically or in tabular format, allowing easy comparison across strains. Graphical summaries (bar charts and heat maps) provide a rapid method to identify strains with abnormal phenotypes or groups of phenotypes that correspond to disease traits. In addition to providing phenotype driven model identification, PhenoMiner generates standard ranges for clinical measurements under control conditions to be used to identify strains with potential disease traits.Supported by R01HL094271 and R01HL064541.

Carotid body denervation does not affect CO2 sensitivity in multiple rat strains

O2 and CO2/pH are detected by the carotid bodies (CBs) and central respiratory chemoreceptors, respectively. CB activity appears to modulate central chemoreceptor activity, suggesting chemoreceptor interdependence. Here, we studied the effects of CB denervation in CO2‐insensitive Brown Norway (BN) and CO2‐sensitive Dahl Salt‐sensitive (SS) and Sprague Dawley (SD) rats by chronic measurements of ventilation (VE) and blood gases at rest, and during hypercapnia (7% CO2) or hypoxia (12% O2) before and for 21 days (d) after CBD. Peak eupneic hypoventilation (Δ PaCO2) occurred 1–2 d post‐CBD in all strains, increasing 11.0 (SS), 9.4 (BN) and 7.0 (SD) mmHg. Resting PaCO2 returned to control by 12 d post‐CBD (BN and SD), but remained elevated (+3.9 mmHg) in SS rats. SS and SD rats showed high sensitivity (VE ~300% of control) and BN rats a low sensitivity (VE ~150% of control) to hypercapnia pre‐CBD, which was unaffected by CBD. In addition, CO2 sensitivity (measured as ΔVE/ΔPaCO2) was also unaffected by CBD in all strains, despite a near‐complete loss of the hypoxic ventilatory response and attenuation of the ventilatory response to i.v. NaCN. As seen in other species, these data suggest that CBD in rats leads to eupneic hypoventilation and elimination of the hypoxic ventilatory response, but the lack of effect on CO2 sensitivity does not support the concept of chemoreceptor interdependence. Supported by NIH HL097033.

Analysis of the Iddm14 Rat Diabetes Susceptibility Locus in Multiple Rat Strains: Identification of a Susceptibility Haplotype in the Tcrb-V13 Gene and Prevention of Diabetes by Depletion of Vbeta13+ T Cells

Analysis of the Iddm14 Rat Diabetes Susceptibility Locus in Multiple Rat Strains: Identification of a Susceptibility Haplotype in the Tcrb-V13 Gene and Prevention of Diabetes by Depletion of Vbeta13+ T Cells

Knockout Rats via Embryo Microinjection of Zinc-Finger Nucleases

The toolbox of rat genetics currently lacks the ability to introduce site-directed, heritable mutations into the genome to create knockout animals. By using engineered zinc-finger nucleases (ZFNs) designed to target an integrated reporter and two endogenous rat genes, Immunoglobulin M (IgM) and Rab38, we demonstrate that a single injection of DNA or messenger RNA encoding ZFNs into the one-cell rat embryo leads to a high frequency of animals carrying 25 to 100% disruption at the target locus. These mutations are faithfully and efficiently transmitted through the germline. Our data demonstrate the feasibility of targeted gene disruption in multiple rat strains within 4 months time, paving the way to a humanized monoclonal antibody platform and additional human disease models.

Analysis of Cochlear Protein Profiles of Wistar, Sprague−Dawley, and Fischer 344 Rats with Normal Hearing Function

Differences in the expression of cochlear proteins are likely to affect the susceptibility of different animal models to specific types of auditory pathology. However, little is currently known about proteins that are abundantly expressed in inner ear. Identification of these proteins may facilitate the search for biomarkers of susceptibility and intervention targets. To begin to address this issue, we analyzed cochlear protein profiles of three strains of rats, Wistar, Sprague-Dawley, and Fischer 344, using a broad spectrum antibody microarray. Normal hearing function of the animals was ascertained using distortion product otoacoustic emissions (DPOAE). Of 725 proteins screened in whole cochlea, more than 80% were detected in all three strains. However, there were striking differences in the levels at which they occur. Among 213 proteins expressed at levels>or=2 fold of actin, only 7.5% were detected at these levels in all three strains. Myosin light chain kinase (MLCK) was immunolocalized in cuticular plate of outer hair cells (OHC) while mitogen activated protein (MAP) kinase-extracellular-signal regulated kinase1/2 (ERK1/2) was detected as foci in OHC, pillar cells, strial marginal cells, and fibroblasts of spiral ligament. A review of literature indicated that the expression of 7 (44%) of these 16 proteins were detected for the first time in the inner ear, although there were implications of the presence of some of these proteins. One of these abundant, but unstudied, proteins, MAP kinase activated protein kinase2 (MAPKAPK2), shows strong immunolabeling in pillar cells and inner hair cells (IHC). There was moderate MAPKAPK2 labeling in OHC, supporting cells, neurons, and marginal, intermediate, and basal cells. The current study provides the first, large cochlear protein profile of multiple rat strains. The diversity in expression of abundant proteins in these strains may contribute to differences in susceptibility of these strains to aging, noise, or ototoxic drugs.

Analysis of the rat Iddm14 diabetes susceptibility locus in multiple rat strains: identification of a susceptibility haplotype in the Tcrb-V locus

Iddm14 (formerly Iddm4) is a non-MHC-linked genetic locus associated with autoimmune diabetes. Its effects have been well-documented in BB-derived rats in which diabetes is either induced by immunologic perturbation or occurs spontaneously. The role of Iddm14 in non-BB rat strains is unknown. Our goal was to extend the analysis of Iddm14 in new diabetes-susceptible strains and to identify candidate genes in the rat Iddm14 diabetes susceptibility locus that are common to these multiple diabetic strains. To determine if Iddm14 is important in strains other than BB, we first genotyped a (LEW.1WR1 x WF)F2 cohort in which diabetes was induced by perturbation with polyinosinic:polycytidylic acid. We found that Iddm14 is a major determinant of diabetes susceptibility in LEW.1WR1 rats. We then used nucleotide sequencing to establish a strain distribution pattern of polymorphisms (insertions, deletions, and single nucleotide polymorphisms [SNPs]) that predicts susceptibility to diabetes in a panel of inbred and congenic rats. Using the positional information from the congenic strains and the new linkage data, we identified a susceptibility haplotype in the T-cell receptor Vbeta chain (Tcrb-V) locus. This haplotype includes Tcrb-V13, which is identical in five susceptible strains but different in resistant WF and F344 rats. We conclude that Iddm14 is a powerful determinant of both spontaneous and induced autoimmune diabetes in multiple rat strains, and that Tcrb-V13 SNPs constitute a haplotype of gene elements that may be critical for autoimmune diabetes in rats.

Loss of Caveolin-3 Induces a Lactogenic Microenvironment that Is Protective Against Mammary Tumor Formation

Here, we show that functional loss of a single gene is sufficient to confer constitutive milk protein production and protection against mammary tumor formation. Caveolin-3 (Cav-3), a muscle-specific caveolin-related gene, is highly expressed in muscle cells. We demonstrate that Cav-3 is also expressed in myoepithelial cells within the mammary gland. To determine whether genetic ablation of Cav-3 expression affects adult mammary gland development, we studied the phenotype(s) of Cav-3(-/-)-null mice. Interestingly, Cav-3(-/-) virgin mammary glands developed lobulo-alveolar hyperplasia, akin to the changes normally observed during pregnancy and lactation. Genome-wide expression profiling revealed up-regulation of gene transcripts associated with pregnancy/lactation, mammary stem cells, and human breast cancers, consistent with a constitutive lactogenic phenotype. Expression levels of three key transcriptional regulators of lactation, namely Elf5, Stat5a, and c-Myc, were also significantly elevated. Experiments with pregnant mice directly showed that Cav-3(-/-) mice underwent precocious lactation. Finally, using orthotopic tumor cell implantation, we demonstrated that virgin Cav-3(-/-) mice were dramatically protected against mammary tumor formation. Thus, Cav-3(-/-) mice are a novel preclinical model to study the protective effects of a lactogenic microenvironment on mammary tumor onset and progression. Our current studies have broad implications for using the lactogenic microenvironment as a paradigm to discover new therapies for the prevention and/or treatment of human breast cancers.

Congenic mapping of a blood pressure QTL region on rat chromosome 10 using the Dahl salt-sensitive rat with introgressed alleles from the Milan normotensive strain

Multiple blood pressure (BP) quantitative trait loci (QTLs) are reported on rat chromosome 10 (RNO10). Of these, QTLs detected by contrasting the genome of the hypertensive Dahl salt-sensitive (S) rat with two different relatively normotensive strains, Lewis (LEW) and the Milan normotensive strain (MNS), are reported. Because the deduced QTL regions of both S vs. LEW and S vs. MNS comparisons are within large genomic segments encompassing more than 2 cM, there was a need to further localize these QTLs and determine whether the QTLs are unique to specific strain comparisons. Previously, the S.MNS QTL1 was mapped to less than 2.6 cM as a differential segment between two congenic strains. In this study, multiple congenic strains spanning the projected interval were studied. The BP effect of each strain was interpreted as the net effect of alleles introgressed within that congenic strain. The results suggest that the MNS alleles within the previously proposed differential segment (D10Rat27-D10Rat24) do not independently lower BP of the S rat. However, another congenic strain, S.MNS(10) x 9, containing introgressed MNS alleles that are outside of the previously proposed differential segment is of interest because (1) it demonstrated a BP-lowering effect, (2) it is contained within a single congenic strain and is not based on the observed effect of a differential segment, and, more importantly, (3) it overlaps with the previously identified S.LEW BP QTL region. Identification of the same QTL affecting BP in multiple rat strains will provide further support for the QTL's involvement and importance in human essential hypertension.

NTP Workshop: Animal Models for the NTP Rodent Cancer Bioassay: Stocks and Strains—Should We Switch?

The National Toxicology Program (NTP) hosted a workshop, "Animal Models for the NTP Rodent Cancer Bioassay: Strains and Stocks--Should We Switch?" on June 16-17, 2005, at the National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park, North Carolina. The workshop's objectives were to determine (1) whether the currently used models, the F344/N rat and B6C3F1/N mouse, continue to be appropriate to identify substances that may pose a carcinogenic hazard for humans and (2) whether the NTP should consider conducting cancer bioassays using multiple strains of rats and/or mice to better capture the range of genetic variability. Workshop participants advised the NTP to discontinue using the current F344/N strain due to the recent issues with fertility, seizure activity, and chylothorax and provided several options on how the program should approach identifying and selecting a new rat model. Participants believed that the B6C3F1/N mouse is still appropriate for use by the NTP, but suggested the NTP take steps to better understand and address increases in background rates of liver tumors in this strain. Finally, the participants supported the NTP exploring the use of the multiple strain approach, although they raised many questions concerning data interpretation and feasibility. This article also outlines the NTP's next steps in pursuing the workshop recommendations.

Relationship between nocturnal serotonin surge and melatonin onset in rodent pineal gland

BackgroundWe have recently reported dynamic circadian rhythms of serotonin (5-HT, 5-hydroxytryptamine) output in the pineal gland of rat, which precedes the onset of N-acetylserotonin (NAS) and melatonin secretion at night. The present study was aimed at investigating in detail the relationship between 5-HT onset (5HT-on) and melatonin onset (MT-on) in multiple strains of rats and comparing them with those of hamsters.MethodsAnimals were maintained in chambers equipped with light (250 lux at cage levels) and ventilation in a temperature-controlled room. Following surgical implantation of a microdialysis probe in the pineal gland, animals were individually housed for on-line pineal microdialysis and for automated HPLC analysis of 5-HT and melatonin. Animals were under a light-dark cycle of 12:12 h for the duration of the experiments.ResultsAll animals displayed dynamic 5-HT and melatonin rhythms at night. In all cases, 5HT-on (taken at 80% of the daily maximum levels) preceded MT-on (taken at 20% of the daily maximum levels). Within the same animals, 5HT-on as well as MT-on across multiple circadian cycles exhibited minimum variations under entrained conditions. Large inter-individual variations of both 5HT-on and MT-on were found in outbred rats and hamsters under entrained conditions. In comparison, inbred rats displayed very small individual variations of 5HT-on and MT-on. Importantly, we have uncovered a species-specific relationship of 5HT-on and MT-on. 5HT-on of rats, regardless of the strain, preceded MT-on of the same rats by 50 min. In contrast, 5HT-on of hamsters led MT-on by as much as 240 min. Thus, while a constant relationship of 5HT-on and MT-on exists for animals of the same species, the relative timings of 5HT-on and MT-on differ between animals of different species.ConclusionThese results suggest that both 5-HT and melatonin could serve as reliable markers of the circadian clock because of their day-to-day precision of onset timings within the same animals or within individuals of the same strain or same species. The results also demonstrate that data for MT-on cannot be compared directly between different species, and that 5HT-on may be a more reliable circadian marker when data from animals of different species are compared.

Hormone-Induced Protection against Mammary Tumorigenesis Is Conserved in Multiple Rat Strains and Identifies a Core Gene Expression Signature Induced by Pregnancy

Women who have their first child early in life have a substantially lower lifetime risk of breast cancer. The mechanism for this is unknown. Similar to humans, rats exhibit parity-induced protection against mammary tumorigenesis. To explore the basis for this phenomenon, we identified persistent pregnancy-induced changes in mammary gene expression that are tightly associated with protection against tumorigenesis in multiple inbred rat strains. Four inbred rat strains that exhibit marked differences in their intrinsic susceptibilities to carcinogen-induced mammary tumorigenesis were each shown to display significant protection against methylnitrosourea-induced mammary tumorigenesis following treatment with pregnancy levels of estradiol and progesterone. Microarray expression profiling of parous and nulliparous mammary tissue from these four strains yielded a common 70-gene signature. Examination of the genes constituting this signature implicated alterations in transforming growth factor-beta signaling, the extracellular matrix, amphiregulin expression, and the growth hormone/insulin-like growth factor I axis in pregnancy-induced alterations in breast cancer risk. Notably, related molecular changes have been associated with decreased mammographic density, which itself is strongly associated with decreased breast cancer risk. Our findings show that hormone-induced protection against mammary tumorigenesis is widely conserved among divergent rat strains and define a gene expression signature that is tightly correlated with reduced mammary tumor susceptibility as a consequence of a normal developmental event. Given the conservation of this signature, these pathways may contribute to pregnancy-induced protection against breast cancer.

Differential expression of genes related to levels of mucosal cell proliferation among multiple rat strains by using oligonucleotide microsarays

Differential expression of genes related to levels of mucosal cell proliferation among multiple rat strains by using oligonucleotide microsarays

Profiling and selection of genes differentially expressed in the pylorus of rat strains with different proliferative responses and stomach cancer susceptibility.

Rat stomach cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) are widely used as a model of differentiated-type human stomach cancers. ACI/NJcl (ACI) rats show persistent and strong cell proliferation in response to gastric mucosal damage by MNNG while BUF/NacJcl (BUF) rats show transient and limited cell proliferation. This difference is considered as one of the mechanisms for the high susceptibility of ACI rats to MNNG-induced stomach carcinogenesis. To identify genes involved in the differential induction of cell proliferation, cDNA subtraction was performed using RNA isolated from the pylorus of ACI and BUF rats treated with MNNG. By the temporal patterns of their expressions, the isolated 16 genes were overviewed and clustered into groups. Expression of the genes in group 1 (such as MHC class I and class II genes and interferon-inducible genes Iigp, Mx2 and Ubd) was induced by MNNG treatment, and the genes in group 2 (such as cellular retinoic acid-binding protein II (CrabpII)) were constantly expressed regardless of MNNG treatment. Then, expression profiles among multiple rat strains were compared with the extents of induction of cell proliferation. Iigp, CrabpII and EST222005 were found to show relatively good accordance, and these three genes were considered as candidates for genes that control differential induction of cell proliferation. Presence of polymorphisms at the genomic DNA level was indicated for CrabpII and EST222005, and these two genes were considered to be better candidates than IIGP: It was shown that the temporal profiles and profiles among strains, taking advantage of animal models, are useful to select candidate genes from a collection of genes isolated by various genome-wide scanning methods.

Genetic Approaches to the Neurobiology of Electroconvulsive Therapy

Although electroconvulsive therapy effectively treats severe psychiatric disorders, its neurobiologic mechanisms are not fully understood. Also unclear is the basis for variability in seizure threshold and duration among patients. We used multiple strains of rats and mice to test for genetic variation in the properties of seizures induced by electroconvulsive shock (ECS). We specifically measured seizure duration, sensitivity to proconvulsant actions of caffeine, and relative refractoriness to postictal induction of further seizures, all of which showed significant interstrain variability. In addition, tonic-clonic seizure durations correlated with rates of immediate mortality, suggesting variations in underlying levels of cellular excitability across strains. By using quantitative autoradiography to relate these findings to neurobiologic mechanisms, we found significant correlations between hippocampal A1-receptor binding, cortical and striatal N-methyl-D-aspartate (NMDA)-receptor binding, and the modification of seizure duration by caffeine. These studies suggest that heritable factors modulate the neurobiologic determinants of electrically induced seizures. Furthermore, they suggest that genetic factors may contribute to clinically observed variability in seizure thresholds. Finally, the data provide a basis for future molecular genetic approaches to link ECS-induced changes in seizure properties to relevant transmitter systems.