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Sample records for genetically epilepsy-prone rat

  1. Genetically Epilepsy-Prone Rats Have Increased Brain Regional Activity of an Enzyme Which Liberates Glutamate from N-acetyl-aspartyl-glutamate

    DTIC Science & Technology

    1992-01-01

    genetically epilepsy -prone iats "was 11-26% greater than control in brain regions, including the amygdala, hippocarrpus and cerebellum, as well as the...9 -0 3 Genetically epilepsy -prone rats have increased brain regional activity of an enzyme which liberates glutamate from N-acetyl-aspartyl...in genctically epilepsy -prone rats was 11-~261; greater than control in brain regions. including the amygdala. hippocampus and cerebellum, as well as

  2. Calcium Channel Dysfunction in Inferior Colliculus Neurons of the Genetically Epilepsy-Prone Rat

    PubMed Central

    N’Gouemo, Prosper; Faingold, Carl L.; Morad, Martin

    2008-01-01

    Summary Voltage-gated calcium (Ca2+) channels are thought to play an important role in epileptogenesis and seizure generation. Here, using the whole-cell configuration of patch-clamp techniques, we report on the modifications of biophysical and pharmacological properties of high threshold voltage-activated Ca2+ channel currents in inferior colliculus (IC) neurons of the genetically epilepsy-prone rats (GEPR-3s). Ca2+channel currents were measured by depolarizing pulses from a holding potential of −80 mV using barium (Ba2+) as the charge carrier. We found that the current density of high threshold voltage-activated Ca2+ channels was significantly larger in IC neurons of seizure-naive GEPR-3s compared to control Sprague-Dawley rats, and that seizure episodes further enhanced the current density in the GEPR-3s. The increased current density was reflected by both a −20 mV shifts in channel activation and a 25% increase in the non-inactivating fraction of channels in seizure-naive GEPR-3s. Such changes were reduced by seizure episodes in the GEPR-3s. Pharmacological analysis of the current density suggests that upregulation of L-, N- and R-type of Ca2+ channels may contribute to IC neuronal hyperexcitability that leads to seizure susceptibility in the GEPR-3s. PMID:19084544

  3. An Abnormal GABAergic System in the Inferior Colliculus Provides a Basis for Audiogenic Seizures in Genetically Epilepsy-Prone Rats

    PubMed Central

    Ribak, Charles E.

    2015-01-01

    In this review of neuroanatomical studies of the genetically epilepsy-prone rat (GEPR), three main topics will be covered. First, the number of GABAergic neurons and total neurons in the inferior colliculus of GEPRs will be compared to those of the non-epileptic Sprague-Dawley rat. Next, the number of small neurons in the inferior colliculus will be described in both developmental and genetic analyses of GEPRs and their backcrosses. Last, results from two types of studies on the propagation pathways for audiogenic seizures in GEPRs will be shown. Together, these studies demonstrate a unique GABAergic, small neuron defect in the inferior colliculus of GEPRs that may play a vital role in the initiation and spread of seizure activity during audiogenic seizures. PMID:25812940

  4. The influence of manganese supplementation on seizure onset and severity, and brain monoamines in the genetically epilepsy prone rat.

    PubMed

    Critchfield, J W; Carl, G F; Keen, C L

    1993-01-01

    Human and experimental animal studies suggest a relationship between low Mn status and seizures. The genetically epilepsy prone rat (GEPR), which has low tissue Mn levels, was studied in the context of Mn supplementation. Manganese was provided at 45 micrograms/g diet (control) or 1000 micrograms/g diet (supplemented) to dams during pregnancy and lactation, then to the offspring after weaning. Offspring were tested for seizure susceptibility as young adults; tissue trace elements, brain monoamines and brain glutamine synthetase activity were measured as endpoint biochemical indices. Supplementation, although developmentally encompassing and highly effective in elevating tissue Mn levels, had no effect on seizure latency or severity. Similarly, brain monoamine concentrations and glutamine synthetase activities were resistant to Mn supplementation. Notably, the GEPR was confirmed to have low whole brain glutamine synthetase activity. These findings suggest that seizure activity in the GEPR does not stem from an increased nutritional/metabolic need for Mn.

  5. Anatomical changes of the GABAergic system in the inferior colliculus of the genetically epilepsy-prone rat.

    PubMed

    Roberts, R C; Ribak, C E

    1986-09-01

    The number of GABAergic neurons as determined by GAD immunocytochemistry and total neurons as determined from Nissl preparations were counted and classified at the light microscopic level in the inferior colliculus (IC) of the genetically epilepsy prone rat (GEPR) and the non-epileptic Sprague-Dawley (SD) strain of rat. GAD-positive neurons are abundant in the IC and a significant increase in the number of GAD-positive neurons occurs in the GEPR as compared to the SD in all three subdivisions. However, the most pronounced difference occurs in the ventral lateral portion of the central nucleus, where there is a selective increase in the small (200%) and medium-sized (90%) GABAergic somata (10-15 microns in diameter and 15-25 microns in diameter, respectively). As determined from Nissl preparations an increase in total numbers of neurons also occurs. Thus, a 100% increase in the number of small neurons and a 30% increase in the number of medium-sized neurons occur in the adult GEPR as compared to the SD rat. A statistically significant increase in the numbers of small neurons also occurred in the IC of the young GEPR. At 4 days of age, a 55% increase in the number of small neurons was found, and at 10 days of age this increase was 105%. The numbers of the medium and large neurons were similar in the older group of rats. These data suggest that the increase in cell number observed in the adult GEPR is not compensatory to the seizure activity, but may either be genetically programmed or be a failure of cell death. Based on other studies of genetic models of epilepsy, we propose that the additional GABAergic neurons may disinhibit excitatory projection neurons in the IC.

  6. Comparative analysis of the treatment of chronic antipsychotic drugs on epileptic susceptibility in genetically epilepsy-prone rats.

    PubMed

    Citraro, Rita; Leo, Antonio; Aiello, Rossana; Pugliese, Michela; Russo, Emilio; De Sarro, Giovambattista

    2015-01-01

    Antipsychotic drugs (APs) are of great benefit in several psychiatric disorders, but they can be associated with various adverse effects, including seizures. To investigate the effects of chronic antipsychotic treatment on seizure susceptibility in genetically epilepsy-prone rats, some APs were administered for 7 weeks, and seizure susceptibility (audiogenic seizures) was evaluated once a week during treatment and for 5 weeks after drug withdrawal. Furthermore, acute and subchronic (5-day treatment) effects were also measured. Rats received haloperidol (0.2-1.0 mg/kg), clozapine (1-5 mg/kg), risperidone (0.03-0.50 mg/kg), quetiapine (2-10 mg/kg), aripriprazole (0.2-1.0 mg/kg), and olanzapine (0.13-0.66 mg/kg), and tested according to treatment duration. Acute administration of APs had no effect on seizures, whereas, after regular treatment, aripiprazole reduced seizure severity; haloperidol had no effects and all other APs increased seizure severity. In chronically treated rats, clozapine showed the most marked proconvulsant effects, followed by risperidone and olanzapine. Quetiapine and haloperidol had only modest effects, and aripiprazole was anticonvulsant. Finally, the proconvulsant effects lasted at least 2-3 weeks after treatment suspension; for aripiprazole, a proconvulsant rebound effect was observed. Taken together, these results indicate and confirm that APs might have the potential to increase the severity of audiogenic seizures but that aripiprazole may exert anticonvulsant effects. The use of APs in patients, particularly in patients with epilepsy, should be monitored for seizure occurrence, including during the time after cessation of therapy. Further studies will determine whether aripiprazole really has a potential as an anticonvulsant drug and might also be clinically relevant for epileptic patients with psychiatric comorbidities.

  7. Decreased norepinephrine (NE) uptake in cerebral cortex and inferior colliculus of genetically epilepsy prone (GEP) rats

    SciTech Connect

    Browning, R.A.; Rigler-Daugherty, S.K.; Long, G.; Jobe, P.C.; Wade, D.R.

    1986-03-01

    GEP rats are characterized by an enhanced susceptibility to seizures caused by a variety of stimuli, most notably sound. Pharmacological treatments that reduce the synaptic concentration of NE increase seizure severity in GEP rats while elevations in NE have the opposite effect. GEP rats also display a widespread deficit in brain NE concentration suggesting that their increased seizure susceptibility is related to a deficit in noradrenergic transmission. The authors have compared the kinetics of /sup 3/H-NE uptake in the P/sub 2/ synaptosomal fraction isolated from the cerebral cortex of normal and GEP-rats. Although the apparent Kms were not significantly different (Normal +/- SEM:0.37 +/- 0.13..mu..M; GEP +/- SEM: 0.29 +/- 0.07..mu..M), the Vmax for GEP rats was 48% lower than that of normal rats (Normal +/- SEM: 474 +/- 45 fmole/mg/4min; GEP +/- SEM: 248 +/- 16 fmole/mg/4min). Because of the possible role of the inferior colliculus (IC) in the initiation of sound-induced seizures in GEP rats, the authors measured synaptosomal NE uptake in the IC using a NE concentration of 50 nM. The IC synaptosomal NE uptake was found to be 35% lower in GEP than in normal rats. These findings are consistent with the hypothesis that a deficit in noradrenergic transmission is related to the increased seizure susceptibility of GEP rats.

  8. Inhibition of adenosine metabolism induces changes in post-ictal depression, respiration, and mortality in genetically epilepsy prone rats.

    PubMed

    Kommajosyula, Srinivasa P; Randall, Marcus E; Faingold, Carl L

    2016-01-01

    A major cause of mortality in epilepsy patients is sudden unexpected death in epilepsy (SUDEP). Post-ictal respiratory dysfunction following generalized convulsive seizures is most commonly observed in witnessed cases of human SUDEP. DBA mouse models of SUDEP are induced by audiogenic seizures (AGSz) and show high incidences of seizure-induced death due to respiratory depression. The relatively low incidence of human SUDEP suggests that it may be useful to examine seizure-associated death in an AGSz model that rarely exhibits sudden death, such as genetically epilepsy-prone rats (GEPR-9s). Adenosine is released extensively during seizures and depresses respiration, which may contribute to seizure-induced death. The present study examined the effects of inhibiting adenosine metabolism on the durations of post-ictal depression (PID) and respiratory distress (RD), changes in blood oxygen saturation (% SpO2), and the incidence of post-seizure mortality in GEPR-9s. Systemic administration of adenosine metabolism inhibitors, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA, 30 mg/kg) with 5-Iodotubericidin (5-ITU, 3mg/kg) in GEPR-9s resulted in significant changes in the duration of AGSz-induced PID as compared to vehicle in both genders. These agents also significantly increased the duration of post-seizure RD and significantly decreased the mean% SpO2 after AGSz, as compared to vehicle but only in females. Subsequently, we observed that the incidences of death in both genders 12-48 h post-seizure were significantly greater in drug vs. vehicle treatment. The incidence of death in females was also significantly higher than in males, which is consistent with the elevated seizure sensitivity of female GEPR-9s developmentally. These results support a potentially important role of elevated adenosine levels following generalized seizures in the increased incidence of death in GEPR-9s induced by adenosine metabolism inhibitors. These findings may also be relevant to human SUDEP, in

  9. Genetically epilepsy-prone rats (GEPRs) and DBA/2 mice: Two animal models of audiogenic reflex epilepsy for the evaluation of new generation AEDs.

    PubMed

    De Sarro, Giovambattista; Russo, Emilio; Citraro, Rita; Meldrum, Brian S

    2015-08-06

    This review summarizes the current knowledge about DBA/2 mice and genetically epilepsy-prone rats (GEPRs) and discusses the contribution of such animal models on the investigation of possible new therapeutic targets and new anticonvulsant compounds for the treatment of epilepsy. Also, possible chemical or physical agents acting as proconvulsant agents are described. Abnormal activities of enzymes involved in catecholamine and serotonin synthesis and metabolism were reported in these models, and as a result of all these abnormalities, seizure susceptibility in both animals is greatly affected by pharmacological manipulations of the brain levels of monoamines and, prevalently, serotonin. In addition, both genetic epileptic models permit the evaluation of pharmacodynamic and pharmacokinetic interactions among several drugs measuring plasma and/or brain level of each compound. Audiogenic models of epilepsy have been used not only for reflex epilepsy studies, but also as animal models of epileptogenesis. The seizure predisposition (epileptiform response to sound stimulation) and substantial characterization of behavioral, cellular, and molecular alterations in both acute and chronic (kindling) protocols potentiate the usefulness of these models in elucidating ictogenesis, epileptogenesis, and their mechanisms. This article is part of a Special Issue entitled "Genetic Models-Epilepsy".

  10. Protein expression of small conductance calcium-activated potassium channels is altered in inferior colliculus neurons of the genetically epilepsy-prone rat

    PubMed Central

    N’Gouemo, Prosper; Yasuda, Robert P.; Faingold, Carl L.

    2009-01-01

    The genetically epilepsy-prone rat (GEPR) exhibits inherited predisposition to sound stimuli-induced generalized tonic-clonic seizures (audiogenic reflex seizures) and is a valid model to study the physiopathology of epilepsy. In this model, the inferior colliculus (IC) exhibits enhanced neuronal firing that is critical in the initiation of reflex audiogenic seizures. The mechanisms underlying IC neuronal hyperexcitability that leads to seizure susceptibility are not as yet fully understood. The present report shows that the levels of protein expression of SK1 and SK3 subtypes of the small conductance Ca2+-activated K+ channels were significantly decreased, while SK2 channel proteins were increased in IC neurons of seizure-naive GEPR-3s (SN-GEPR-3), as compared to control Sprague-Dawley rats. No significant change was found in the expression of BK channel proteins in IC neurons of SN-GEPR-3s. Single episode of reflex audiogenic seizures in the GEPR-3s did not significantly alter the protein expression of SK1-3 and BK channels in IC neurons compared to SN-GEPR-3s. Thus, downregulation of SK1 and SK3 channels and upregulation of SK2 channels provide direct evidence that these Ca2+-activated K+ channels play important roles in IC neuronal hyperexcitability that leads to inherited seizure susceptibility in the GEPR. PMID:19254702

  11. Increased responsiveness and failure of habituation in neurons of the external nucleus of inferior colliculus associated with audiogenic seizures of the genetically epilepsy-prone rat.

    PubMed

    Chakravarty, D N; Faingold, C L

    1996-10-01

    Initiation of audiogenic seizures (AGS) emanates from the inferior colliculus (IC) to other IC subnuclei in the genetically epilepsy-prone rat (GEPR). The external nucleus of IC (ICx) is a suggested site of convergence of the auditory output onto the sensorimotor integration network components for AGS in the brainstem. Neuronal firing was recorded from the ICx of the awake, freely moving GEPR and normal Sprague-Dawley rats using microwire electrodes in the present study. Auditory stimuli consisted of 12-kHz tones (100 ms, 5-ms rise-fall at rates of 1/4s, 1/2s, and 1/s). AGS incidence in the GEPR is highest at 12 kHz. In the GEPR, ICx neuronal responses to acoustic stimuli were significantly greater than those seen in normal rats. This increased ICx firing was observed at relatively high acoustic intensities (> 80 dB SPL), which are near the threshold for AGS induction. Repetition-induced response attenuation (habituation) is commonly observed in ICx neurons, which appears to be overcome in the GEPR during AGS initiation. Tonic, acoustically evoked ICx neuronal firing was observed just prior to wild running. ICx firing was suppressed during the tonic and postictal phases of AGS. Recovery of ICx responses occurred when the animal regained postural control. Abnormal, intense output has previously been observed in the GEPR IC central nucleus (ICc) neurons. The neuronal firing pattern changes observed in the ICx in the present study may result from this intense ICc output. Diminished efficacy of GABA, which has been observed in several regions of the GEPR brain, including the IC, in a number of previous studies, may be involved in the exaggerated ICx responses to acoustic stimuli in the GEPR. Participation of the ICx in the AGS neuronal network may be subserved by this acoustic hyperresponsiveness.

  12. Elevation of naloxone-sensitive /sup 3/H-dihydromorphine binding in hippocampal formation of genetically epilepsy-prone rats

    SciTech Connect

    Savage, D.D.; Mills, S.A.; Jobe, P.C.; Reigel, C.E.

    1988-01-01

    /sup 3/H-Dihydromorphine (DHM) binding sites were measured in the brain of non-epileptic control and GEPR rats using in vitro autoradiographic techniques. The number of naloxone-sensitive /sup 3/H-DHM binding sites was increased 38-57% in the pyramidal cell layer of ventral hippocampal CA/sub 3/ and CA/sub 1/ of GEPR-3 and GEPR-9 rats compared to non-epileptic controls. No significant differences in /sup 3/H-DHM binding were observed in dorsal hippocampal formation, lateral entorhinal cortex, lateral geniculate or cerebellum. The results suggest that an increase in the number of opioid receptors in ventral hippocampus of GEPR rats may be one factor contributing to the enhanced sensitivity of GEPR-9 rats to the proconvulsant effects of morphine.

  13. Advances on genetic rat models of epilepsy.

    PubMed

    Serikawa, Tadao; Mashimo, Tomoji; Kuramoro, Takashi; Voigt, Birger; Ohno, Yukihiro; Sasa, Masashi

    2015-01-01

    Considering the suitability of laboratory rats in epilepsy research, we and other groups have been developing genetic models of epilepsy in this species. After epileptic rats or seizure-susceptible rats were sporadically found in outbred stocks, the epileptic traits were usually genetically-fixed by selective breeding. So far, the absence seizure models GAERS and WAG/Rij, audiogenic seizure models GEPR-3 and GEPR-9, generalized tonic-clonic seizure models IER, NER and WER, and Canavan-disease related epileptic models TRM and SER have been established. Dissection of the genetic bases including causative genes in these epileptic rat models would be a significant step toward understanding epileptogenesis. N-ethyl-N-nitrosourea (ENU) mutagenesis provides a systematic approach which allowed us to develop two novel epileptic rat models: heat-induced seizure susceptible (Hiss) rats with an Scn1a missense mutation and autosomal dominant lateral temporal epilepsy (ADLTE) model rats with an Lgi1 missense mutation. In addition, we have established episodic ataxia type 1 (EA1) model rats with a Kcna1 missense mutation derived from the ENU-induced rat mutant stock, and identified a Cacna1a missense mutation in a N-Methyl-N-nitrosourea (MNU)-induced mutant rat strain GRY, resulting in the discovery of episodic ataxia type 2 (EA2) model rats. Thus, epileptic rat models have been established on the two paths: 'phenotype to gene' and 'gene to phenotype'. In the near future, development of novel epileptic rat models will be extensively promoted by the use of sophisticated genome editing technologies.

  14. Advances on genetic rat models of epilepsy

    PubMed Central

    Serikawa, Tadao; Mashimo, Tomoji; Kuramoto, Takashi; Voigt, Birger; Ohno, Yukihiro; Sasa, Masashi

    2014-01-01

    Considering the suitability of laboratory rats in epilepsy research, we and other groups have been developing genetic models of epilepsy in this species. After epileptic rats or seizure-susceptible rats were sporadically found in outbred stocks, the epileptic traits were usually genetically-fixed by selective breeding. So far, the absence seizure models GAERS and WAG/Rij, audiogenic seizure models GEPR-3 and GEPR-9, generalized tonic-clonic seizure models IER, NER and WER, and Canavan-disease related epileptic models TRM and SER have been established. Dissection of the genetic bases including causative genes in these epileptic rat models would be a significant step toward understanding epileptogenesis. N-ethyl-N-nitrosourea (ENU) mutagenesis provides a systematic approach which allowed us to develop two novel epileptic rat models: heat-induced seizure susceptible (Hiss) rats with an Scn1a missense mutation and autosomal dominant lateral temporal epilepsy (ADLTE) model rats with an Lgi1 missense mutation. In addition, we have established episodic ataxia type 1 (EA1) model rats with a Kcna1 missense mutation derived from the ENU-induced rat mutant stock, and identified a Cacna1a missense mutation in a N-Methyl-N-nitrosourea (MNU)-induced mutant rat strain GRY, resulting in the discovery of episodic ataxia type 2 (EA2) model rats. Thus, epileptic rat models have been established on the two paths: ‘phenotype to gene’ and ‘gene to phenotype’. In the near future, development of novel epileptic rat models will be extensively promoted by the use of sophisticated genome editing technologies. PMID:25312505

  15. Beta-endorphin in genetically hypoprolactinemic rat: IPL nude rat

    SciTech Connect

    Cohen, H.; Sabbagh, I.; Abou-Samra, A.B.; Bertrand, J.

    1986-01-20

    Beta-endorphin has been reported to regulate not only stress- and suckling-induced but also basal prolactin secretion. In the aim to better evaluate the endogenous beta-endorphin-prolactin interrelation, the authors measured beta-endorphin levels in a new rat strain, genetically hypoprolactinemic and characterized by a total lack of lactation: IPL nude rat. Beta-endorphin was measured using a specific anti-h-..beta.. endorphin in plasma and extracts of anterior and neurointermediate lobes of the pituitary, hypothalamus and brain. Pituitary extracts were also chromatographed on Sephadex G50 column. Results obtained showed that in IPL nude females on diestrus and males, the beta-endorphin contents of the neurointermediate lobe was significantly lower than in normal rats, while the values found in the other organs and plasma were similar. However, elution pattern of the anterior pituitary extracts from male rats showed greater immunoactivity eluting as I/sup 125/ h-beta-endorphin than in normal rat; this was not the case for the female rat. These results are consistent with a differential regulation of beta-endorphin levels of anterior and neurointermediate lobe by catecholamines. Moreover they suggest that PRL secretion was more related to neurointermediate beta-endorphin. 40 references, 2 figures, 4 tables.

  16. ENU mutagenesis to generate genetically modified rat models.

    PubMed

    van Boxtel, Ruben; Gould, Michael N; Cuppen, Edwin; Smits, Bart M G

    2010-01-01

    The rat is one of the most preferred model organisms in biomedical research and has been extremely useful for linking physiology and pathology to the genome. However, approaches to genetically modify specific genes in the rat germ line remain relatively scarce. To date, the most efficient approach for generating genetically modified rats has been the target-selected N-ethyl-N-nitrosourea (ENU) mutagenesis-based technology. Here, we describe the detailed protocols for ENU mutagenesis and mutant retrieval in the rat model organism.

  17. Genetic influence on brain catecholamines: high brain norepinephrine in salt-sensitive rats

    SciTech Connect

    Iwai, J; Friedman, R; Tassinari, L

    1980-01-01

    Rats genetically sensitive to salt-induced hypertension evinced higher levels of plasma norepinephrine and epinephrine than rats genetically resistant to hypertension. The hypertension-sensitive rats showed higher hypothalamic norepinephrine and lower epinephrine than resistant rats. In response to a high salt diet, brain stem norepinephrine increased in sensitive rats while resistant rats exhibited a decrease on the same diet.

  18. Mapping genetic determinants of kidney damage in rat models.

    PubMed

    Schulz, Angela; Kreutz, Reinhold

    2012-07-01

    During the last two decades, significant progress in our understanding of the development of kidney diseases has been achieved by unravelling the mechanisms underlying rare familial forms of human kidney diseases. Due to the genetic heterogeneity in human populations and the complex multifactorial pathogenesis of the disease phenotypes, the dissection of the genetic basis of common chronic kidney diseases (CKD) remains a difficult task. In this regard, several inbred rat models provide valuable complementary tools to uncover the genetic basis of complex renal disease phenotypes that are related to common forms of CKD. In this review, data obtained in nine experimental rat models, including the Buffalo (BUF), Dahl salt-sensitive (SS), Fawn-hooded hypertensive (FHH), Goto-Kakizaki (GK), Lyon hypertensive (LH), Munich Wistar Frömter (MWF), Sabra hypertension-prone (SBH), spontaneously hypertensive rat (SHR) and stroke-prone spontaneously hypertensive rat (SHRSP) inbred strains, that contributed to the genetic dissection of renal disease phenotypes are presented. In this panel of inbred strains, a large number of quantitative trait loci (QTL) linked to albuminuria/proteinuria and other functional or structural kidney abnormalities could be identified by QTL mapping analysis and follow-up studies including consomic and congenic rat lines. The comprehensive exploitation of the genotype-renal phenotype associations that are inherited in this panel of rat strains is suitable for making a significant contribution to the development of an integrated approach to the systems genetics of common CKD.

  19. Genetic architecture of Wistar-Kyoto rat and spontaneously hypertensive rat substrains from different sources.

    PubMed

    Zhang-James, Yanli; Middleton, Frank A; Faraone, Stephen V

    2013-07-02

    The spontaneously hypertensive rat (SHR) has been widely used as a model for studies of hypertension and attention deficit/hyperactivity disorder. The inbred Wistar-Kyoto (WKY) rat, derived from the same ancestral outbred Wistar rat as the SHR, are normotensive and have been used as the closest genetic control for the SHR, although the WKY has also been used as a model for depression. Notably, however, substantial behavioral and genetic differences among the WKY substrains, usually from the different vendors and breeders, have been observed. These differences have often been overlooked in prior studies, leading to inconsistent and even contradictory findings. The complicated breeding history of the SHR and WKY rats and the lack of a comprehensive understanding of the genetic background of different commercial substrains make the selection of control rats a daunting task, even for researchers who are mindful of their genetic heterogeneity. In this study, we examined the genetic relationship of 16 commonly used WKY and SHR rat substrains using genome-wide SNP genotyping data. Our results confirmed a large genetic divergence and complex relationships among the SHR and WKY substrains. This understanding, although incomplete without the genome sequence, provides useful guidance in selecting substrains and helps to interpret previous reports when the source of the animals was known. Moreover, we found two closely related, yet distinct WKY substrains that may provide novel opportunities in modeling psychiatric disorders.

  20. Origins of albino and hooded rats: implications from molecular genetic analysis across modern laboratory rat strains.

    PubMed

    Kuramoto, Takashi; Nakanishi, Satoshi; Ochiai, Masako; Nakagama, Hitoshi; Voigt, Birger; Serikawa, Tadao

    2012-01-01

    Albino and hooded (or piebald) rats are one of the most frequently used laboratory animals for the past 150 years. Despite this fact, the origin of the albino mutation as well as the genetic basis of the hooded phenotype remained unclear. Recently, the albino mutation has been identified as the Arg299His missense mutation in the Tyrosinase gene and the hooded (H) locus has been mapped to the ∼460-kb region in which only the Kit gene exists. Here, we surveyed 172 laboratory rat strains for the albino mutation and the hooded (h) mutation that we identified by positional cloning approach to investigate possible genetic roots and relationships of albino and hooded rats. All of 117 existing laboratory albino rats shared the same albino missense mutation, indicating they had only one single ancestor. Genetic fine mapping followed by de novo sequencing of BAC inserts covering the H locus revealed that an endogenous retrovirus (ERV) element was inserted into the first intron of the Kit gene where the hooded allele maps. A solitary long terminal repeat (LTR) was found at the same position to the ERV insertion in another allele of the H locus, which causes the so called Irish (h(i)) phenotype. The ERV and the solitary LTR insertions were completely associated with the hooded and Irish coat patterns, respectively, across all colored rat strains examined. Interestingly, all 117 albino rat strains shared the ERV insertion without any exception, which strongly suggests that the albino mutation had originally occurred in hooded rats.

  1. Dynamic genetic architecture of metabolic syndrome attributes in the rat.

    PubMed

    Seda, Ondrej; Liska, Frantisek; Krenova, Drahomira; Kazdova, Ludmila; Sedova, Lucie; Zima, Tomas; Peng, Junzheng; Pelinkova, Kveta; Tremblay, Johanne; Hamet, Pavel; Kren, Vladimir

    2005-04-14

    The polydactylous rat strain (PD/Cub) is a highly inbred (F > 90) genetic model of metabolic syndrome. The aim of this study was to analyze the genetic architecture of the metabolic derangements found in the PD/Cub strain and to assess its dynamics in time and in response to diet and medication. We derived a PD/Cub x BN/Cub (Brown Norway) F2 intercross population of 149 male rats and performed metabolic profiling and genotyping and multiple levels of genetic linkage and statistical analyses at five different stages of ontogenesis and after high-sucrose diet feeding and dexamethasone administration challenges. The interval mapping analysis of 83 metabolic and morphometric traits revealed over 50 regions genomewide with significant or suggestive linkage to one or more of the traits in the segregating PD/Cub x BN/Cub population. The multiple interval mapping showed that, in addition to "single" quantitative train loci, there are more than 30 pairs of loci across the whole genome significantly influencing the variation of particular traits in an epistatic fashion. This study represents the first whole genome analysis of metabolic syndrome in the PD/Cub model and reveals several new loci previously not connected to the genetics of insulin resistance and dyslipidemia. In addition, it attempts to present the concept of "dynamic genetic architecture" of metabolic syndrome attributes, evidenced by shifts in the genetic determination of syndrome features during ontogenesis and during adaptation to the dietary and pharmacological influences.

  2. Neurodevelopmental Malformations of the Cerebellar Vermis in Genetically Engineered Rats.

    PubMed

    Ramos, Raddy L; Van Dine, Sarah E; Gilbert, Mary E; Leheste, Joerg R; Torres, German

    2015-12-01

    The cerebellar vermis is particularly vulnerable to neurodevelopmental malformations in humans and rodents. Sprague-Dawley, and Long-Evans rats exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis. Malformations are almost exclusively found along the primary fissure and are indicative of deficits of neuronal migration during cerebellar development. In the present report, we test the prediction that genetically engineered rats on Sprague-Dawley or Long-Evans backgrounds will also exhibit the same cerebellar malformations. Consistent with our hypothesis, we found that three different transgenic lines on two different backgrounds had cerebellar malformations. Heterotopia in transgenic rats had identical cytoarchitecture as that observed in wild-type rats including altered morphology of Bergmann glia. In light of the possibility that heterotopia could affect results from behavioral studies, these data suggest that histological analyses be performed in studies of cerebellar function or development when using genetically engineered rats on these backgrounds in order to have more careful interpretation of experimental findings.

  3. Modeling Hypercalciuria in the Genetic Hypercalciuric Stone-Forming Rat

    PubMed Central

    Frick, Kevin K.; Krieger, Nancy S.; Bushinsky, David A.

    2015-01-01

    Purpose of Review In this review we discuss how the Genetic Hypercalciuric Stone-Forming (GHS) rats, which closely model idiopathic hypercalciuria and stone formation in humans, provide insights into the pathophysiology and consequences of clinical hypercalciuria. Recent Findings Hypercalciuria in the GHS rats is due to a systemic dysregulation of calcium transport, as manifest by increased intestinal calcium absorption, increased bone resorption and decreased renal tubule calcium reabsorption. Increased levels of vitamin D receptor in intestine, bone and kidney appear to mediate these changes. The excess receptors are biologically active and increase tissue sensitivity to exogenous vitamin D. Bones of GHS rats have decreased bone mineral density (BMD) as compared with Sprague Dawley rats, and exogenous 1,25(OH)2D3 exacerbates the loss of BMD. Thiazide diuretics improve the BMD in GHS rats. Summary Studying GHS rats allows direct investigation of the effects of alterations in diet and utilization of pharmacologic therapy on hypercalciuria, urine supersaturation, stone formation and bone quality in ways that are not possible in humans. PMID:26050120

  4. Coping style and stress hormone responses in genetically heterogeneous rats: comparison with the Roman rat strains.

    PubMed

    Díaz-Morán, Sira; Palència, Marta; Mont-Cardona, Carme; Cañete, Toni; Blázquez, Gloria; Martínez-Membrives, Esther; López-Aumatell, Regina; Tobeña, Adolf; Fernández-Teruel, Alberto

    2012-03-01

    The purpose of the present study was to evaluate for the first time the stress-induced hypothalamus-pituitary-adrenal (HPA), adrenocorticotropic hormone (ACTH), corticosterone and prolactin responses of the National Institutes of Health genetically heterogeneous rat stock (N/Nih-HS rats) in comparison with responses of the relatively high and low stress-prone Roman Low- (RLA-I) and High-Avoidance (RHA-I) rat strains. The same rats were also compared (experiment 1) with respect to their levels of unconditioned anxiety (elevated zero-maze test), novelty-induced exploratory behavior, conditioned fear and two-way active avoidance acquisition. In experiment 2, naive rats from these three strains/stocks were evaluated for "depressive-like" behavior in the forced swimming test. N/Nih-HS and RLA-I rats showed significantly higher post-stress ACTH, corticosterone and prolactin levels than RHA-I rats. N/Nih-HS rats also presented the highest context-conditioned freezing responses, extremely poor two-way avoidance acquisition and very low novelty-induced exploratory behavior. Experiment 2 showed that, compared to RHA-I rats, N/Nih-HS and RLA-I rats displayed significantly less struggling (escape-directed) and increased immobility responses in the forced swimming test. Factor analysis of data from experiment 1 showed associations among behavioral and hormonal responses, with a first factor comprising high loadings of elevated zero-maze variables and lower loadings of conditioned fear, two-way avoidance acquisition and hormonal measures, while a second factor mainly grouped conditioned fear and two-way avoidance acquisition with novelty-induced exploration and post-stress prolactin. Thus, regarding their anxiety/fearfulness, passive coping style, "depressive-like" and stress-induced hormonal responses the N/Nih-HS rats resemble the phenotype profiles of the relatively high-anxious and stress-prone RLA-I rat strain.

  5. Genetically selected alcohol preferring rats to model human alcoholism

    PubMed Central

    Ciccocioppo, Roberto

    2016-01-01

    Animal models have been successfully developed to mimic and study alcoholism. These models have the unique feature of allowing the researcher to control for the genetic characteristics of the animal, alcohol exposure and environment. Moreover, these animal models allow pharmacological, neurochemical and behavioural manipulations otherwise impossible. Unquestionably, one of the major contributions to the understanding of the neurobiological basis of alcoholism comes from data that have been obtained from the study of genetically selected alcohol-preferring rat lines and from the consequences that alcohol drinking and environmental manipulations (/i.e., protracted alcohol drinking, intoxication, exposure to stress etc) have on them. In fact, if on the one hand genetic factors may account for about 50–60% of the risk of developing alcohol dependence, on the other hand protracted alcohol exposure is a necessary precondition to actually develop the disease, while environmental vulnerability factors may be crucial for disease progression. The present article will offer an overview of the different genetically selected alcohol preferring rat lines developed and used to study alcoholism. The predictive, face and construct validity of these animal models and the translational significance of findings achieved through their use will be critically discussed. PMID:22328453

  6. Mitochondrial polymorphisms in rat genetic models of hypertension.

    PubMed

    Kumarasamy, Sivarajan; Gopalakrishnan, Kathirvel; Shafton, Asher; Nixon, Jeremy; Thangavel, Jayakumar; Farms, Phyllis; Joe, Bina

    2010-06-01

    Hypertension is a complex trait that has been studied extensively for genetic contributions of the nuclear genome. We examined mitochondrial genomes of the hypertensive strains: the Dahl Salt-Sensitive (S) rat, the Spontaneously Hypertensive Rat (SHR), and the Albino Surgery (AS) rat, and the relatively normotensive strains: the Dahl Salt-Resistant (R) rat, the Milan Normotensive Strain (MNS), and the Lewis rat (LEW). These strains were used previously for linkage analysis for blood pressure (BP) in our laboratory. The results provide evidence to suggest that variations in the mitochondrial genome do not account for observed differences in blood pressure between the S and R rats. However, variants were detected among the mitochondrial genomes of the various hypertensive strains, S, SHR, and AS, and also among the normotensive strains R, MNS, and LEW. A total of 115, 114, 106, 106, and 16 variations in mtDNA were observed between the comparisons S versus LEW, S versus MNS, S versus SHR, S versus AS, and SHR versus AS, respectively. Among the 13 genes coding for proteins of the electron transport chain, 8 genes had nonsynonymous variations between S, LEW, MNS, SHR, and AS. The lack of any sequence variants between the mitochondrial genomes of S and R rats provides conclusive evidence that divergence in blood pressure between these two inbred strains is exclusively programmed through their nuclear genomes. The variations detected among the various hypertensive strains provides the basis to construct conplastic strains and further evaluate the effects of these variants on hypertension and associated phenotypes.

  7. Early genetic responses in rat vascular tissue after simulated diving.

    PubMed

    Eftedal, Ingrid; Jørgensen, Arve; Røsbjørgen, Ragnhild; Flatberg, Arnar; Brubakk, Alf O

    2012-12-18

    Diving causes a transient reduction of vascular function, but the mechanisms behind this are largely unknown. The aim of this study was therefore to analyze genetic reactions that may be involved in acute changes of vascular function in divers. Rats were exposed to 709 kPa of hyperbaric air (149 kPa Po(2)) for 50 min followed by postdive monitoring of vascular bubble formation and full genome microarray analysis of the aorta from diving rats (n = 8) and unexposed controls (n = 9). Upregulation of 23 genes was observed 1 h after simulated diving. The differential gene expression was characteristic of cellular responses to oxidative stress, with functions of upregulated genes including activation and fine-tuning of stress-responsive transcription, cytokine/cytokine receptor signaling, molecular chaperoning, and coagulation. By qRT-PCR, we verified increased transcription of neuron-derived orphan receptor-1 (Nr4a3), plasminogen activator inhibitor 1 (Serpine1), cytokine TWEAK receptor FN14 (Tnfrsf12a), transcription factor class E basic helix-loop-helix protein 40 (Bhlhe40), and adrenomedullin (Adm). Hypoxia-inducible transcription factor HIF1 subunit HIF1-α was stabilized in the aorta 1 h after diving, and after 4 h there was a fivefold increase in total protein levels of the procoagulant plasminogen activator inhibitor 1 (PAI1) in blood plasma from diving rats. The study did not have sufficient power for individual assessment of effects of hyperoxia and decompression-induced bubbles on postdive gene expression. However, differential gene expression in rats without venous bubbles was similar to that of all the diving rats, indicating that elevated Po(2) instigated the observed genetic reactions.

  8. Amino acid uptake by liver of genetically obese Zucker rats.

    PubMed Central

    Ruiz, B; Felipe, A; Casado, J; Pastor-Anglada, M

    1991-01-01

    Alanine and glutamine uptake by the liver of 50-52-day-old genetically obese Zucker rats and their lean littermates has been studied. The net uptake in vivo of L-alanine is 2-fold higher in the obese animals. No significant change in L-glutamine net balance was found. We also studied the Na(+)-dependent uptake of L-alanine and L-glutamine into plasma-membrane vesicles isolated from either obese- or lean-rat livers. Vmax. values of both L-alanine and L-glutamine transport were 2-fold higher in those preparations from obese rats. No change in Km was observed. As suggested by inhibition studies, this seemed to be mediated by an enhancement of the activities of systems A, ASC and N. We conclude that the liver of the obese Zucker rat is extremely efficient in taking up neutral amino acids from the afferent blood, which results in an enhanced net uptake of L-alanine in vivo. The changes in transport activities at the plasma-membrane level might contribute to increase amino acid disposal by liver, probably for lipogenic purposes, as recently reported by Terrettaz & Jeanrenaud [Biochem. J. (1990) 270, 803-807]. PMID:1684102

  9. Does antiepileptogenesis affect sleep in genetic epileptic rats?

    PubMed

    van Luijtelaar, Gilles; Wilde, Matthias; Citraro, Rita; Scicchitano, Francesca; van Rijn, Clementina

    2012-07-01

    Recently it was established that early long lasting treatment with the anti-absence drug ethosuximide (ETX) delays the occurrence of absences and reduces depressive-like symptoms in a genetic model for absence epilepsy, rats of the WAG/Rij strain. Here it is investigated whether anti-epileptogenesis (chronic treatments with ETX for 2 and 4 months) affects REM sleep in this model. Four groups of weaned male WAG/Rij rats were treated with ETX for 4 months, two groups for 2 months (at 2-3 and 4-5 months of age), the fourth group was untreated. Next, the rats were recorded 6 days after the last day of the treatment for 22.5 h. Non-REM sleep and REM sleep parameters and delta power were analyzed in four characteristic and representative hours of the recoding period. Four months treatment with ETX reduced the amount of REM sleep and REM sleep as percentage of total sleep time. Other sleep parameters were not affected by the treatment. Clear differences between the various hours of the light-dark phase in amounts of non-REM and REM sleep and delta power were found, in line with commonly reported circadian sleep patterns. It can be concluded that the reduction of REM sleep is unique for the early and long lasting chronic treatment. The outcomes may explain our earlier finding that a reduction of REM sleep might alleviate depressive like symptoms.

  10. Genetic profiling of two phenotypically distinct outbred rats derived from a colony of the Zucker fatty rats maintained at Tokyo Medical University.

    PubMed

    Nakanishi, Satoshi; Kuramoto, Takashi; Kashiwazaki, Naomi; Yokoi, Norihide

    2017-05-03

    The Zucker fatty (ZF) rat is an outbred rat and a well-known model of obesity without diabetes, harboring a missense mutation (fatty, abbreviated as fa) in the leptin receptor gene (Lepr). Slc:Zucker (Slc:ZF) outbred rats exhibit obesity while Hos:ZFDM-Lepr(fa) (Hos:ZFDM) outbred rats exhibit obesity and type 2 diabetes. Both outbred rats have been derived from an outbred ZF rat colony maintained at Tokyo Medical University. So far, genetic profiles of these outbred rats remain unknown. Here, we applied a simple genotyping method using Ampdirect reagents and FTA cards (Amp-FTA) in combination with simple sequence length polymorphisms (SSLP) markers to determine genetic profiles of Slc:ZF and Hos:ZFDM rats. Among 27 SSLP marker loci, 24 loci (89%) were fixed for specific allele at each locus in Slc:ZF rats and 26 loci (96%) were fixed in Hos:ZFDM rats, respectively. This indicates the low genetic heterogeneity in both colonies of outbred rats. Nine loci (33%) showed different alleles between the two outbred rats, suggesting considerably different genetic profiles between the two outbred rats in spite of the same origin. Additional analysis using 72 SSLP markers further supported these results and clarified the profiles in detail. This study revealed that genetic profiles of the Slc:ZF and Hos:ZFDM outbred rats are different for about 30% of the SSLP marker loci, which is the underlying basis for the phenotypic difference between the two outbred rats.

  11. Nutritional evaluation of genetically modified maize corn performed on rats.

    PubMed

    Chrenková, Mária; Sommer, A; Ceresnáková, Zuzana; Nitrayová, Sona; Prostredná, Miroslava

    2002-06-01

    The aim of this study was to determine the composition and nutritional value of conventional and transgenic, so-called Roundup Ready (RR) maize with an introduced gene of glyphosate resistance. Crude protein, crude fibre, ash, fat, starch, sugar, amino acids, fatty acid and macroelement levels were determined by chemical analysis. In both maize lines a low level of Ca (0.15 g.kg-1 DM) and of the essential amino acids lysine and tryptophan (2.6 and 1.7 g.kg-1 DM, respectively) were observed. In the biological experiment carried out on rats the tested maize lines were the only dietary sources of nitrogen, thus, the experimental diets contained 9% CP in dietary dry matter. In the feeding experiment no significant differences in the protein efficiency ratio (PER) were observed between groups receiving conventional or transgenic maize (1.51 and 1.41, respectively). Also almost equal results were obtained in the balance experiments. Both maize lines revealed a high nitrogen digestibility (84.9 and 84.5%, respectively) and the net protein utilization amounted to 63.5 and 63.2%, respectively. From these results can be concluded that regarding nutrient composition and utilisation, genetically modified (RR) maize is equivalent to isogenic maize.

  12. Heart mass and blood pressure have separate genetic determinants in the New Zealand genetically hypertensive (GH) rat.

    PubMed

    Harris, E L; Phelan, E L; Thompson, C M; Millar, J A; Grigor, M R

    1995-04-01

    To determine associations between cardiovascular parameters and genotype in 205 F2 rats of both sexes and lineages from reciprocal crosses made between rats of the New Zealand genetically hypertensive (GH) and Brown Norway (BN) rat strains. Systolic tail blood pressure, mean arterial blood pressure, pulse rate, heart mass, body mass and relative heart mass were determined for each rat in the age range 17-19 weeks, and DNA polymorphisms were examined for the guanylyl cyclase A (GCA), angiotensin converting enzyme (ACE) and renin (REN) genes. The phenotypic data indicated the presence of genes on the X and Y chromosomes that affected blood pressure. The GH GCA allele, in males only, and the GH ACE allele, in females only, both cosegregated with increased blood pressure. The ACE effect was confined to rats of one lineage only, namely those with GH grandfathers. A cosegregation of the GH REN allele with decreased blood pressure was also detected in females with BN grandfathers. In contrast, the GH REN allele cosegregated with a smaller heart in males only, whereas the GH ACE allele cosegregated with a larger heart both in males and in females. In males this was the consequence of a decrease in body mass with no change in absolute heart mass, whereas in females there were changes in both of these parameters. The results show that cardiac hypertrophy and blood pressure have independent genetic determinants in the GH rat, and indicate the importance of sex in determining the phenotypic expression of genes underlying cardiovascular pathology.

  13. Genetic and phenotypic characterization of a Japanese wild-derived DOB/Oda rat strain.

    PubMed

    Kuramoto, Takashi; Inoue, Satoko; Neoda, Yuki; Yamasaki, Ken-ichi; Hashimoto, Ryoko; Mashimo, Tomoji; Oda, Sen-ichi; Serikawa, Tadao

    2013-08-01

    Wild-derived rat strains can provide novel genome resources that are not available in standard laboratory strains. Genetic backgrounds of wild-derived strains can facilitate effective genetic linkage analyses and often modulate the expression of mutant phenotypes. Here we describe the development and characterization of a new inbred rat strain, DOB/Oda, from wild rats (Rattus norvegicus) captured in Shitara, Aichi, Japan. Phenotype analysis of 109 parameters revealed that the DOB/Oda rats had small body weight, preference for darkness, and high locomotor activity compared with the rat strains in the National BioResource Project for the Rat (NBRP-Rat) database. Genome analysis with 357 SSLP markers identified DOB/Oda-specific alleles in 70 markers. The percentage of SSLP markers that showed polymorphism between the DOB/Oda strain and any of 132 laboratory strains from NBRP-Rat varied from 89 to 95 %. The polymorphic rate (average of the values of the percentage) for the DOB/Oda strain was 91.6 %, much higher than the rates for available wild-derived strains such as the Brown Norway rat. A phylogenic tree constructed with DOB/Oda and all the strains in NBRP-Rat showed that the DOB/Oda strain localized within the wild rat groups, apparently separate from the laboratory strains. Together, these findings indicated that the DOB/Oda rat has a unique genome that is not available in the laboratory strains. Therefore, the new DOB/Oda strain will provide an important genome resource that will be useful for designing genetic experiments and for the discovery of genes that modulate mutant phenotypes.

  14. Heterogeneous stock rats: a new model to study the genetics of renal phenotypes

    PubMed Central

    Solberg Woods, Leah C.; Stelloh, Cary; Regner, Kevin R.; Schwabe, Tiffany; Eisenhauer, Jessica

    2010-01-01

    Chronic kidney disease is a growing medical concern, with an estimated 25.6 million people in the United States exhibiting some degree of kidney injury and/or decline in kidney function. Animal models provide great insight into the study of the genetics of complex diseases. In particular, heterogeneous stock (HS) rats represent a unique genetic resource enabling rapid fine-mapping of complex traits. However, they have not been explored as a model to study renal phenotypes. To evaluate the usefulness of HS rats in the genetics of renal traits, a time course evaluation (weeks 8–40) was performed for several renal phenotypes. As expected, a large degree of variation was seen for most renal traits. By week 24, three (of 40) rats exhibited marked proteinuria that increased gradually until week 40 and ranged from 33.7 to 80.2 mg/24 h. Detailed histological analysis confirmed renal damage in these rats. In addition, several rats consistently exhibited significant hematuria (5/41). Interestingly, these rats were not the same rats that exhibited proteinuria, indicating that susceptibility to different types of kidney injury is likely segregating within the HS population. One HS rat exhibited unilateral renal agenesis (URA), which was accompanied by a significant degree of proteinuria and glomerular and tubulointerstitial injury. The parents of this HS rat were identified and bred further. Additional offspring of this pair were observed to exhibit URA at frequency between 40% and 60%. In summary, these novel data demonstrate that HS rats exhibit variation in proteinuria and other kidney-related traits, confirming that the model harbors susceptibility alleles for kidney injury and providing the basis for further genetic studies. PMID:20219828

  15. Heredity mode of genetic polymorphism in aldehyde oxidase activity in Donryu strain rats.

    PubMed

    Adachi, M; Itoh, K; Abe, H; Tanaka, Y

    2008-01-01

    Donryu strain rats show genetic polymorphisms in the aldehyde oxidase gene, resulting in the phenotypic expression of ultrarapid metabolizers with homozygous nucleotide sequences (337G, 2604C), extensive metabolizers with heterozygous nucleotide sequences (377G/A, 2604C/T), and poor metabolizers with homozygous nucleotide sequences (377A, 2604T). In the mating experiments the ratio of the number of ultrarapid metabolizers, extensive metabolizers, and poor metabolizers rats in the F1 generation from the heterozygous F0 extensive metabolizers male and female rats was roughly 0.6 : 1.5 : 1, and the ratio converged to approximately 1 : 2 : 1 in the F2 generation from the heterozygous F1 extensive metabolizers male and female rats. On the contrary, all the F2 generation from homozygous F1 ultrarapid metabolizers male and female rats or from homozygous F1 poor metabolizers male and female rats had the ultrarapid metabolizers or the poor metabolizers genotypes and phenotypes. The genotypes completely agreed with the phenotypes in all individuals of F0, F1, and F2 generations. The results indicate that the genetic polymorphism of aldehyde oxidase in Donryu strain rats obeys Mendelian heredity. The reason for a low ratio of the ultrarapid metabolizers rats in the commercially available Donryu strain rats - not more than several per cent - compared with the ratio expected from the Mendelian rule is unknown.

  16. Pathophysiology of the Hypercalciuria in the Genetic Hypercalciuric Stone-Forming Rats

    NASA Astrophysics Data System (ADS)

    Bushinsky, David A.

    2007-04-01

    Given evidence for a genetic cause of hypercalciuria, we screened adult male and female Sprague-Dawley (SD) rats for hypercalciuria and used those with the highest urinary calcium excretion to breed the next generation, followed by subsequent selection and inbreeding of their most hypercalciuric progeny. By the 30th generation, and continuing to the present, the GHS rats (for Genetic Hypercalciuric Stone-forming rats) excrete 8-10 times as much calcium as simultaneously studied control rats The GHS rats were found to have defects in calcium transport in the intestine, kidneys and bone, similar to abnormalities found in many patients with idiopathic hypercalciuria. The GHS rats also form kidney stones. By the conclusion of an 18 wk study, all of the GHS rats formed stones, while there was no stone formation in similarly treated SD controls. The GHS rats, when fed a standard 1.2% calcium diet, form only poorly crystalline apatite stones. However, when 5% hydroxyproline is added to the diet of the GHS rats, they form only calcium oxalate stones.

  17. Heterogeneous stock rats: a model to study the genetics of despair-like behavior in adolescence.

    PubMed

    Holl, Katie; He, Hong; Wedemeyer, Michael; Clopton, Larissa; Wert, Stephanie; Meckes, Jeanie K; Cheng, Riyan; Kastner, Abigail; Palmer, Abraham A; Redei, Eva E; Solberg Woods, Leah C

    2017-08-22

    Major depressive disorder (MDD) is a complex illness caused by both genetic and environmental factors. Antidepressant resistance also has a genetic component. To date, however, very few genes have been identified for major depression or antidepressant resistance. In the current study, we investigated whether outbred heterogeneous stock (HS) rats would be a suitable model to uncover the genetics of depression and its connection to antidepressant resistance. The Wistar Kyoto (WKY) rat, one of the eight founders of the HS, is a recognized animal model of juvenile depression and is resistant to fluoxetine antidepressant treatment. We therefore hypothesized that adolescent HS rats would exhibit variation in both despair-like behavior and response to fluoxetine treatment. We assessed heritability of despair-like behavior and response to sub-acute fluoxetine using a modified forced swim test (FST) in four-week old HS rats. We also tested whether blood transcript levels previously identified as depression biomarkers in adolescent human subjects are differentially expressed in HS rats with high versus low FST immobility. We demonstrate heritability of despair-like behavior in four-week old HS rats and show that many HS rats are resistant to fluoxetine treatment. In addition, blood transcript levels of Amfr, Cdr2, and Kiaa1539, genes previously identified in human adolescents with MDD, are differentially expressed between HS rats with high vs low immobility. These data demonstrate that FST despair-like behavior will be amenable to genetic fine-mapping in adolescent HS rats. The overlap between human and HS blood biomarkers suggest that these studies may translate to depression in humans. This article is protected by copyright. All rights reserved.

  18. Genetic bases of renal agenesis in the ACI rat: mapping of Renag1 to chromosome 14.

    PubMed

    Shull, James D; Lachel, Cynthia M; Strecker, Tracy E; Spady, Thomas J; Tochacek, Martin; Pennington, Karen L; Murrin, Clare R; Meza, Jane L; Schaffer, Beverly S; Flood, Lisa A; Gould, Karen A

    2006-07-01

    Unilateral renal agenesis (URA) is a common developmental defect in humans, occurring at a frequency of approximately 1 in 500-1,000 births. Several genetic syndromes include bilateral or unilateral renal agenesis as an associated phenotype. However, URA frequently occurs in individuals not afflicted by these syndromes and is often asymptomatic. Although it is clear that genetic factors contribute to the etiology of URA, the genetic bases of URA are poorly defined at this time. ACI rats, both males and females, exhibit URA at an incidence of 5%-15%. In this article we characterize the incidence of URA in female and male F(1), F(2), and backcross (BC) progeny from reciprocal genetic crosses between the ACI strain and the unaffected Brown Norway (BN) strain. Through interval mapping analyses of 353 phenotypically defined female F(2) progeny, we mapped to rat Chromosome 14 (RNO14) a genetic locus, designated Renag1 (Renal agenesis 1), that serves as the major determinant of URA in these crosses. Further genotypic analyses of URA-affected female and male F(2) and BC progeny localized Renag1 to a 14.4-Mb interval on RNO14 bounded by markers D14Rat50 and D14Rat12. The data from these genetic studies suggest that the ACI allele of Renag1 acts in an incompletely dominant and incompletely penetrant manner to confer URA.

  19. Genetic background of nonmutant Piebald-Virol-Glaxo rats does not influence nephronophthisis phenotypes

    PubMed Central

    Yengkopiong, Jada Pasquale; Lako, Joseph Daniel Wani

    2013-01-01

    Background Nephronophthisis (NPHP), which affects multiple organs, is a hereditary cystic kidney disease (CKD), characterized by interstitial fibrosis and numerous fluid-filled cysts in the kidneys. It is caused by mutations in NPHP genes, which encode for ciliary proteins known as nephrocystins. The disorder affects many people across the world and leads to end-stage renal disease. The aim of this study was to determine if the genetic background of the nonmutant female Piebald-Virol-Glaxo (PVG/Seac–/–) rat influences phenotypic inheritance of NPHP from mutant male Lewis polycystic kidney rats. Methods Mating experiments were performed between mutant Lewis polycystic kidney male rats with CKD and nonmutant PVG and Wistar Kyoto female rats without cystic kidney disease to raise second filial and backcross 1 progeny, respectively. Rats that developed cystic kidneys were identified. Systolic blood pressure was determined in each rat at 12 weeks of age using the tail and cuff method. After euthanasia, blood samples were collected and chemistry was determined. Histological examination of the kidneys, pancreas, and liver of rats with and without cystic kidney disease was performed. Results It was established that the genetic background of nonmutant female PVG rats did not influence the phenotypic inheritance of the CKD from mutant male Lewis polycystic kidney rats. The disease arose as a result of a recessive mutation in a single gene (second filial generation, CKD = 13, non-CKD = 39, χ2 = 0.00, P ≥ 0.97; backcross 1 generation, CKD = 67, non-CKD = 72, χ2 = 0.18, P > 0.05) and inherited as NPHP. The rats with CKD developed larger fluid-filled cystic kidneys, higher systolic blood pressure, and anemia, but there were no extrarenal cysts and disease did not lead to early pup mortality. Conclusion The genetic background of the nonmutant PVG rats does not influence the genetic and phenotypic inheritance of CKD from mutant Lewis polycystic kidney rats. A single

  20. Genetic and Dietary Effects on Dendrites in the Rat Hypothalamic Ventromedial Nucleus

    PubMed Central

    LaBelle, Denise R.; Cox, Julia M.; Dunn-Meynell, Ambrose A.; Levin, Barry E.; Flanagan-Cato, Loretta M.

    2009-01-01

    Both genetic and environmental factors contribute to individual differences in body weight regulation. The present study examined a possible role for the dendritic arbor of hypothalamic ventromedial nucleus (VMH) neurons in a model of diet-induced obesity (DIO) in male rats. Rats were screened and selectively bred for being either susceptible, i.e., exhibiting DIO, or diet resistant (DR) when exposed to a 31% fat diet. A 2×2 experimental design was used, based on these two strains of rats and exposure to rat chow versus the 31% fat diet for seven weeks. Golgi-impregnated neurons were measured for soma size and dendrite parameters, including number, length, and direction. As previously observed, each VMH neuron had a single long primary dendrite. Genetic background and diet did not affect soma size or the number of dendrites of VMH neurons. However, genetic background exerted a main effect on the length of the long primary dendrites. In particular, the long primary dendrites were approximately 12.5% shorter on the VMH neurons in the DIO rats compared with DR rats regardless of diet. This effect was isolated to the long primary dendrites extending in the dorsolateral direction, with these long primary dendrites 19% shorter for the DIO group compared with the DR group. This finding implicates the connectivity of the long primary dendrites on VMH neurons in the control of energy balance. The functional significance of these shortened dendrites and their afferents warrants further study. PMID:19698729

  1. Neurodevelopmental malformations of the cerebellar vermis in genetically engineered rats

    EPA Science Inventory

    The cerebellar vermis is particularly vulnerable to neurodevelopmental malformations in humans and rodents. Sprague-Dawley, and Long-Evans rats exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis. Malformati...

  2. Neurodevelopmental malformations of the cerebellar vermis in genetically engineered rats

    EPA Science Inventory

    The cerebellar vermis is particularly vulnerable to neurodevelopmental malformations in humans and rodents. Sprague-Dawley, and Long-Evans rats exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis. Malformati...

  3. Genetic heterogeneity of Pneumocystis carinii from rats of several regions and strains

    PubMed Central

    Chung, Byung-Suk; Pars, Yun-Kyu; Huh, Sun; Yu, Jae-Ran; Kim, Jin; Shi, Xiaohua; Cho, Sang Rock; Lee, Soon-Hyung

    2000-01-01

    Pneumocystis carinii is a major opportunistic pathogen which has been found in the lungs of a wide variety of mammalian host species, and the fact suggests the possibility of intraspecific variation. Until now, P. carinii from different mammalian species are differentiated as subspecies, and the rats are known to be infected by two subspecies. The present study investigated genetic heterogeneity of P. carinii isolates from two strains of rats in Korea and China by molecular karyotyping, RFLP and sequencing analysis. Karyotypes of P. carinii were grouped into three, two from two strains of rats in Korea and one from rats in China. However RFLP of PCR product of ribosomal and MSG gene of the P. carinii isolates showed same pattern. The sequence homology rates of α-tubulin DNA of the P. carinii isolates were 96% in Seoul Wistar rats, 93% in Seoul Sprague-Dawley rats, and 85% in Chinese Sprague-Dawley rats. The present finding confirmed that P. carinii from rats in Korea are grouped into two karyotype strains which are different from that of P. carinii from rats in China. The Chinese isolate shows a little different sequences of α-tubulin DNA. PMID:11002650

  4. Combined sequence-based and genetic mapping analysis of complex traits in outbred rats.

    PubMed

    Baud, Amelie; Hermsen, Roel; Guryev, Victor; Stridh, Pernilla; Graham, Delyth; McBride, Martin W; Foroud, Tatiana; Calderari, Sophie; Diez, Margarita; Ockinger, Johan; Beyeen, Amennai D; Gillett, Alan; Abdelmagid, Nada; Guerreiro-Cacais, Andre Ortlieb; Jagodic, Maja; Tuncel, Jonatan; Norin, Ulrika; Beattie, Elisabeth; Huynh, Ngan; Miller, William H; Koller, Daniel L; Alam, Imranul; Falak, Samreen; Osborne-Pellegrin, Mary; Martinez-Membrives, Esther; Canete, Toni; Blazquez, Gloria; Vicens-Costa, Elia; Mont-Cardona, Carme; Diaz-Moran, Sira; Tobena, Adolf; Hummel, Oliver; Zelenika, Diana; Saar, Kathrin; Patone, Giannino; Bauerfeind, Anja; Bihoreau, Marie-Therese; Heinig, Matthias; Lee, Young-Ae; Rintisch, Carola; Schulz, Herbert; Wheeler, David A; Worley, Kim C; Muzny, Donna M; Gibbs, Richard A; Lathrop, Mark; Lansu, Nico; Toonen, Pim; Ruzius, Frans Paul; de Bruijn, Ewart; Hauser, Heidi; Adams, David J; Keane, Thomas; Atanur, Santosh S; Aitman, Tim J; Flicek, Paul; Malinauskas, Tomas; Jones, E Yvonne; Ekman, Diana; Lopez-Aumatell, Regina; Dominiczak, Anna F; Johannesson, Martina; Holmdahl, Rikard; Olsson, Tomas; Gauguier, Dominique; Hubner, Norbert; Fernandez-Teruel, Alberto; Cuppen, Edwin; Mott, Richard; Flint, Jonathan

    2013-07-01

    Genetic mapping on fully sequenced individuals is transforming understanding of the relationship between molecular variation and variation in complex traits. Here we report a combined sequence and genetic mapping analysis in outbred rats that maps 355 quantitative trait loci for 122 phenotypes. We identify 35 causal genes involved in 31 phenotypes, implicating new genes in models of anxiety, heart disease and multiple sclerosis. The relationship between sequence and genetic variation is unexpectedly complex: at approximately 40% of quantitative trait loci, a single sequence variant cannot account for the phenotypic effect. Using comparable sequence and mapping data from mice, we show that the extent and spatial pattern of variation in inbred rats differ substantially from those of inbred mice and that the genetic variants in orthologous genes rarely contribute to the same phenotype in both species.

  5. Combined sequence-based and genetic mapping analysis of complex traits in outbred rats

    PubMed Central

    Baud, Amelie; Hermsen, Roel; Guryev, Victor; Stridh, Pernilla; Graham, Delyth; McBride, Martin W.; Foroud, Tatiana; Calderari, Sophie; Diez, Margarita; Ockinger, Johan; Beyeen, Amennai D.; Gillett, Alan; Abdelmagid, Nada; Guerreiro-Cacais, Andre Ortlieb; Jagodic, Maja; Tuncel, Jonatan; Norin, Ulrika; Beattie, Elisabeth; Huynh, Ngan; Miller, William H.; Koller, Daniel L.; Alam, Imranul; Falak, Samreen; Osborne-Pellegrin, Mary; Martinez-Membrives, Esther; Canete, Toni; Blazquez, Gloria; Vicens-Costa, Elia; Mont-Cardona, Carme; Diaz-Moran, Sira; Tobena, Adolf; Hummel, Oliver; Zelenika, Diana; Saar, Kathrin; Patone, Giannino; Bauerfeind, Anja; Bihoreau, Marie-Therese; Heinig, Matthias; Lee, Young-Ae; Rintisch, Carola; Schulz, Herbert; Wheeler, David A.; Worley, Kim C.; Muzny, Donna M.; Gibbs, Richard A.; Lathrop, Mark; Lansu, Nico; Toonen, Pim; Ruzius, Frans Paul; de Bruijn, Ewart; Hauser, Heidi; Adams, David J.; Keane, Thomas; Atanur, Santosh S.; Aitman, Tim J.; Flicek, Paul; Malinauskas, Tomas; Jones, E. Yvonne; Ekman, Diana; Lopez-Aumatell, Regina; Dominiczak, Anna F; Johannesson, Martina; Holmdahl, Rikard; Olsson, Tomas; Gauguier, Dominique; Hubner, Norbert; Fernandez-Teruel, Alberto; Cuppen, Edwin; Mott, Richard; Flint, Jonathan

    2013-01-01

    Genetic mapping on fully sequenced individuals is transforming our understanding of the relationship between molecular variation and variation in complex traits. Here we report a combined sequence and genetic mapping analysis in outbred rats that maps 355 quantitative trait loci for 122 phenotypes. We identify 35 causal genes involved in 31 phenotypes, implicating novel genes in models of anxiety, heart disease and multiple sclerosis. The relation between sequence and genetic variation is unexpectedly complex: at approximately 40% of quantitative trait loci a single sequence variant cannot account for the phenotypic effect. Using comparable sequence and mapping data from mice, we show the extent and spatial pattern of variation in inbred rats differ significantly from those of inbred mice, and that the genetic variants in orthologous genes rarely contribute to the same phenotype in both species. PMID:23708188

  6. Neonatal sensory deprivation promotes development of absence seizures in adult rats with genetic predisposition to epilepsy.

    PubMed

    Sitnikova, Evgenia

    2011-03-04

    Absence epilepsy has age-related onset. In a WAG/Rij rat genetic model, absence seizures appear after puberty and they are increased with age. It is known that (1) epileptic activity in WAG/Rij rats is initiated at the perioral area in the somatosensory cortex; (2) sensory deprivation, i.e., whisker trimming during the critical period of development, could enhance excitatory activity in the somatosensory cortex. It is hypothesized that the cortex may become more excitable after neonatal vibrissae removal, and this may precipitate absence seizures in adult rats. We found that whisker trimming during the first postnatal weeks caused more rapid development of EEG seizure activity in adult WAG/Rij rats. Epileptic discharges in the trimmed rats were more numerous (vs control), showed longer duration and often appeared in desynchronized and drowsy EEG. The number of absence-like spindle-shaped EEG events (spike-wave spindles) in the whisker-trimmed rats was higher than in control, especially during the intermediate sleep state. An age-dependent increase of intermediate sleep state was found in the trimmed rats, but not in the intact animals. We discuss epigenetic factors that can modulate absence epilepsy in genetically prone subjects.

  7. From integrative genomics to systems genetics in the rat to link genotypes to phenotypes

    PubMed Central

    Moreno-Moral, Aida

    2016-01-01

    ABSTRACT Complementary to traditional gene mapping approaches used to identify the hereditary components of complex diseases, integrative genomics and systems genetics have emerged as powerful strategies to decipher the key genetic drivers of molecular pathways that underlie disease. Broadly speaking, integrative genomics aims to link cellular-level traits (such as mRNA expression) to the genome to identify their genetic determinants. With the characterization of several cellular-level traits within the same system, the integrative genomics approach evolved into a more comprehensive study design, called systems genetics, which aims to unravel the complex biological networks and pathways involved in disease, and in turn map their genetic control points. The first fully integrated systems genetics study was carried out in rats, and the results, which revealed conserved trans-acting genetic regulation of a pro-inflammatory network relevant to type 1 diabetes, were translated to humans. Many studies using different organisms subsequently stemmed from this example. The aim of this Review is to describe the most recent advances in the fields of integrative genomics and systems genetics applied in the rat, with a focus on studies of complex diseases ranging from inflammatory to cardiometabolic disorders. We aim to provide the genetics community with a comprehensive insight into how the systems genetics approach came to life, starting from the first integrative genomics strategies [such as expression quantitative trait loci (eQTLs) mapping] and concluding with the most sophisticated gene network-based analyses in multiple systems and disease states. Although not limited to studies that have been directly translated to humans, we will focus particularly on the successful investigations in the rat that have led to primary discoveries of genes and pathways relevant to human disease. PMID:27736746

  8. Urban population genetics of slum-dwelling rats (Rattus norvegicus) in Salvador, Brazil

    PubMed Central

    Kajdacsi, Brittney; Costa, Federico; Hyseni, Chaz; Porter, Fleur; Brown, Julia; Rodrigues, Gorete; Farias, Helena; Reis, Mitermeyer G.; Childs, James E.; Ko, Albert I.; Caccone, Adalgisa

    2013-01-01

    Throughout the developing world, urban centers with sprawling slum settlements are rapidly expanding and invading previously forested ecosystems. Slum communities are characterized by untended refuse, open sewers, and overgrown vegetation, which promote rodent infestation. Norway rats (Rattus norvegicus), are reservoirs for epidemic transmission of many zoonotic pathogens of public health importance. Understanding the population ecology of R. norvegicus is essential to formulate effective rodent control strategies, as this knowledge aids estimation of the temporal stability and spatial connectivity of populations. We screened for genetic variation, characterized the population genetic structure, and evaluated the extent and patterns of gene flow in the urban landscape using 17 microsatellite loci in 146 rats from 9 sites in the city of Salvador, Brazil. These sites were divided between three neighborhoods within the city spaced an average of 2.7 km apart. Surprisingly, we detected very little relatedness among animals trapped at the same site and found high levels of genetic diversity, as well as structuring across small geographic distances. Most FST comparisons among sites were statistically significant, including sites <400 m apart. Bayesian analyses grouped the samples in three genetic clusters, each associated with distinct sampling sites from different neighborhoods or valleys within neighborhoods. These data indicate the existence of complex genetic structure in R. norvegicus in Salvador, linked to the heterogeneous urban landscape. Future rodent control measures need to take into account the spatial and temporal linkage of rat populations in Salvador, as revealed by genetic data, to develop informed eradication strategies. PMID:24118116

  9. Genetic and Molecular Basis of Quantitative Trait Loci of Arthritis in Rat: Genes and Polymorphisms1

    PubMed Central

    Xiong, Qing; Jiao, Yan; Hasty, Karen A.; Stuart, John M.; Postlethwaite, Arnold; Kang, Andrew H.; Gu, Weikuan

    2012-01-01

    Rheumatoid arthritis (RA) is an autoimmune disease, the pathogenesis of which is affected by multiple genetic and environmental factors. To understand the genetic and molecular basis of RA, a large number of quantitative trait loci (QTL) that regulate experimental autoimmune arthritis have been identified using various rat models for RA. However, identifying the particular responsible genes within these QTL remains a major challenge. Using currently available genome data and gene annotation information, we systematically examined RA-associated genes and polymorphisms within and outside QTL over the whole rat genome. By the whole genome analysis of genes and polymorphisms, we found that there are significantly more RA-associated genes in QTL regions as contrasted with non-QTL regions. Further experimental studies are necessary to determine whether these known RA-associated genes or polymorphisms are genetic components causing the QTL effect. PMID:18606636

  10. Whole-Genome Sequencing Reveals Genetic Variation in the Asian House Rat

    PubMed Central

    Teng, Huajing; Zhang, Yaohua; Shi, Chengmin; Mao, Fengbiao; Hou, Lingling; Guo, Hongling; Sun, Zhongsheng; Zhang, Jianxu

    2016-01-01

    Whole-genome sequencing of wild-derived rat species can provide novel genomic resources, which may help decipher the genetics underlying complex phenotypes. As a notorious pest, reservoir of human pathogens, and colonizer, the Asian house rat, Rattus tanezumi, is successfully adapted to its habitat. However, little is known regarding genetic variation in this species. In this study, we identified over 41,000,000 single-nucleotide polymorphisms, plus insertions and deletions, through whole-genome sequencing and bioinformatics analyses. Moreover, we identified over 12,000 structural variants, including 143 chromosomal inversions. Further functional analyses revealed several fixed nonsense mutations associated with infection and immunity-related adaptations, and a number of fixed missense mutations that may be related to anticoagulant resistance. A genome-wide scan for loci under selection identified various genes related to neural activity. Our whole-genome sequencing data provide a genomic resource for future genetic studies of the Asian house rat species and have the potential to facilitate understanding of the molecular adaptations of rats to their ecological niches. PMID:27172215

  11. Chromatographic determination of 7,8-methylenedioxy-4H-2,3-benzodiazepin-4-ones in rat plasma: relationship to their anticonvulsant activity.

    PubMed

    Rizzo, M; De Sarro, G; Zappalà, M; Grasso, S

    2002-07-25

    The present investigation was designed to develop an assay suitable for pharmacokinetic studies of new compounds, i.e. the novel 7,8-methylenedioxy-4H-2,3-benzodiazepin-4-one derivatives (2a and 2b), acting as non-competitive AMPA-receptor antagonists. A reversed-phase high-performance liquid chromatographic method has been developed to determine the time-course of plasma concentrations of derivatives 2a and 2b administered intraperitoneally to Sprague-Dawley rats. The separation of compounds studied and a N-methyl-2,3-benzodiazepin-4-one derivative as internal standard (I.S.) from plasma, were carried out by liquid-liquid extraction using diethyl ether. The samples were injected onto the analytical column (Partisil 10 ODS) eluted with acetonitrile/0.01 M acetate buffer (pH 5.3) at a flow-rate of 2 ml/min and detected at 240 nm. Compounds 2a, 2b and I.S. gave retention times of 8.5, 5.25 and 11.1 min, respectively. The selectivity of the method was satisfactory. The mean recovery from spiked rat plasma ranged from 86.7 to 91.6% for 2a, and from 85.1 to 87.0% for 2b. The procedures were validated with a good reproducibility and linear response from 0.0625 to 2 microg/ml, with a regression coefficient of 0.9932 for 2a and 0.9854 for 2b. The lower limit of quantification (LOQ) was taken as 15 ng/ml for the two compounds. 2a and 2b showed no signs of significant degradation in rat plasma during storage at -20 degrees C and following freeze/thaw cycles. Moreover, plasma levels of the tested compounds have been correlated with their anticonvulsant activity, determined in vivo in genetically epilepsy-prone rats. Due to its sensitivity, the method was suitable for application to pharmacokinetic study.

  12. Acupuncture modulates mechanical responses of smooth muscle produced by transmural nerve stimulation in gastric antrum of genetically hyperglycemic rats.

    PubMed

    Fukuta, Hiroyasu; Koshita, Makoto; Nakamura, Eri; Nakamura, Hironori; Yamada, Atsushi; Kawase, Yoshiyuki; Ishigami, Tatsuyo; Kurono, Yasuzo; Iino, Satoshi; Suzuki, Hikaru

    2009-08-01

    Effects of acupuncture treatment on mechanical responses produced by transmural nerve stimulation (TNS) and acetylcholine (ACh) were investigated in circular smooth muscle preparations isolated from the antrum of the stomach of genetically hyperglycemic rats. While control rats had blood glucose levels of about 140 mg/dl, this was approximately tripled in the genetically hyperglycemic rats, but only doubled in the acupuncture treated genetically hyperglycemic rats. Antrum smooth muscle produced phasic contractions spontaneously, with a similar frequency and amplitude in the three groups of rats. Effects of atropine and Nomega-nitro-L-arginine (L-NA) on TNS-induced responses revealed that in the antrum smooth muscle of the control rats, cholinergic excitatory, non-adrenergic non-cholinergic excitatory (NANCE), nitrergic inhibitory and off-responses produced projections: the last projection was considered to be non-adrenergic non-cholinergic non-nitrergic (NANCNN) in nature. In genetically hyperglycemic rats, nitrergic and NANCNN projections were enhanced and NANCE projections were absent. Acupuncture treated genetically hyperglycemic rats showed a reduction of NANCNN projection and enhancement of cholinergic projection, with no alteration to nitrergic projection, but a recovery of NANCE projection. ACh elicited inhibitory responses at low concentrations (1-30 nM) and excitatory responses at high concentrations (100-300 nM), in the three groups of rats. L-NA converted the ACh-induced inhibitory responses to excitatory responses. Immunohistochemical examination indicated no significant difference in the distribution of c-Kit expressing cells in the antrum smooth muscle from the three groups of rats. The results indicated that in antral smooth muscle, hyperglycemia was associated with enhanced activity in nitrergic and NANCNN projections and attenuation of NANCE projections, and that acupuncture treatment caused both a reduced blood glucose level and attenuated NANCNN

  13. [A 104-week feeding study of genetically modified soybeans in F344 rats].

    PubMed

    Sakamoto, Yoshimitsu; Tada, Yukie; Fukumori, Nobutaka; Tayama, Kuniaki; Ando, Hiroshi; Takahashi, Hiroshi; Kubo, Yoshikazu; Nagasawa, Akemichi; Yano, Norio; Yuzawa, Katsuhiro; Ogata, Akio

    2008-08-01

    A chronic feeding study to evaluate the safety of genetically modified glyphosate-tolerant soybeans (GM soybeans) was conducted using F344 DuCrj rats. The rats were fed diet containing GM soybeans or Non-GM soybeans at the concentration of 30% in basal diet. Non-GM soybeans were a closely related strain to the GM soybeans. These two diets were adjusted to an identical nutrient level. In this study, the influence of GM soybeans in rats was compared with that of the Non-GM soybeans, and furthermore, to assess the effect of soybeans themselves, the groups of rats fed GM and Non-GM soybeans were compared with a group fed commercial diet (CE-2). General conditions were observed daily and body weight and food consumption were recorded. At the termination (104 weeks), animals were subjected to hematology, serum biochemistry, and pathological examinations. There were several differences in animal growth, food intake, organ weights and histological findings between the rats fed the GM and/or Non-GM soybeans and the rats fed CE-2. However, body weight and food intake were similar for the rats fed the GM and Non-GM soybeans. Gross necropsy findings, hematological and serum biochemical parameters, and organ weights showed no meaningful difference between rats fed the GM and Non-GM soybeans. In pathological observation, there was neither an increase in incidence nor any specific type of nonneoplastic or neoplastic lesions in the GM soybeans group in each sex. These results indicate that long-term intake of GM soybeans at the level of 30% in diet has no apparent adverse effect in rats.

  14. A comparison of molecular alterations in environmental and genetic rat models of ADHD: a pilot study.

    PubMed

    DasBanerjee, Tania; Middleton, Frank A; Berger, David F; Lombardo, John P; Sagvolden, Terje; Faraone, Stephen V

    2008-12-05

    Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder in school-aged children. In addition to genetic factors, environmental influences or gene x environmental interactions also play an important role in ADHD. One example of a well studied environmental risk factor for ADHD is exposure to polychlorinated biphenyls (PCBs). In this study, we investigated whether the well-established genetic model of ADHD based on the spontaneously hypertensive rat (SHR) and a well established PCB-based model of ADHD exhibited similar molecular changes in brain circuits involved in ADHD. The brains from 28 male rats (8 SHR, 8 Sprague-Dawley (SD) controls, 8 Wistar/Kyoto (WKY) controls, and 4 PCB-exposed SD rats) were harvested at postnatal days (PNDs) 55-65 and RNA was isolated from six brain regions of interest. The RNA was analyzed for differences in expression of a set of 308 probe sets interrogating 218 unique genes considered highly relevant to ADHD or epigenetic gene regulation using the Rat RAE230 2.0 GeneChip (Affymetrix). Selected observations were confirmed by real-time quantitative RT-PCR. The results show that the expression levels of genes Gnal, COMT, Adrbk1, Ntrk2, Hk1, Syt11, and Csnk1a1 were altered in both the SHR rats and the PCB-exposed SD rats. Arrb2, Stx12, Aqp6, Syt1, Ddc, and Pgk1 expression levels were changed only in the PCB-exposed SD rats. Genes with altered expression only in the SHRs included Oprm1, Calcyon, Calmodulin, Lhx1, and Hes6. The epigenetic genes Crebbp, Mecp2, and Hdac5 are significantly altered in both models. The data provide strong evidence that genes and environment can affect different set of genes in two different models of ADHD and yet result in the similar disease-like symptoms. Copyright 2008 Wiley-Liss, Inc.

  15. A Comparison of Molecular Alterations in Environmental and Genetic Rat Models of ADHD: a pilot study

    PubMed Central

    DasBanerjee, Tania; Middleton, Frank A.; Berger, David F.; Lombardo, John P.; Sagvolden, Terje; Faraone, Stephen V.

    2008-01-01

    Attention Deficit Hyperactivity Disorder (ADHD) is the most common neurobehavioral disorder in school-aged children. In addition to genetic factors, environmental influences or gene × environmental interactions also play an important role in ADHD. One example of a well studied environmental risk factor for ADHD is exposure to polychlorinated biphenyls (PCBs). In this study, we investigated whether the well-established genetic model of ADHD based on the Spontaneously Hypertensive Rat (SHR) and a well established PCB-based model of ADHD exhibited similar molecular changes in brain circuits involved in ADHD. The brains from 28 male rats (8 SHR, 8 Sprague-Dawley (SD) controls, 8 Wistar-Kyoto (WKY) controls, and 4 PCB-exposed SD rats) were harvested at postnatal day 55-65 and RNA was isolated from six brain regions of interest. The RNA was analyzed for differences in expression of a set of 308 probe sets interrogating 218 unique genes considered highly relevant to ADHD or epigenetic gene regulation using the Rat RAE 230 2.0 GeneChip (Affymetrix). Selected observations were confirmed by real time quantitative RT-PCR. The results show that the expression levels of genes Gnal, COMT, Adrbk1, Ntrk2, Hk1, Syt11 and Csnk1a1 were altered in both the SHR rats and the PCB-exposed SD rats. Arrb2, Stx12, Aqp6, Syt1, Ddc and Pgk1 expression levels were changed only in the PCB-exposed SD rats. Genes with altered expression only in the SHRs included Oprm1, Calcyon, Calmodulin, Lhx1 and Hes6. The epigenetic genes Crebbp, Mecp2 and Hdac5 are significantly altered in both models. The data provide strong evidence that genes and environment can affect different set of genes in two different models of ADHD and yet result in the similar disease-like symptoms. PMID:18937310

  16. Urban population genetics of slum-dwelling rats (Rattus norvegicus) in Salvador, Brazil.

    PubMed

    Kajdacsi, Brittney; Costa, Federico; Hyseni, Chaz; Porter, Fleur; Brown, Julia; Rodrigues, Gorete; Farias, Helena; Reis, Mitermayer G; Childs, James E; Ko, Albert I; Caccone, Adalgisa

    2013-10-01

    Throughout the developing world, urban centres with sprawling slum settlements are rapidly expanding and invading previously forested ecosystems. Slum communities are characterized by untended refuse, open sewers and overgrown vegetation, which promote rodent infestation. Norway rats (Rattus norvegicus) are reservoirs for epidemic transmission of many zoonotic pathogens of public health importance. Understanding the population ecology of R. norvegicus is essential to formulate effective rodent control strategies, as this knowledge aids estimation of the temporal stability and spatial connectivity of populations. We screened for genetic variation, characterized the population genetic structure and evaluated the extent and patterns of gene flow in the urban landscape using 17 microsatellite loci in 146 rats from nine sites in the city of Salvador, Brazil. These sites were divided between three neighbourhoods within the city spaced an average of 2.7 km apart. Surprisingly, we detected very little relatedness among animals trapped at the same site and found high levels of genetic diversity, as well as structuring across small geographical distances. Most F(ST) comparisons among sites were statistically significant, including sites <400 m apart. Bayesian analyses grouped the samples in three genetic clusters, each associated with distinct sampling sites from different neighbourhoods or valleys within neighbourhoods. These data indicate the existence of complex genetic structure in R. norvegicus in Salvador, linked to the heterogeneous urban landscape. Future rodent control measures need to take into account the spatial and temporal linkage of rat populations in Salvador, as revealed by genetic data, to develop informed eradication strategies. © 2013 John Wiley & Sons Ltd.

  17. Rats: gnawing through the barriers to understanding genetic susceptibility and breast cancer.

    PubMed

    Blackburn, Anneke C

    2011-10-12

    Advances in genotyping technology have provided us with a large number of genetic loci associated with cancer susceptibility; however, our ability to understand the functional effects of the genetic variants of these loci remains limited. In the previous issue, Smits and colleagues demonstrate the use of congenic rat strains to discover that the Mcs5a breast cancer susceptibility locus is most likely acting through the immune system, via novel transcriptional regulatory mechanisms. This challenges our conventional thinking of cancer susceptibility and gene regulation pathways, and illustrates the potential for rodent models to help us functionally characterize polymorphisms of cancer-associated loci.

  18. Genetic basis of the impaired renal myogenic response in FHH rats

    PubMed Central

    Burke, Marilyn; Pabbidi, Malikarjuna; Fan, Fan; Ge, Ying; Liu, Ruisheng; Williams, Jan Michael; Sarkis, Allison; Lazar, Jozef; Jacob, Howard J.

    2013-01-01

    This study examined the effect of substitution of a 2.4-megabase pair (Mbp) region of Brown Norway (BN) rat chromosome 1 (RNO1) between 258.8 and 261.2 Mbp onto the genetic background of fawn-hooded hypertensive (FHH) rats on autoregulation of renal blood flow (RBF), myogenic response of renal afferent arterioles (AF-art), K+ channel activity in renal vascular smooth muscle cells (VSMCs), and development of proteinuria and renal injury. FHH rats exhibited poor autoregulation of RBF, while FHH.1BN congenic strains with the 2.4-Mbp BN region exhibited nearly perfect autoregulation of RBF. The diameter of AF-art from FHH rats increased in response to pressure but decreased in congenic strains containing the 2.4-Mbp BN region. Protein excretion and glomerular and interstitial damage were significantly higher in FHH rats than in congenic strains containing the 2.4-Mbp BN region. K+ channel current was fivefold greater in VSMCs from renal arterioles of FHH rats than cells obtained from congenic strains containing the 2.4-Mbp region. Sequence analysis of the known and predicted genes in the 2.4-Mbp region of FHH rats revealed amino acid-altering variants in the exons of three genes: Add3, Rbm20, and Soc-2. Quantitative PCR studies indicated that Mxi1 and Rbm20 were differentially expressed in the renal vasculature of FHH and FHH.1BN congenic strain F. These data indicate that transfer of this 2.4-Mbp region from BN to FHH rats restores the myogenic response of AF-art and autoregulation of RBF, decreases K+ current, and slows the progression of proteinuria and renal injury. PMID:23220727

  19. Heritable multiplex genetic engineering in rats using CRISPR/Cas9.

    PubMed

    Ma, Yuanwu; Shen, Bin; Zhang, Xu; Lu, Yingdong; Chen, Wei; Ma, Jing; Huang, Xingxu; Zhang, Lianfeng

    2014-01-01

    The CRISPR/Cas9 system has been proven to be an efficient gene-editing tool for genome modification of cells and organisms. Multiplex genetic engineering in rat holds a bright future for the study of complex disease. Here, we show that this system enables the simultaneous disruption of four genes (ApoE, B2m, Prf1, and Prkdc) in rats in one-step, by co-injection of Cas9 mRNA and sgRNAs into fertilized eggs. We further observed the gene modifications are germline transmittable, and confirmed the off-target mutagenesis and mosaicism are rarely detected by comprehensive analysis. Thus, the CRISPR/Cas9 system makes it possible to efficiently and reliably generate gene knock-out rats.

  20. EXPERIMENTAL INDUCTION OF CHRONIC PULMONARY DISEASE IN GENETICALLY SUSCEPTIBLE RAT MODEL

    EPA Science Inventory



    Experimental induction of chronic pulmonary disease in genetically susceptible rat model. M.C.Schladweiler, BS 1, A.D.Ledbetter 1, K.E.Pinkerton, PhD 2, K.R.Smith, PhD 2, P.S.Gilmour, PhD 1, P.A.Evansky 1, D.L.Costa, ScD 1, W.P.Watkinson, PhD 1, J.P.Nolan 1 and U.P.Kodava...

  1. EXPERIMENTAL INDUCTION OF CHRONIC PULMONARY DISEASE IN GENETICALLY SUSCEPTIBLE RAT MODEL

    EPA Science Inventory



    Experimental induction of chronic pulmonary disease in genetically susceptible rat model. M.C.Schladweiler, BS 1, A.D.Ledbetter 1, K.E.Pinkerton, PhD 2, K.R.Smith, PhD 2, P.S.Gilmour, PhD 1, P.A.Evansky 1, D.L.Costa, ScD 1, W.P.Watkinson, PhD 1, J.P.Nolan 1 and U.P.Kodava...

  2. IMPACT OF GENETIC STRAIN ON BODY FAT LOSS, FOOD CONSUMPTION, METABOLISM, VENTILATION, AND MOTOR ACTIVITY IN FREE RUNNING FEMALE RATS

    EPA Pesticide Factsheets

    Physiologic data associated with different strains of common laboratory rat strains.This dataset is associated with the following publication:Gordon , C., P. Phillips , and A. Johnstone. Impact of Genetic Strain on Body Fat Loss, Food Consumption, Metabolism, Ventilation, and Motor Activity in Free Running Female Rats. PHYSIOLOGY AND BEHAVIOR. Elsevier Science Ltd, New York, NY, USA, 153: 56-63, (2016).

  3. Low-Anxiety Rat Phenotypes Can Be Further Reduced through Genetic Intervention

    PubMed Central

    Granzotto, Natalli; Ramos, André

    2013-01-01

    Background A previous study using an intercross between the inbred rat strains Lewis (LEW) and Spontaneously Hypertensive Rats (SHR) identified a locus on chromosome 4, named Anxrr16, influencing an experimental index of anxiety and showing a transgressive effect, with alleles from the LEW strain (more anxious) decreasing rather than increasing anxiety. Objective To confirm the location and isolate the effect of a rat genome region named Anxrr16 through a planned genomic recombination strategy, where the target locus in SHR rats was replaced with LEW genetic material. Methods A new congenic strain, named SHR.LEW-Anxrr16 (SLA16), was developed from a cross between LEW (donor) and SHR (receptor) rats and then evaluated in several anxiety-related tests. The activity and attention levels of the new strain were also evaluated, since hyperactivity was observed during its construction and because SHR is a model of attention deficit hyperactivity disorder. Results Significant effects of Anxrr16 were found for open field central locomotion, as well as for other indices of anxiety from the light/dark box, triple test and T-maze. In all cases, the low-anxiety levels of SHR rats were further reduced by the insertion of LEW alleles. Differences in locomotor activity were found only in unfamiliar (hence stressful) environments and no genetic effects were observed in indices of attention. Conclusion The SLA16 strain can help in the identification of the molecular pathways involved in experimental anxiety and it demonstrates how apparently extreme phenotypes sometimes hide major opposite-acting genes. PMID:24386249

  4. Unique Regulatory Properties of Mesangial Cells Are Genetically Determined in the Rat

    PubMed Central

    Lai, Ping-Chin; Chiu, Ling-Yin; Srivastava, Prashant; Trento, Cristina; Dazzi, Francesco; Petretto, Enrico; Cook, H. Terence; Behmoaras, Jacques

    2014-01-01

    Mesangial cells are glomerular cells of stromal origin. During immune complex mediated crescentic glomerulonephritis (Crgn), infiltrating and proliferating pro-inflammatory macrophages lead to crescent formation. Here we have hypothesised that mesangial cells, given their mesenchymal stromal origin, show similar immunomodulatory properties as mesenchymal stem cells (MSCs), by regulating macrophage function associated with glomerular crescent formation. We show that rat mesangial cells suppress conA-stimulated splenocyte proliferation in vitro, as previously shown for MSCs. We then investigated mesangial cell-macrophage interaction by using mesangial cells isolated from nephrotoxic nephritis (NTN)-susceptible Wistar Kyoto (WKY) and NTN-resistant Lewis (LEW) rats. We first determined the mesangial cell transcriptome in WKY and LEW rats and showed that this is under marked genetic control. Supernatant transfer results show that WKY mesangial cells shift bone marrow derived macrophage (BMDM) phenotype to M1 or M2 according to the genetic background (WKY or LEW) of the BMDMs. Interestingly, these effects were different when compared to those of MSCs suggesting that mesangial cells can have unique immunomodulatory effects in the kidney. These results demonstrate the importance of the genetic background in the immunosuppressive effects of cells of stromal origin and specifically of mesangial cell-macrophage interactions in the pathophysiology of crescentic glomerulonephritis. PMID:25343449

  5. [Expression of apoptosis genes in the brain of rats with genetically defined fear-induced aggression].

    PubMed

    Ilchibaeva, T V; Tsybko, A S; Kozhemyakina, R V; Naumenko, V S

    2016-01-01

    The programmed cell death (or apoptosis) plays an important role both in developing and mature brains. Multiple data indicate the involvement of processes of apoptosis in mechanisms of different psychopathologies. At the same time, nothing is known about the role of apoptosis in the regulation of genetically defined aggression. In the present work, the expression of the genes that encode main pro- and antiapoptotic BAX and BCL-XL proteins, as well as caspase 3 (the main effector of apoptosis), in different brain structures of rats that were selected on a high aggression towards human (or its absence) was studied. A significant increase in the expression of the gene encoding caspase 3 was detected in the hypothalamus. This was accompanied by a significant decrease in the expression of proapoptotic Bax gene in the hippocampus and increase in mRNA level of antiapoptotic Bcl-xl gene in the raphe nuclei area of midbrain in highly aggressive rats. An increase in the ratio Bcl-xl: Bax was found in the midbrain and amygdala; a trend towards an increase in the ratio was also found in hippocampus of aggressive animals compared to tame animals. Thus, we demonstrated that genetically defined fear-induced aggression is associated with significant changes in the genetic control of apoptosis in the brain. It is assumed that an increase in the Bcl-xl gene expression (accompanied by a decrease in the Bax gene expression) can indicate an increase in the threshold of neuronal apoptosis in highly aggressive rats.

  6. Locus-specific genetic differentiation at Rw among warfarin-resistant rat (Rattus norvegicus) populations.

    PubMed Central

    Kohn, Michael H; Pelz, Hans-Joachim; Wayne, Robert K

    2003-01-01

    Populations may diverge at fitness-related genes as a result of adaptation to local conditions. The ability to detect this divergence by marker-based genomic scans depends on the relative magnitudes of selection, recombination, and migration. We survey rat (Rattus norvegicus) populations to assess the effect that local selection with anticoagulant rodenticides has had on microsatellite marker variation and differentiation at the warfarin resistance gene (Rw) relative to the effect on the genomic background. Initially, using a small sample of 16 rats, we demonstrate tight linkage of microsatellite D1Rat219 to Rw by association mapping of genotypes expressing an anticoagulant-rodenticide-insensitive vitamin K 2,3-epoxide reductase (VKOR). Then, using allele frequencies at D1Rat219, we show that predicted and observed resistance levels in 27 populations correspond, suggesting intense and recent selection for resistance. A contrast of F(ST) values between D1Rat219 and the genomic background revealed that rodenticide selection has overwhelmed drift-mediated population structure only at Rw. A case-controlled design distinguished these locus-specific effects of selection at Rw from background levels of differentiation more effectively than a population-controlled approach. Our results support the notion that an analysis of locus-specific population genetic structure may assist the discovery and mapping of novel candidate loci that are the object of selection or may provide supporting evidence for previously identified loci. PMID:12871915

  7. Anxiety and locomotion in Genetic Absence Epilepsy Rats from Strasbourg (GAERS): inclusion of Wistar rats as a second control.

    PubMed

    Marques-Carneiro, José Eduardo; Faure, Jean-Baptiste; Cosquer, Brigitte; Koning, Estelle; Ferrandon, Arielle; de Vasconcelos, Anne Pereira; Cassel, Jean-Christophe; Nehlig, Astrid

    2014-09-01

    The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) is a genetic model, derived from Wistar rats by selective breeding. In all previous studies, GAERS were compared to their paired selected strain not expressing spike-and-wave discharges (SWDs), namely nonepileptic controls (NECs). Because the occurrence/absence of SWDs is of polygenic origin, some other traits could have been selected along with occurrence/absence of SWDs. Therefore, we explored the importance of using a second control group consisting in Wistar rats, the strain of origin of GAERS, in addition to NECs, on locomotion and anxiety in GAERS. A test battery encompassing home-cage, open-field, beam-walking and elevated plus-maze evaluations was used. In addition, stereologic analyses were performed to assess the volume of thalamus, amygdala, and hippocampus. The occurrence/absence of SWDs was determined in all three strains by electroencephalography (EEG) recording. When compared to NECs and Wistars, GAERS displayed lower exploratory activity and fastened habituation to novelty. In the plus-maze, scores of GAERS and Wistars were similar, but NECs appeared significantly less anxious (possibly in association with increased amygdala volume); evidence for weaker anxiety in NECs was also found in the open-field evaluation. The volumetric study revealed increased thalamic volume in GAERS compared to both control groups. SWDs were present in all GAERS and in 80% of Wistars. Compared to the original Wistar strain as an additional control group, the selective breeding that generated the GAERS has no incidence on anxiety-related behavior, conversely to the selection of SWD suppression in NECs, in which anxiety is attenuated. These findings point to the importance of using a second control group composed of Wistar rats in studies characterizing the behavioral profile of GAERS. Thereby, possible confusions between occurrence/absence of SWDs and other features that come along with selection and/or differential

  8. Genetic influences on brain gene expression in rats selected for tameness and aggression.

    PubMed

    Heyne, Henrike O; Lautenschläger, Susann; Nelson, Ronald; Besnier, François; Rotival, Maxime; Cagan, Alexander; Kozhemyakina, Rimma; Plyusnina, Irina Z; Trut, Lyudmila; Carlborg, Örjan; Petretto, Enrico; Kruglyak, Leonid; Pääbo, Svante; Schöneberg, Torsten; Albert, Frank W

    2014-11-01

    Interindividual differences in many behaviors are partly due to genetic differences, but the identification of the genes and variants that influence behavior remains challenging. Here, we studied an F2 intercross of two outbred lines of rats selected for tame and aggressive behavior toward humans for >64 generations. By using a mapping approach that is able to identify genetic loci segregating within the lines, we identified four times more loci influencing tameness and aggression than by an approach that assumes fixation of causative alleles, suggesting that many causative loci were not driven to fixation by the selection. We used RNA sequencing in 150 F2 animals to identify hundreds of loci that influence brain gene expression. Several of these loci colocalize with tameness loci and may reflect the same genetic variants. Through analyses of correlations between allele effects on behavior and gene expression, differential expression between the tame and aggressive rat selection lines, and correlations between gene expression and tameness in F2 animals, we identify the genes Gltscr2, Lgi4, Zfp40, and Slc17a7 as candidate contributors to the strikingly different behavior of the tame and aggressive animals. Copyright © 2014 by the Genetics Society of America.

  9. Production of WTC.ZI-zi rat congenic strain and its pathological and genetic analyses.

    PubMed

    Kuramoto, T; Yamasaki, K; Kondo, A; Nakajima, K; Yamada, M; Serikawa, T

    1998-04-01

    A new rat congenic strain, WTC.ZI-zi, was produced after eleven generations of backcrossing between ZI strain as a donor strain and WTC strain as an inbred partner. WTC.ZI-zi/zi homozygous rats generally exhibit more conspicuous body tremor and much earlier occurrence of flaccid paresis than the original ZI strain. The average life span of the congenic strain is approximately nine months, which is also much shorter than that of the original ZI strain. Pathological analysis of the central nervous system of the congenic strain revealed more aggravated vacuolation and hypomyelination than in the original ZI strain. Establishment of the genetic profile with microsatellite markers showed that the congenic strain was genetically almost identical to the WTC strain except for a small chromosome segment bearing the zitter gene. Analysis of markers in this region implied that the length of the donor segment was approximately 13.4 centimorgans which corresponded to 0.65% of the total genome. Thus, these results suggested that expressional alterations of zitter gene were due to replacement of the genetic background from the original ZI strain to the WTC strain. Furthermore, the WTC.ZI-zi congenic strain could provide a refined tool for the analysis of zitter mutation, because the congenic strain has a strict control strain, WTC, and the length of the donor chromosome is genetically defined.

  10. Channelrhodopsin-2 gene transduced into retinal ganglion cells restores functional vision in genetically blind rats.

    PubMed

    Tomita, Hiroshi; Sugano, Eriko; Isago, Hitomi; Hiroi, Teru; Wang, Zhuo; Ohta, Emi; Tamai, Makoto

    2010-03-01

    To test the hypothesis that transduction of the channelrhodopsin-2 (ChR2) gene, a microbial-type rhodopsin gene, into retinal ganglion cells of genetically blind rats will restore functional vision, we recorded visually evoked potentials and tested the experimental rats for the presence of optomotor responses. The N-terminal fragment of the ChR2 gene was fused to the fluorescent protein Venus and inserted into an adeno-associated virus to make AAV2-ChR2V. AAV2-ChR2V was injected intravitreally into the eyes of 6-month-old dystrophic RCS (rdy/rdy) rats. Visual function was evaluated six weeks after the injection by recording visually evoked potentials (VEPs) and testing optomotor responses. The expression of ChR2V in the retina was investigated histologically. We found that VEPs could not be recorded from 6-month-old dystrophic RCS rats that had not been injected with AAV2-ChR2V. In contrast, VEPs were elicited from RCS rats six weeks after injection with AAV2-ChR2V. The VEPs were recorded at stimulation rates <20Hz, which was the same as that of normal rats. Optomotor responses were also significantly better after the AAV2-ChR2V injection. Expression of ChR2V was observed mainly in the retinal ganglion cells. These findings demonstrate that visual function can be restored in blind rats by transducing the ChR2V gene into retinal ganglion cells.

  11. A 90-Day Feeding Study in Rats to Assess the Safety of Genetically Engineered Pork

    PubMed Central

    Xiao, Gao-jun; Jiang, Sheng-Wang; Qian, Li-Li; Cai, Chun-Bo; Wang, Qing-qing; Ma, De-Zun; Li, Biao; Xie, Shan-shan; Cui, Wen-Tao; Li, Kui

    2016-01-01

    Our laboratory recently produced genetically engineered (GE) Meishan pigs containing a ZFN-edited myostatin loss-of-function mutant. These GE pigs develop and grow as normal as wild type pigs but produce pork with greater lean yield and lower fat mass. To assess any potential subchronic toxicity risks of this GE pork, a 90-day feeding study was conducted in Sprague-Dawley rats. Rats were randomly divided into five groups, and fed for 90 days with basic diet and basic diets formulated with low dose and high dose pork prepared from wild type pigs and GE pigs, respectively. Animal behaviors and clinical signs were monitored twice daily, and body weight and food consumption were measured and recorded weekly. At days 45 and 90, blood tests (lipid panel, electrolytes, parameters related to liver and kidney functions, and complete blood counts) were performed. Additionally, gross pathology and histopathological analyses were performed for major organs in each group. Data analysis shows that there were no significant differences in growth rate, food consumption, and blood test parameters between rat groups fed with GE pork and wild type pork. Although differences in some liver function parameters (such as aspartate aminotransferase, total proteins, albumin, and alkaline phosphatase) and white blood cell counts (such as lymphocyte percentage and monocyte percentage) were observed between rats fed with high dose GE pork and basic diet, all test results in rats fed with GE pork are in the normal range. Additionally, there are no apparent lesions noted in all organs isolated from rats in all five feeding groups on days 45 and 90. Overall, our results clearly indicate that food consumption of GE pork produced by ZFN-edited myostatin loss-of-function mutant pigs did not have any long-term adverse effects on the health status in rats. PMID:27812153

  12. A 90-Day Feeding Study in Rats to Assess the Safety of Genetically Engineered Pork.

    PubMed

    Xiao, Gao-Jun; Jiang, Sheng-Wang; Qian, Li-Li; Cai, Chun-Bo; Wang, Qing-Qing; Ma, De-Zun; Li, Biao; Xie, Shan-Shan; Cui, Wen-Tao; Li, Kui

    2016-01-01

    Our laboratory recently produced genetically engineered (GE) Meishan pigs containing a ZFN-edited myostatin loss-of-function mutant. These GE pigs develop and grow as normal as wild type pigs but produce pork with greater lean yield and lower fat mass. To assess any potential subchronic toxicity risks of this GE pork, a 90-day feeding study was conducted in Sprague-Dawley rats. Rats were randomly divided into five groups, and fed for 90 days with basic diet and basic diets formulated with low dose and high dose pork prepared from wild type pigs and GE pigs, respectively. Animal behaviors and clinical signs were monitored twice daily, and body weight and food consumption were measured and recorded weekly. At days 45 and 90, blood tests (lipid panel, electrolytes, parameters related to liver and kidney functions, and complete blood counts) were performed. Additionally, gross pathology and histopathological analyses were performed for major organs in each group. Data analysis shows that there were no significant differences in growth rate, food consumption, and blood test parameters between rat groups fed with GE pork and wild type pork. Although differences in some liver function parameters (such as aspartate aminotransferase, total proteins, albumin, and alkaline phosphatase) and white blood cell counts (such as lymphocyte percentage and monocyte percentage) were observed between rats fed with high dose GE pork and basic diet, all test results in rats fed with GE pork are in the normal range. Additionally, there are no apparent lesions noted in all organs isolated from rats in all five feeding groups on days 45 and 90. Overall, our results clearly indicate that food consumption of GE pork produced by ZFN-edited myostatin loss-of-function mutant pigs did not have any long-term adverse effects on the health status in rats.

  13. Maternal and genetic factors in stress-resilient and -vulnerable rats: a cross-fostering study.

    PubMed

    Uchida, Shusaku; Hara, Kumiko; Kobayashi, Ayumi; Otsuki, Koji; Hobara, Teruyuki; Yamagata, Hirotaka; Watanabe, Yoshifumi

    2010-02-26

    Early environmental factors can modulate the development of the hypothalamic-pituitary-adrenal (HPA) axis response to stress, together with subsequent brain functions and emotional behaviors. Two rat strains, Sprague-Dawley (SD) and Fischer 344 (F344), are known to exhibit differences in HPA axis reactivity and anxiety behavior in response to restraint stress in adulthood. To investigate the contribution of maternal influences in determining HPA axis and behavioral responses to stress, a cross-fostering study was performed using stress-resilient (SD) or stress-susceptible (F344) strains. We found that SD rats adopted by either an SD (in-fostered) or an F344 (cross-fostered) dam and F344 rats adopted by an SD dam (cross-fostered) showed a suppression of the HPA axis response following 14 days of repeated restraint stress. In contrast, F344 rats adopted by an F344 dam (in-fostered) did not show such HPA axis habituation. We also found that F344 rats adopted by an F344 dam showed increased anxiety-related behaviors in social interaction and novelty-suppressed feeding tests as a result of the 14 days of restraint stress, while SD rats adopted by either an SD or an F344 dam and F344 rats adopted by an SD dam showed normal anxiety-related behaviors under the same experimental conditions. These results suggest that while genetic differences between SD and F344 strains account for some of the variations in stress vulnerability, maternal factors also contribute. (c) 2009 Elsevier B.V. All rights reserved.

  14. Chlorthalidone Improves Vertebral Bone Quality in Genetic Hypercalciuric Stone-Forming Rats

    PubMed Central

    Bushinsky, David A.; Willett, Thomas; Asplin, John R.; Culbertson, Christopher; Che, Sara P.Y.; Grynpas, Marc

    2015-01-01

    We have bred a strain of rats to maximize urine (U) calcium (Ca) excretion and model hypercalciuric nephrolithiasis. These genetic hypercalciuric stone-forming (GHS) rats excrete more UCa than control Sprague-Dawley rats, uniformly form kidney stones and, similar to patients, demonstrate lower bone mineral density. Clinically thiazide diuretics reduce UCa and prevent stone formation; however, whether they benefit bone is not clear. We used GHS rats to test the hypothesis that the thiazide diuretic chlorthalidone (CTD) would have a favorable effect on bone density and quality. Twenty GHS rats received a fixed amount of a 1.2% Ca diet and half were also fed CTD (4–5 mg/kg/day). Rats fed CTD had a marked reduction in UCa. The axial and appendicular skeletons were studied. An increase in trabecular mineralization was observed with CTD compared to controls. CTD also improved the architecture of trabecular bone. Using µCT, trabecular bone volume (BV/TV), trabecular thickness and trabecular number were increased with CTD. A significant increase in trabecular thickness with CTD was confirmed by static histomorphometry. CTD also improved the connectivity of trabecular bone. Significant improvements in vertebral strength and stiffness were measured by vertebral compression. Conversely, a slight loss of bending strength was detected in the femoral diaphysis with CTD. Thus, results obtained in hypercalciuric rats suggest that CTD can favorably influence vertebral fracture risk. CTD did not alter formation parameters suggesting that the improved vertebral bone strength was due to decreased bone resorption and retention of bone structure. PMID:21351146

  15. Brain network reorganization differs in response to stress in rats genetically predisposed to depression and stress-resilient rats.

    PubMed

    Gass, N; Becker, R; Schwarz, A J; Weber-Fahr, W; Clemm von Hohenberg, C; Vollmayr, B; Sartorius, A

    2016-12-06

    Treatment-resistant depression (TRD) remains a pressing clinical problem. Optimizing treatment requires better definition of the specificity of the involved brain circuits. The rat strain bred for negative cognitive state (NC) represents a genetic animal model of TRD with high face, construct and predictive validity. Vice versa, the positive cognitive state (PC) strain represents a stress-resilient phenotype. Although NC rats show depressive-like behavior, some symptoms such as anhedonia require an external trigger, i.e. a stressful event, which is similar to humans when stressful event induces a depressive episode in genetically predisposed individuals (gene-environment interaction). We aimed to distinguish neurobiological predisposition from the depressogenic pathology at the level of brain-network reorganization. For this purpose, resting-state functional magnetic resonance imaging time series were acquired at 9.4 Tesla scanner in NC (N=11) and PC (N=7) rats before and after stressful event. We used a graph theory analytical approach to calculate the brain-network global and local properties. There was no difference in the global characteristics between the strains. At the local level, the response in the risk strain was characterized with an increased internodal role and reduced local clustering and efficiency of the anterior cingulate cortex (ACC) and prelimbic cortex compared to the stress-resilient strain. We suggest that the increased internodal role of these prefrontal regions could be due to the enhancement of some of their long-range connections, given their connectivity with the amygdala and other default-mode-like network hubs, which could create a bias to attend to negative information characteristic for depression.

  16. Brain network reorganization differs in response to stress in rats genetically predisposed to depression and stress-resilient rats

    PubMed Central

    Gass, N; Becker, R; Schwarz, A J; Weber-Fahr, W; Clemm von Hohenberg, C; Vollmayr, B; Sartorius, A

    2016-01-01

    Treatment-resistant depression (TRD) remains a pressing clinical problem. Optimizing treatment requires better definition of the specificity of the involved brain circuits. The rat strain bred for negative cognitive state (NC) represents a genetic animal model of TRD with high face, construct and predictive validity. Vice versa, the positive cognitive state (PC) strain represents a stress-resilient phenotype. Although NC rats show depressive-like behavior, some symptoms such as anhedonia require an external trigger, i.e. a stressful event, which is similar to humans when stressful event induces a depressive episode in genetically predisposed individuals (gene–environment interaction). We aimed to distinguish neurobiological predisposition from the depressogenic pathology at the level of brain-network reorganization. For this purpose, resting-state functional magnetic resonance imaging time series were acquired at 9.4 Tesla scanner in NC (N=11) and PC (N=7) rats before and after stressful event. We used a graph theory analytical approach to calculate the brain-network global and local properties. There was no difference in the global characteristics between the strains. At the local level, the response in the risk strain was characterized with an increased internodal role and reduced local clustering and efficiency of the anterior cingulate cortex (ACC) and prelimbic cortex compared to the stress-resilient strain. We suggest that the increased internodal role of these prefrontal regions could be due to the enhancement of some of their long-range connections, given their connectivity with the amygdala and other default-mode-like network hubs, which could create a bias to attend to negative information characteristic for depression. PMID:27922640

  17. Estimates of genetic parameters of body weight in descendants of X-irradiated rat spermatogonia.

    PubMed

    Gianola, D; Chapman, A B; Rutledge, J J

    1977-08-01

    Effects of nine generations of 450r per generation of ancestral spermatogonial X irradiation of inbred rats on genetic parameters of body weight at 3, 6, and 10 weeks of age and of weight gains between these periods were studied. Covariances among relatives were estimated by mixed model and regression techniques in randomly selected lines with (R) and without (C) radiation history. Analyses of the data were based on five linear genetic models combining additive direct, additive indirect (maternal), dominance and environmental effects. Parameters in these models were estimated by generalized least-squares. A model including direct and indirect genetic effects fit more closely to the data in both R and C lines. Overdominance of induced mutations did not seem to be present. Ancestral irradiation increased maternal additive genetic variances of body weights and gains but not direct genetic variances. Theoretically, due to a negative direct-maternal genetic correlation, within full-sib family selection would be ineffective in increasing body weight at six weeks in both R and C lines. However, progress from mass selection would be expected to be faster in the R lines.

  18. Genetic mapping of two blood pressure quantitative trait loci on rat chromosome 1.

    PubMed Central

    Gu, L; Dene, H; Deng, A Y; Hoebee, B; Bihoreau, M T; James, M; Rapp, J P

    1996-01-01

    A genetic map for rat chromosome 1 was constructed using 66 microsatellite markers typed on either or both of two populations derived from inbred Dahl salt-sensitive (S) rats: F2(LEW x S) n = 151, and F2(WKY x S) n = 159. These populations had been raised on a high salt (8% NaCl) diet. Systolic blood pressure and heart weight were found to be genetically linked to two separate regions on rat chromosome 1 in the F2(LEW x S) population. One region was centered around the anonymous SA locus and accounted for 24 mmHg of blood pressure. The other region was 55 cM from the SA locus centered around a cluster of cytochromes P450 loci, and accounted for 30 mmHg of blood pressure. Since blood pressure and heart weight were highly correlated these same regions were also linked to heart weight. These results were cross-specific as linkage of these chromosome 1 regions to blood pressure and heart weight was not observed in several other F2 populations derived by crossing S and other normotensive control strains. This is presumably due to different alleles and/or different genetic backgrounds in the various populations. The SA region of chromosome 1 was found to influence body weight in F2(LEW x S) rats. Combining the present data with our previously published data on the F2(LEW x S) population showed that four separate quantitative trait loci with additive effects accounted for 106 mmHg and 38% of the total variance of blood pressure and for 506 mg and 34% of the total variance of heart wt. PMID:8609235

  19. Fischer 344 and Lewis Rat Strains as a Model of Genetic Vulnerability to Drug Addiction.

    PubMed

    Cadoni, Cristina

    2016-01-01

    Today it is well acknowledged that both nature and nurture play important roles in the genesis of psychopathologies, including drug addiction. Increasing evidence suggests that genetic factors contribute for at least 40-60% of the variation in liability to drug dependence. Human genetic studies suggest that multiple genes of small effect, rather than single genes, contribute to the genesis of behavioral psychopathologies. Therefore, the use of inbred rat strains might provide a valuable tool to identify differences, linked to genotype, important in liability to addiction and related disorders. In this regard, Lewis and Fischer 344 inbred rats have been proposed as a model of genetic vulnerability to drug addiction, given their innate differences in sensitivity to the reinforcing and rewarding effects of drugs of abuse, as well their different responsiveness to stressful stimuli. This review will provide evidence in support of this model for the study of the genetic influence on addiction vulnerability, with particular emphasis on differences in mesolimbic dopamine (DA) transmission, rewarding and emotional function. It will be highlighted that Lewis and Fischer 344 rats differ not only in several indices of DA transmission and adaptive changes following repeated drug exposure, but also in hypothalamic-pituitary-adrenal (HPA) axis responsiveness, influencing not only the ability of the individual to cope with stressful events, but also interfering with rewarding and motivational processes, given the influence of corticosteroids on dopamine neuron functionality. Further differences between the two strains, as impulsivity or anxiousness, might contribute to their different proneness to addiction, and likely these features might be linked to their different DA neurotransmission plasticity. Although differences in other neurotransmitter systems might deserve further investigation, results from the reviewed studies might open new vistas in understanding aberrant

  20. Fischer 344 and Lewis Rat Strains as a Model of Genetic Vulnerability to Drug Addiction

    PubMed Central

    Cadoni, Cristina

    2016-01-01

    Today it is well acknowledged that both nature and nurture play important roles in the genesis of psychopathologies, including drug addiction. Increasing evidence suggests that genetic factors contribute for at least 40–60% of the variation in liability to drug dependence. Human genetic studies suggest that multiple genes of small effect, rather than single genes, contribute to the genesis of behavioral psychopathologies. Therefore, the use of inbred rat strains might provide a valuable tool to identify differences, linked to genotype, important in liability to addiction and related disorders. In this regard, Lewis and Fischer 344 inbred rats have been proposed as a model of genetic vulnerability to drug addiction, given their innate differences in sensitivity to the reinforcing and rewarding effects of drugs of abuse, as well their different responsiveness to stressful stimuli. This review will provide evidence in support of this model for the study of the genetic influence on addiction vulnerability, with particular emphasis on differences in mesolimbic dopamine (DA) transmission, rewarding and emotional function. It will be highlighted that Lewis and Fischer 344 rats differ not only in several indices of DA transmission and adaptive changes following repeated drug exposure, but also in hypothalamic-pituitary-adrenal (HPA) axis responsiveness, influencing not only the ability of the individual to cope with stressful events, but also interfering with rewarding and motivational processes, given the influence of corticosteroids on dopamine neuron functionality. Further differences between the two strains, as impulsivity or anxiousness, might contribute to their different proneness to addiction, and likely these features might be linked to their different DA neurotransmission plasticity. Although differences in other neurotransmitter systems might deserve further investigation, results from the reviewed studies might open new vistas in understanding aberrant

  1. Spatial learning in the genetically heterogeneous NIH-HS rat stock and RLA-I/RHA-I rats: revisiting the relationship with unconditioned and conditioned anxiety.

    PubMed

    Martínez-Membrives, Esther; López-Aumatell, Regina; Blázquez, Gloria; Cañete, Toni; Tobeña, Adolf; Fernández-Teruel, Alberto

    2015-05-15

    To characterize learning/memory profiles for the first time in the genetically heterogeneous NIH-HS rat stock, and to examine whether these are associated with anxiety, we evaluated NIH-HS rats for spatial learning/memory in the Morris water maze (MWM) and in the following anxiety/fear tests: the elevated zero-maze (ZM; unconditioned anxiety), a context-conditioned fear test and the acquisition of two-way active avoidance (conditioned anxiety). NIH-HS rats were compared with the Roman High- (RHA-I) and Low-Avoidance (RLA-I) rat strains, given the well-known differences between the Roman strains/lines in anxiety-related behavior and in spatial learning/memory. The results show that: (i) As expected, RLA-I rats were more anxious in the ZM test, displayed more frequent context-conditioned freezing episodes and fewer avoidances than RHA-I rats. (ii) Scores of NIH-HS rats in these tests/tasks mostly fell in between those of the Roman rat strains, and were usually closer to the values of the RLA-I strain. (iii) Pigmented NIH-HS (only a small part of NIH-HS rats were albino) rats were the best spatial learners and displayed better spatial memory than the other three (RHA-I, RLA-I and NIH-HS albino) groups. (iv) Albino NIH-HS and RLA-I rats also showed better learning/memory than the RHA-I strain. (v) Within the NIH-HS stock, the most anxious rats in the ZM test presented the best learning and/or memory efficiency (regardless of pigmentation). In summary, NIH-HS rats display a high performance in spatial learning/memory tasks and a passive coping strategy when facing conditioned conflict situations. In addition, unconditioned anxiety in NIH-HS rats predicts better spatial learning/memory.

  2. GENETIC INFLUENCE ON THE DEVELOPMENT OF RENAL HYPERTENSION IN PARABIOTIC RATS

    PubMed Central

    Iwai, J.; Knudsen, K. D.; Dahl, L. K.; Heine, M.; Leitl, G.

    1969-01-01

    The effects of several renal manipulations including uninephrectomy, unilateral renal artery constriction, and a combination of these two (Goldblatt procedure) were studied in two strains of rats with opposite constitutional predispositions to experimental hypertension. The protective value of intact renal tissue to protect against hypertension was shown to be genetically determined. The Goldblatt procedure carried out on only one member of a parabiotic pair induced hypertension in this operated rat but significant hypertension developed in the intact partner only when the operated animal belonged to the strain predisposed to hypertension. It was speculated that there were qualitative differences in the pressor signals of the two strains of rats. In the strain genetically predisposed to hypertension there are at least two pressor principles: (a) one which is common to both strains, not transmittable via the parabiosis junction and presumably related to the renin-angiotensin system; and (b) a second which is specific for the hypertension-prone strain and can be transmitted through the parabiosis junction. This transmittable agent is probably identical with the factor that produces salt hypertension and is associated with the salt-excreting mechanism. PMID:4304137

  3. Organic and genetically modified soybean diets: consequences in growth and in hematological indicators of aged rats.

    PubMed

    Daleprane, Julio Beltrame; Feijó, Tatiana Silveira; Boaventura, Gilson Teles

    2009-03-01

    The aim of this study was to evaluate the protein quality of organic and genetically modified soy by feeding specific diets to rats. Three groups of Wistar rats (n=10) were used, and each group was named according to the food that they ate. There was an organic soy group (OG), a genetically modified soy group (GG), and a control group (CG). All animals received water and diet ad libitum for 455 days. At the end of this period, the weight of the GG group was the same as that of the OG, and both were higher than CG. Protein intake was similar for the OG and GG, which were significantly lower (p<0.0005) than the CG. The growth rate (GR) of the rats, albumin levels, and total levels of serum protein were comparable for all groups. Hematocrit (p<0.04) and hemoglobin (p<0.03) for the OG and GG were less than the CG. Although the OG and GG demonstrated reduced hematocrit and hemoglobin, both types of soy were utilized in a way similar to casein. This result suggests that the protein quality of soy is parallel to the standard protein casein in terms of growth promotion but not hematological indicators.

  4. Progesterone is not responsible for the blood pressure fall in late-pregnant New Zealand genetically hypertensive rats.

    PubMed

    Boyd, R M; Baer, P G

    1984-05-01

    In various models of experimental and genetic hypertension in rats, blood pressure is markedly reduced during late pregnancy. The period during which the blood pressure reduction occurs is also the period when plasma progesterone is maximally elevated, and administration of progesterone to renal hypertensive rats has been reported to reduce blood pressure (J. Armstrong, 1959, Proc. Soc. Exp. Biol. Med. 102:452-455). To test the possibility that elevated plasma progesterone is responsible for the blood pressure reduction in late pregnancy, on Day 14 of pregnancy a group of New Zealand genetically hypertensive (NZGH) rats was ovariectomized and implanted with progesterone-filled capsules, to maintain plasma progesterone at low levels just sufficient to maintain pregnancy, and compared with intact, pregnant NZGH. Ovariectomy did not alter the characteristic course of blood pressure reduction seen in late-pregnant intact NZGH rats. In addition, daily administration of progesterone (15 mg/kg, sc) for 14 days did not alter blood pressure of either nonpregnant NZGH rats or New Zealand normotensive rats with chronic 1-kidney, 1-clip hypertension. It is concluded that blood pressure of NZGH rats is reduced to near normotensive levels in late pregnancy, as reported for other models of rat hypertension, but that elevated plasma progesterone levels are not requisite for that reduction and do not reduce blood pressure of renal hypertensive rats.

  5. Multigeneration reproductive and developmental toxicity study of bar gene inserted into genetically modified potato on rats.

    PubMed

    Rhee, Gyu Seek; Cho, Dae Hyun; Won, Yong Hyuck; Seok, Ji Hyun; Kim, Soon Sun; Kwack, Seung Jun; Lee, Rhee Da; Chae, Soo Yeong; Kim, Jae Woo; Lee, Byung Mu; Park, Kui Lea; Choi, Kwang Sik

    2005-12-10

    Each specific protein has an individual gene encoding it, and a foreign gene introduced to a plant can be used to synthesize a new protein. The identification of potential reproductive and developmental toxicity from novel proteins produced by genetically modified (GM) crops is a difficult task. A science-based risk assessment is needed in order to use GM crops as a conventional foodstuff. In this study, the specific characteristics of GM food and low-level chronic exposure were examined using a five-generation animal study. In each generation, rats were fed a solid pellet containing 5% GM potato and non-GM potato for 10 wk prior to mating in order to assess the potential reproductive and developmental toxic effects. In the multigeneration animal study, there were no GM potato-related changes in body weight, food consumption, reproductive performance, and organ weight. Polymerase chain reaction (PCR) was carried out using extracted genomic DNA to examine the possibility of gene persistence in the organ tissues after a long-term exposure to low levels of GM feed. In each generation, the gene responsible for bar was not found in any of the reproductive organs of the GM potato-treated male and female rats, and the litter-related indexes did not show any genetically modified organism (GMO)-related changes. The results suggest that genetically modified crops have no adverse effects on the multigeneration reproductive-developmental ability.

  6. Genetic Influences on Brain Gene Expression in Rats Selected for Tameness and Aggression

    PubMed Central

    Heyne, Henrike O.; Lautenschläger, Susann; Nelson, Ronald; Besnier, François; Rotival, Maxime; Cagan, Alexander; Kozhemyakina, Rimma; Plyusnina, Irina Z.; Trut, Lyudmila; Carlborg, Örjan; Petretto, Enrico; Kruglyak, Leonid; Pääbo, Svante; Schöneberg, Torsten; Albert, Frank W.

    2014-01-01

    Interindividual differences in many behaviors are partly due to genetic differences, but the identification of the genes and variants that influence behavior remains challenging. Here, we studied an F2 intercross of two outbred lines of rats selected for tame and aggressive behavior toward humans for >64 generations. By using a mapping approach that is able to identify genetic loci segregating within the lines, we identified four times more loci influencing tameness and aggression than by an approach that assumes fixation of causative alleles, suggesting that many causative loci were not driven to fixation by the selection. We used RNA sequencing in 150 F2 animals to identify hundreds of loci that influence brain gene expression. Several of these loci colocalize with tameness loci and may reflect the same genetic variants. Through analyses of correlations between allele effects on behavior and gene expression, differential expression between the tame and aggressive rat selection lines, and correlations between gene expression and tameness in F2 animals, we identify the genes Gltscr2, Lgi4, Zfp40, and Slc17a7 as candidate contributors to the strikingly different behavior of the tame and aggressive animals. PMID:25189874

  7. Important genetic checkpoints for insulin resistance in salt-sensitive (S) Dahl rats

    PubMed Central

    Shehata, Marlene F

    2008-01-01

    Despite the marked advances in research on insulin resistance (IR) in humans and animal models of insulin resistance, the mechanisms underlying high salt-induced insulin resistance remain unclear. Insulin resistance is a multifactorial disease with both genetic and environmental factors (such as high salt) involved in its pathogenesis. High salt triggers insulin resistance in genetically susceptible patients and animal models of insulin resistance. One of the mechanisms by which high salt might precipitate insulin resistance is through its ability to enhance an oxidative stress-induced inflammatory response that disrupts the insulin signaling pathway. The aim of this hypothesis is to discuss two complementary approaches to find out how high salt might interact with genetic defects along the insulin signaling and inflammatory pathways to predispose to insulin resistance in a genetically susceptible model of insulin resistance. The first approach will consist of examining variations in genes involved in the insulin signaling pathway in the Dahl S rat (an animal model of insulin resistance and salt-sensitivity) and the Dahl R rat (an animal model of insulin sensitivity and salt-resistance), and the putative cellular mechanisms responsible for the development of insulin resistance. The second approach will consist of studying the over-expressed genes along the inflammatory pathway whose respective activation might be predictive of high salt-induced insulin resistance in Dahl S rats. Variations in genes encoding the insulin receptor substrates -1 and/or -2 (IRS-1, -2) and/or genes encoding the glucose transporter (GLUTs) proteins have been found in patients with insulin resistance. To better understand the combined contribution of excessive salt and genetic defects to the etiology of the disease, it is essential to investigate the following question: Question 1: Do variations in genes encoding the IRS -1 and -2 and/or genes encoding the GLUTs proteins predict high salt

  8. Impulsive-choice patterns for food in genetically lean and obese Zucker rats.

    PubMed

    Boomhower, Steven R; Rasmussen, Erin B; Doherty, Tiffany S

    2013-03-15

    Behavioral-economic studies have shown that differences between lean and obese Zuckers in food consumption depend on the response requirement for food. Since a response requirement inherently increases the delay to reinforcement, differences in sensitivity to delay may also be a relevant mechanism of food consumption in the obese Zucker rat. Furthermore, the endocannabinoid neurotransmitter system has been implicated in impulsivity, but studies that attempt to characterize the effects of cannabinoid drugs (e.g., rimonabant) on impulsive choice may be limited by floor effects. The present study aimed to characterize impulsive-choice patterns for sucrose using an adjusting-delay procedure in genetically lean and obese Zuckers. Ten lean and ten obese Zucker rats chose between one lever that resulted in one pellet after a standard delay (either 1 s or 5 s) and a second lever that resulted in two or three pellets after an adjusting delay. After behavior stabilized under baseline, rimonabant (0-10 mg/kg) was administered prior to some choice sessions in the two-pellet condition. Under baseline, obese Zuckers made more impulsive choices than leans in three of the four standard-delay/pellet conditions. Additionally, in the 2-pellet condition, rimonabant increased impulsive choice in lean rats in the 1-s standard-delay condition; however, rimonabant decreased impulsive choice in obese rats in the 1-s and 5-s standard-delay conditions. These data suggest that genetic factors that influence impulsive choice are stronger in some choice conditions than others, and that the endocannabinoid system may be a relevant neuromechanism.

  9. Effects of microgravity on vestibular development and function in rats: genetics and environment.

    PubMed

    Ronca, A E; Fritzsch, B; Alberts, J R; Bruce, L L

    2000-09-01

    Our anatomical and behavioral studies of embryonic rats that developed in microgravity suggest that the vestibular sensory system, like the visual system, has genetically mediated processes of development that establish crude connections between the periphery and the brain. Environmental stimuli also regulate connection formation including terminal branch formation and fine-tuning of synaptic contacts. Axons of vestibular sensory neurons from gravistatic as well as linear acceleration receptors reach their targets in both microgravity and normal gravity, suggesting that this is a genetically regulated component of development. However, microgravity exposure delays the development of terminal branches and synapses in gravistatic but not linear acceleration-sensitive neurons and also produces behavioral changes. These latter changes reflect environmentally controlled processes of development.

  10. Effects of microgravity on vestibular development and function in rats: genetics and environment

    NASA Technical Reports Server (NTRS)

    Ronca, A. E.; Fritzsch, B.; Alberts, J. R.; Bruce, L. L.

    2000-01-01

    Our anatomical and behavioral studies of embryonic rats that developed in microgravity suggest that the vestibular sensory system, like the visual system, has genetically mediated processes of development that establish crude connections between the periphery and the brain. Environmental stimuli also regulate connection formation including terminal branch formation and fine-tuning of synaptic contacts. Axons of vestibular sensory neurons from gravistatic as well as linear acceleration receptors reach their targets in both microgravity and normal gravity, suggesting that this is a genetically regulated component of development. However, microgravity exposure delays the development of terminal branches and synapses in gravistatic but not linear acceleration-sensitive neurons and also produces behavioral changes. These latter changes reflect environmentally controlled processes of development.

  11. Effects of microgravity on vestibular development and function in rats: genetics and environment

    NASA Technical Reports Server (NTRS)

    Ronca, A. E.; Fritzsch, B.; Alberts, J. R.; Bruce, L. L.

    2000-01-01

    Our anatomical and behavioral studies of embryonic rats that developed in microgravity suggest that the vestibular sensory system, like the visual system, has genetically mediated processes of development that establish crude connections between the periphery and the brain. Environmental stimuli also regulate connection formation including terminal branch formation and fine-tuning of synaptic contacts. Axons of vestibular sensory neurons from gravistatic as well as linear acceleration receptors reach their targets in both microgravity and normal gravity, suggesting that this is a genetically regulated component of development. However, microgravity exposure delays the development of terminal branches and synapses in gravistatic but not linear acceleration-sensitive neurons and also produces behavioral changes. These latter changes reflect environmentally controlled processes of development.

  12. Changes in skeletal muscle and tendon structure and function following genetic inactivation of myostatin in rats.

    PubMed

    Mendias, Christopher L; Lynch, Evan B; Gumucio, Jonathan P; Flood, Michael D; Rittman, Danielle S; Van Pelt, Douglas W; Roche, Stuart M; Davis, Carol S

    2015-04-15

    Myostatin is a negative regulator of skeletal muscle and tendon mass. Myostatin deficiency has been well studied in mice, but limited data are available on how myostatin regulates the structure and function of muscles and tendons of larger animals. We hypothesized that, in comparison to wild-type (MSTN(+/+) ) rats, rats in which zinc finger nucleases were used to genetically inactivate myostatin (MSTN(Δ/Δ) ) would exhibit an increase in muscle mass and total force production, a reduction in specific force, an accumulation of type II fibres and a decrease and stiffening of connective tissue. Overall, the muscle and tendon phenotype of myostatin-deficient rats was markedly different from that of myostatin-deficient mice, which have impaired contractility and pathological changes to fibres and their extracellular matrix. Extensor digitorum longus and soleus muscles of MSTN(Δ/Δ) rats demonstrated 20-33% increases in mass, 35-45% increases in fibre number, 20-57% increases in isometric force and no differences in specific force. The insulin-like growth factor-1 pathway was activated to a greater extent in MSTN(Δ/Δ) muscles, but no substantial differences in atrophy-related genes were observed. Tendons of MSTN(Δ/Δ) rats had a 20% reduction in peak strain, with no differences in mass, peak stress or stiffness. The general morphology and gene expression patterns were similar between tendons of both genotypes. This large rodent model of myostatin deficiency did not have the negative consequences to muscle fibres and extracellular matrix observed in mouse models, and suggests that the greatest impact of myostatin in the regulation of muscle mass may not be to induce atrophy directly, but rather to block hypertrophy signalling.

  13. Changes in skeletal muscle and tendon structure and function following genetic inactivation of myostatin in rats

    PubMed Central

    Mendias, Christopher L; Lynch, Evan B; Gumucio, Jonathan P; Flood, Michael D; Rittman, Danielle S; Van Pelt, Douglas W; Roche, Stuart M; Davis, Carol S

    2015-01-01

    Myostatin is a negative regulator of skeletal muscle and tendon mass. Myostatin deficiency has been well studied in mice, but limited data are available on how myostatin regulates the structure and function of muscles and tendons of larger animals. We hypothesized that, in comparison to wild-type (MSTN+/+) rats, rats in which zinc finger nucleases were used to genetically inactivate myostatin (MSTNΔ/Δ) would exhibit an increase in muscle mass and total force production, a reduction in specific force, an accumulation of type II fibres and a decrease and stiffening of connective tissue. Overall, the muscle and tendon phenotype of myostatin-deficient rats was markedly different from that of myostatin-deficient mice, which have impaired contractility and pathological changes to fibres and their extracellular matrix. Extensor digitorum longus and soleus muscles of MSTNΔ/Δ rats demonstrated 20–33% increases in mass, 35–45% increases in fibre number, 20–57% increases in isometric force and no differences in specific force. The insulin-like growth factor-1 pathway was activated to a greater extent in MSTNΔ/Δ muscles, but no substantial differences in atrophy-related genes were observed. Tendons of MSTNΔ/Δ rats had a 20% reduction in peak strain, with no differences in mass, peak stress or stiffness. The general morphology and gene expression patterns were similar between tendons of both genotypes. This large rodent model of myostatin deficiency did not have the negative consequences to muscle fibres and extracellular matrix observed in mouse models, and suggests that the greatest impact of myostatin in the regulation of muscle mass may not be to induce atrophy directly, but rather to block hypertrophy signalling. PMID:25640143

  14. Maternal Style Selectively Shapes Amygdalar Development and Social Behavior in Rats Genetically Prone to High Anxiety.

    PubMed

    Cohen, Joshua L; Glover, Matthew E; Pugh, Phyllis C; Fant, Andrew D; Simmons, Rebecca K; Akil, Huda; Kerman, Ilan A; Clinton, Sarah M

    2015-01-01

    The early-life environment critically influences neurodevelopment and later psychological health. To elucidate neural and environmental elements that shape emotional behavior, we developed a rat model of individual differences in temperament and environmental reactivity. We selectively bred rats for high versus low behavioral response to novelty and found that high-reactive (bred high-responder, bHR) rats displayed greater risk-taking, impulsivity and aggression relative to low-reactive (bred low-responder, bLR) rats, which showed high levels of anxiety/depression-like behavior and certain stress vulnerability. The bHR/bLR traits are heritable, but prior work revealed bHR/bLR maternal style differences, with bLR dams showing more maternal attention than bHRs. The present study implemented a cross-fostering paradigm to examine the contribution of maternal behavior to the brain development and emotional behavior of bLR offspring. bLR offspring were reared by biological bLR mothers or fostered to a bLR or bHR mother and then evaluated to determine the effects on the following: (1) developmental gene expression in the hippocampus and amygdala and (2) adult anxiety/depression-like behavior. Genome-wide expression profiling showed that cross-fostering bLR rats to bHR mothers shifted developmental gene expression in the amygdala (but not hippocampus), reduced adult anxiety and enhanced social interaction. Our findings illustrate how an early-life manipulation such as cross-fostering changes the brain's developmental trajectory and ultimately impacts adult behavior. Moreover, while earlier studies highlighted hippocampal differences contributing to the bHR/bLR phenotypes, our results point to a role of the amygdala as well. Future work will pursue genetic and cellular mechanisms within the amygdala that contribute to bHR/bLR behavior either at baseline or following environmental manipulations. © 2015 S. Karger AG, Basel.

  15. Genetic Background Specific Hypoxia Resistance in Rat is Correlated with Balanced Activation of a Cross-Chromosomal Genetic Network Centering on Physiological Homeostasis.

    PubMed

    Mao, Lei

    2012-01-01

    Genetic background of an individual can drastically influence an organism's response upon environmental stress and pathological stimulus. Previous studies in inbred rats showed that compared to Brown Norway (BN), Dahl salt-sensitive (SS) rat exerts strong hypoxia susceptibility. However, despite extensive narrow-down approaches via the chromosome substitution methodology, this genome-based physiological predisposition could not be traced back to distinct quantitative trait loci. Upon the completion and public data availability of PhysGen SS-BN consomic (CS) rat platform, I employed systems biology approach attempting to further our understanding of the molecular basis of genetic background effect in light of hypoxia response. I analyzed the physiological screening data of 22 CS rat strains under normoxia and 2-weeks of hypoxia, and cross-compared them to the parental strains. The analyses showed that SS-9(BN) and SS-18(BN) represent the most hypoxia-resistant CS strains with phenotype similar to BN, whereas SS-6(BN) and SS-Y(BN) segregated to the direction of SS. A meta-analysis on the transcriptomic profiles of these CS rat strains under hypoxia treatment showed that although polymorphisms on the substituted BN chromosomes could be directly involved in hypoxia resistance, this seems to be embedded in a more complex trans-chromosomal genetic regulatory network. Via information theory based modeling approach, this hypoxia relevant core genetic network was reverse engineered. Network analyses showed that the protective effects of BN chromosome 9 and 18 were reflected by a balanced activation of this core network centering on physiological homeostasis. Presumably, it is the system robustness constituted on such differential network activation that acts as hypoxia response modifier. Understanding of the intrinsic link between the individual genetic background and the network robustness will set a basis in the current scientific efforts toward personalized medicine.

  16. Nature and nurture: environmental influences on a genetic rat model of depression.

    PubMed

    Mehta-Raghavan, N S; Wert, S L; Morley, C; Graf, E N; Redei, E E

    2016-03-29

    In this study, we sought to learn whether adverse events such as chronic restraint stress (CRS), or 'nurture' in the form of environmental enrichment (EE), could modify depression-like behavior and blood biomarker transcript levels in a genetic rat model of depression. The Wistar Kyoto More Immobile (WMI) is a genetic model of depression that aided in the identification of blood transcriptomic markers, which successfully distinguished adolescent and adult subjects with major depressive disorders from their matched no-disorder controls. Here, we followed the effects of CRS and EE in adult male WMIs and their genetically similar control strain, the Wistar Kyoto Less Immobile (WLI), that does not show depression-like behavior, by measuring the levels of these transcripts in the blood and hippocampus. In WLIs, increased depression-like behavior and transcriptomic changes were present in response to CRS, but in WMIs no behavioral or additive transcriptomic changes occurred. Environmental enrichment decreased both the inherent depression-like behavior in the WMIs and the behavioral difference between WMIs and WLIs, but did not reverse basal transcript level differences between the strains. The inverse behavioral change induced by CRS and EE in the WLIs did not result in parallel inverse expression changes of the transcriptomic markers, suggesting that these behavioral responses to the environment work via separate molecular pathways. In contrast, 'trait' transcriptomic markers with expression differences inherent and unchanging between the strains regardless of the environment suggest that in our model, environmental and genetic etiologies of depression work through independent molecular mechanisms.

  17. Local and Regional Scale Genetic Variation in the Cape Dune Mole-Rat, Bathyergus suillus

    PubMed Central

    Visser, Jacobus H.; Bennett, Nigel C.; Jansen van Vuuren, Bettine

    2014-01-01

    The distribution of genetic variation is determined through the interaction of life history, morphology and habitat specificity of a species in conjunction with landscape structure. While numerous studies have investigated this interplay of factors in species inhabiting aquatic, riverine, terrestrial, arboreal and saxicolous systems, the fossorial system has remained largely unexplored. In this study we attempt to elucidate the impacts of a subterranean lifestyle coupled with a heterogeneous landscape on genetic partitioning by using a subterranean mammal species, the Cape dune mole-rat (Bathyergus suillus), as our model. Bathyergus suillus is one of a few mammal species endemic to the Cape Floristic Region (CFR) of the Western Cape of South Africa. Its distribution is fragmented by rivers and mountains; both geographic phenomena that may act as geographical barriers to gene-flow. Using two mitochondrial fragments (cytochrome b and control region) as well as nine microsatellite loci, we determined the phylogeographic structure and gene-flow patterns at two different spatial scales (local and regional). Furthermore, we investigated genetic differentiation between populations and applied Bayesian clustering and assignment approaches to our data. Nearly every population formed a genetically unique entity with significant genetic structure evident across geographic barriers such as rivers (Berg, Verlorenvlei, Breede and Gourits Rivers), mountains (Piketberg and Hottentots Holland Mountains) and with geographic distance at both spatial scales. Surprisingly, B. suillus was found to be paraphyletic with respect to its sister species, B. janetta–a result largely overlooked by previous studies on these taxa. A systematic revision of the genus Bathyergus is therefore necessary. This study provides a valuable insight into how the biology, life-history and habitat specificity of animals inhabiting a fossorial system may act in concert with the structure of the surrounding

  18. Local and regional scale genetic variation in the Cape dune mole-rat, Bathyergus suillus.

    PubMed

    Visser, Jacobus H; Bennett, Nigel C; Jansen van Vuuren, Bettine

    2014-01-01

    The distribution of genetic variation is determined through the interaction of life history, morphology and habitat specificity of a species in conjunction with landscape structure. While numerous studies have investigated this interplay of factors in species inhabiting aquatic, riverine, terrestrial, arboreal and saxicolous systems, the fossorial system has remained largely unexplored. In this study we attempt to elucidate the impacts of a subterranean lifestyle coupled with a heterogeneous landscape on genetic partitioning by using a subterranean mammal species, the Cape dune mole-rat (Bathyergus suillus), as our model. Bathyergus suillus is one of a few mammal species endemic to the Cape Floristic Region (CFR) of the Western Cape of South Africa. Its distribution is fragmented by rivers and mountains; both geographic phenomena that may act as geographical barriers to gene-flow. Using two mitochondrial fragments (cytochrome b and control region) as well as nine microsatellite loci, we determined the phylogeographic structure and gene-flow patterns at two different spatial scales (local and regional). Furthermore, we investigated genetic differentiation between populations and applied Bayesian clustering and assignment approaches to our data. Nearly every population formed a genetically unique entity with significant genetic structure evident across geographic barriers such as rivers (Berg, Verlorenvlei, Breede and Gourits Rivers), mountains (Piketberg and Hottentots Holland Mountains) and with geographic distance at both spatial scales. Surprisingly, B. suillus was found to be paraphyletic with respect to its sister species, B. janetta-a result largely overlooked by previous studies on these taxa. A systematic revision of the genus Bathyergus is therefore necessary. This study provides a valuable insight into how the biology, life-history and habitat specificity of animals inhabiting a fossorial system may act in concert with the structure of the surrounding

  19. Effect of genetic strain and gender on age-related changes in body composition of the laboratory rat.

    EPA Pesticide Factsheets

    Body composition data for common laboratory strains of rat as a function of age.This dataset is associated with the following publication:Gordon , C., K. Jarema , A. Johnstone , and P. Phillips. Effect of Genetic Strain and Gender on Age-Related Changes in Body Composition of the Laboratory Rat. Physiology & Behavior. Elsevier B.V., Amsterdam, NETHERLANDS, 153(1): 56-63, (2016).

  20. Population genetics, community of parasites, and resistance to rodenticides in an urban brown rat (Rattus norvegicus) population

    PubMed Central

    Gasqui, Patrick; Cosson, Jean-François; Benoît, Etienne; Lattard, Virginie; Crespin, Laurent; Lorvelec, Olivier; Pisanu, Benoît; Teynié, Alexandre; Vayssier-Taussat, Muriel; Bonnet, Sarah; Marianneau, Philippe; Lacôte, Sandra; Bourhy, Pascale; Berny, Philippe; Pavio, Nicole; Le Poder, Sophie; Gilot-Fromont, Emmanuelle; Jourdain, Elsa; Hammed, Abdessalem; Fourel, Isabelle; Chikh, Farid; Vourc’h, Gwenaël

    2017-01-01

    Brown rats are one of the most widespread urban species worldwide. Despite the nuisances they induce and their potential role as a zoonotic reservoir, knowledge on urban rat populations remains scarce. The main purpose of this study was to characterize an urban brown rat population from Chanteraines park (Hauts-de-Seine, France), with regards to haematology, population genetics, immunogenic diversity, resistance to anticoagulant rodenticides, and community of parasites. Haematological parameters were measured. Population genetics was investigated using 13 unlinked microsatellite loci. Immunogenic diversity was assessed for Mhc-Drb. Frequency of the Y139F mutation (conferring resistance to rodenticides) and two linked microsatellites were studied, concurrently with the presence of anticoagulant residues in the liver. Combination of microscopy and molecular methods were used to investigate the occurrence of 25 parasites. Statistical approaches were used to explore multiple parasite relationships and model parasite occurrence. Eighty-six rats were caught. The first haematological data for a wild urban R. norvegicus population was reported. Genetic results suggested high genetic diversity and connectivity between Chanteraines rats and surrounding population(s). We found a high prevalence (55.8%) of the mutation Y139F and presence of rodenticide residues in 47.7% of the sampled individuals. The parasite species richness was high (16). Seven potential zoonotic pathogens were identified, together with a surprisingly high diversity of Leptospira species (4). Chanteraines rat population is not closed, allowing gene flow and making eradication programs challenging, particularly because rodenticide resistance is highly prevalent. Parasitological results showed that co-infection is more a rule than an exception. Furthermore, the presence of several potential zoonotic pathogens, of which four Leptospira species, in this urban rat population raised its role in the maintenance

  1. Population genetics, community of parasites, and resistance to rodenticides in an urban brown rat (Rattus norvegicus) population.

    PubMed

    Desvars-Larrive, Amélie; Pascal, Michel; Gasqui, Patrick; Cosson, Jean-François; Benoît, Etienne; Lattard, Virginie; Crespin, Laurent; Lorvelec, Olivier; Pisanu, Benoît; Teynié, Alexandre; Vayssier-Taussat, Muriel; Bonnet, Sarah; Marianneau, Philippe; Lacôte, Sandra; Bourhy, Pascale; Berny, Philippe; Pavio, Nicole; Le Poder, Sophie; Gilot-Fromont, Emmanuelle; Jourdain, Elsa; Hammed, Abdessalem; Fourel, Isabelle; Chikh, Farid; Vourc'h, Gwenaël

    2017-01-01

    Brown rats are one of the most widespread urban species worldwide. Despite the nuisances they induce and their potential role as a zoonotic reservoir, knowledge on urban rat populations remains scarce. The main purpose of this study was to characterize an urban brown rat population from Chanteraines park (Hauts-de-Seine, France), with regards to haematology, population genetics, immunogenic diversity, resistance to anticoagulant rodenticides, and community of parasites. Haematological parameters were measured. Population genetics was investigated using 13 unlinked microsatellite loci. Immunogenic diversity was assessed for Mhc-Drb. Frequency of the Y139F mutation (conferring resistance to rodenticides) and two linked microsatellites were studied, concurrently with the presence of anticoagulant residues in the liver. Combination of microscopy and molecular methods were used to investigate the occurrence of 25 parasites. Statistical approaches were used to explore multiple parasite relationships and model parasite occurrence. Eighty-six rats were caught. The first haematological data for a wild urban R. norvegicus population was reported. Genetic results suggested high genetic diversity and connectivity between Chanteraines rats and surrounding population(s). We found a high prevalence (55.8%) of the mutation Y139F and presence of rodenticide residues in 47.7% of the sampled individuals. The parasite species richness was high (16). Seven potential zoonotic pathogens were identified, together with a surprisingly high diversity of Leptospira species (4). Chanteraines rat population is not closed, allowing gene flow and making eradication programs challenging, particularly because rodenticide resistance is highly prevalent. Parasitological results showed that co-infection is more a rule than an exception. Furthermore, the presence of several potential zoonotic pathogens, of which four Leptospira species, in this urban rat population raised its role in the maintenance

  2. Does Prenatal Valproate Interact with a Genetic Reduction in the Serotonin Transporter? A Rat Study on Anxiety and Cognition

    PubMed Central

    Ellenbroek, Bart A.; August, Caren; Youn, Jiun

    2016-01-01

    There is ample evidence that prenatal exposure to valproate (or valproic acid, VPA) enhances the risk of developing Autism Spectrum Disorders (ASD). In line with this, a single injection of VPA induces a multitude of ASD-like symptoms in animals, such as rats and mice. However, there is equally strong evidence that genetic factors contribute significantly to the risk of ASD and indeed, like most other psychiatric disorders, ASD is now generally thought to results from an interaction between genetic and environmental factors. Given that VPA significantly impacts on the serotonergic system, and serotonin has strong biochemical and genetic links to ASD, we aimed to investigate the interaction between genetic reduction in the serotonin transporter and prenatal valproate administration. More specifically, we exposed both wildtype (SERT+/+) rats and rats heterozygous for the serotonin transporter deletion (SERT+/−) to a single injection of 400 mg/kg VPA at gestational day (GD) 12. The offspring, in adulthood, was assessed in four different tests: Elevated Plus Maze and Novelty Suppressed Feeding as measures for anxiety and prepulse inhibition (PPI) and latent inhibition as measures for cognition and information processing. The results show that prenatal VPA significantly increased anxiety in both paradigm, reduced PPI and reduced conditioning in the latent inhibition paradigm. However, we failed to find a significant gene–environment interaction. We propose that this may be related to the timing of the VPA injection and suggest that whereas GD12 might be optimal for affecting normal rat, rats with a genetically compromised serotonergic system may be more sensitive to VPA at earlier time points during gestation. Overall our data are the first to investigate gene * environmental interactions in a genetic rat model for ASD and suggest that timing may be of crucial importance to the long-term outcome. PMID:27708559

  3. Molecular Genetic Evidence for the Place of Origin of the Pacific Rat, Rattus exulans

    PubMed Central

    Thomson, Vicki; Aplin, Ken P.; Cooper, Alan; Hisheh, Susan; Suzuki, Hitoshi; Maryanto, Ibnu; Yap, Grace; Donnellan, Stephen C.

    2014-01-01

    Commensal plants and animals have long been used to track human migrations, with Rattus exulans (the Pacific rat) a common organism for reconstructing Polynesian dispersal in the Pacific. However, with no knowledge of the homeland of R. exulans, the place of origin of this human-commensal relationship is unknown. We conducted a mitochondrial DNA phylogeographic survey of R. exulans diversity across the potential natural range in mainland and Island Southeast Asia in order to establish the origin of this human-commensal dyad. We also conducted allozyme electrophoresis on samples from ISEA to obtain a perspective on patterns of genetic diversity in this critical region. Finally, we compared molecular genetic evidence with knowledge of prehistoric rodent faunas in mainland and ISEA. We find that ISEA populations of R. exulans contain the highest mtDNA lineage diversity including significant haplotype diversity not represented elsewhere in the species range. Within ISEA, the island of Flores in the Lesser Sunda group contains the highest diversity in ISEA (across all loci) and also has a deep fossil record of small mammals that appears to include R. exulans. Therefore, in addition to Flores harboring unusual diversity in the form of Homo floresiensis, dwarfed stegodons and giant rats, this island appears to be the homeland of R. exulans. PMID:24637896

  4. Subchronic Immunotoxicity Assessment of Genetically Modified Virus-Resistant Papaya in Rats.

    PubMed

    Lin, Hsin-Tang; Lee, Wei-Cheng; Tsai, Yi-Ting; Wu, Jhaol-Huei; Yen, Gow-Chin; Yeh, Shyi-Dong; Cheng, Ying-Huey; Chang, Shih-Chieh; Liao, Jiunn-Wang

    2016-07-27

    Papaya is an important fruit that provides a variety of vitamins with nutritional value and also holds some pharmacological properties, including immunomodulation. Genetically modified (GM) papaya plants resistant to Papaya ringspot virus (PRSV) infection have been generated by cloning the coat protein gene of the PRSV which can be used as a valuable strategy to fight PRSV infection and to increase papaya production. In order to assess the safety of GM papaya as a food, this subchronic study was conducted to assess the immunomodulatory responses of the GM papaya line 823-2210, when compared with its parent plant of non-GM papaya, Tainung-2 (TN-2), in Sprague-Dawley (SD) rats. Both non-GM and GM 823-2210 papaya fruits at low (1 g/kg bw) and high (2 g/kg bw) dosages were administered via daily oral gavage to male and female rats consecutively for 90 days. Immunophenotyping, mitogen-induced splenic cell proliferation, antigen-specific antibody response, and histopathology of the spleen and thymus were evaluated at the end of the experiment. Results of immunotoxicity assays revealed no consistent difference between rats fed for 90 days with GM 823-2210 papaya fruits, as opposed to those fed non-GM TN-2 papaya fruits, suggesting that with regard to immunomodulatory responses, GM 823-2210 papaya fruits maintain substantial equivalence to fruits of their non-GM TN-2 parent.

  5. Phenobarbital in the genetically obese Zucker rat. II. In vivo and in vitro assessments of microsomal enzyme induction.

    PubMed

    Brouwer, K L; Kostenbauder, H B; McNamara, P J; Blouin, R A

    1984-12-01

    In vivo and in vitro alterations in drug metabolism and the extent of enzyme induction of the hepatic microsomal cytochrome P-450 system were evaluated in obese and lean Zucker and lean Sprague-Dawley rats. Phenobarbital enzyme-inducing regimens were administered p.o. to achieve similar steady-state phenobarbital plasma concentrations. Control rats received p.o. placebo solution. No significant intra- or inter-strain differences in antipyrine clearance (milliliters per hour) or apparent volume of distribution (liters) were observed between the placebo-treated lean Sprague-Dawley, lean Zucker and obese Zucker rats. Intra- and inter-strain differences in hepatic microsomal protein and cytochrome P-450 content were observed. Compared to placebo, antipyrine clearance (milliliters per hour) after chronic phenobarbital pretreatment was increased in the Sprague-Dawley (198%) and lean Zucker rats (131%), but not significantly altered in the obese Zucker rats. Similarly, increases in hepatic weight, whole liver microsomal protein and cytochrome P-450 content were also observed in the Sprague-Dawley (34, 124 and 352%, respectively) and the lean Zucker rats (24, 96 and 249%, respectively). However, no significant alterations in these parameters were observed in the obese Zucker rats after phenobarbital treatment. Results from these in vivo and in vitro studies implicate alterations in drug metabolism and genetic differences in cytochrome P-450 content in Zucker rats relative to the Sprague-Dawley strain. Obese Zucker rats failed to exhibit a significant induction response after phenobarbital pretreatment.

  6. Transcriptome, genetic editing, and microRNA divergence substantiate sympatric speciation of blind mole rat, Spalax.

    PubMed

    Li, Kexin; Wang, Liuyang; Knisbacher, Binyamin A; Xu, Qinqin; Levanon, Erez Y; Wang, Huihua; Frenkel-Morgenstern, Milana; Tagore, Satabdi; Fang, Xiaodong; Bazak, Lily; Buchumenski, Ilana; Zhao, Yang; Lövy, Matěj; Li, Xiangfeng; Han, Lijuan; Frenkel, Zeev; Beiles, Avigdor; Cao, Yi Bin; Wang, Zhen Long; Nevo, Eviatar

    2016-07-05

    Incipient sympatric speciation in blind mole rat, Spalax galili, in Israel, caused by sharp ecological divergence of abutting chalk-basalt ecologies, has been proposed previously based on mitochondrial and whole-genome nuclear DNA. Here, we present new evidence, including transcriptome, DNA editing, microRNA, and codon usage, substantiating earlier evidence for adaptive divergence in the abutting chalk and basalt populations. Genetic divergence, based on the previous and new evidence, is ongoing despite restricted gene flow between the two populations. The principal component analysis, neighbor-joining tree, and genetic structure analysis of the transcriptome clearly show the clustered divergent two mole rat populations. Gene-expression level analysis indicates that the population transcriptome divergence is displayed not only by soil divergence but also by sex. Gene ontology enrichment of the differentially expressed genes from the two abutting soil populations highlights reproductive isolation. Alternative splicing variation of the two abutting soil populations displays two distinct splicing patterns. L-shaped FST distribution indicates that the two populations have undergone divergence with gene flow. Transcriptome divergent genes highlight neurogenetics and nutrition characterizing the chalk population, and energetics, metabolism, musculature, and sensory perception characterizing the abutting basalt population. Remarkably, microRNAs also display divergence between the two populations. The GC content is significantly higher in chalk than in basalt, and stress-response genes mostly prefer nonoptimal codons. The multiple lines of evidence of ecological-genomic and genetic divergence highlight that natural selection overrules the gene flow between the two abutting populations, substantiating the sharp ecological chalk-basalt divergence driving sympatric speciation.

  7. Transcriptome, genetic editing, and microRNA divergence substantiate sympatric speciation of blind mole rat, Spalax

    PubMed Central

    Li, Kexin; Wang, Liuyang; Knisbacher, Binyamin A.; Xu, Qinqin; Levanon, Erez Y.; Wang, Huihua; Frenkel-Morgenstern, Milana; Tagore, Satabdi; Fang, Xiaodong; Bazak, Lily; Buchumenski, Ilana; Zhao, Yang; Lövy, Matěj; Li, Xiangfeng; Han, Lijuan; Frenkel, Zeev; Beiles, Avigdor; Cao, Yi Bin; Wang, Zhen Long; Nevo, Eviatar

    2016-01-01

    Incipient sympatric speciation in blind mole rat, Spalax galili, in Israel, caused by sharp ecological divergence of abutting chalk–basalt ecologies, has been proposed previously based on mitochondrial and whole-genome nuclear DNA. Here, we present new evidence, including transcriptome, DNA editing, microRNA, and codon usage, substantiating earlier evidence for adaptive divergence in the abutting chalk and basalt populations. Genetic divergence, based on the previous and new evidence, is ongoing despite restricted gene flow between the two populations. The principal component analysis, neighbor-joining tree, and genetic structure analysis of the transcriptome clearly show the clustered divergent two mole rat populations. Gene-expression level analysis indicates that the population transcriptome divergence is displayed not only by soil divergence but also by sex. Gene ontology enrichment of the differentially expressed genes from the two abutting soil populations highlights reproductive isolation. Alternative splicing variation of the two abutting soil populations displays two distinct splicing patterns. L-shaped FST distribution indicates that the two populations have undergone divergence with gene flow. Transcriptome divergent genes highlight neurogenetics and nutrition characterizing the chalk population, and energetics, metabolism, musculature, and sensory perception characterizing the abutting basalt population. Remarkably, microRNAs also display divergence between the two populations. The GC content is significantly higher in chalk than in basalt, and stress-response genes mostly prefer nonoptimal codons. The multiple lines of evidence of ecological–genomic and genetic divergence highlight that natural selection overrules the gene flow between the two abutting populations, substantiating the sharp ecological chalk–basalt divergence driving sympatric speciation. PMID:27339131

  8. Genetic, physiological and comparative genomic studies of hypertension and insulin resistance in the spontaneously hypertensive rat

    PubMed Central

    Hummel, Oliver; Garcia Diaz, Ana; Barrier, Marjorie; Alfazema, Neza; Norsworthy, Penny J.; Pravenec, Michal; Petretto, Enrico; Hübner, Norbert

    2017-01-01

    ABSTRACT We previously mapped hypertension-related insulin resistance quantitative trait loci (QTLs) to rat chromosomes 4, 12 and 16 using adipocytes from F2 crosses between spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats, and subsequently identified Cd36 as the gene underlying the chromosome 4 locus. The identity of the chromosome 12 and 16 genes remains unknown. To identify whole-body phenotypes associated with the chromosome 12 and 16 linkage regions, we generated and characterised new congenic strains, with WKY donor segments introgressed onto an SHR genetic background, for the chromosome 12 and 16 linkage regions. We found a >50% increase in insulin sensitivity in both the chromosome 12 and 16 strains. Blood pressure and left ventricular mass were reduced in the two congenic strains consistent with the congenic segments harbouring SHR genes for insulin resistance, hypertension and cardiac hypertrophy. Integrated genomic analysis, using physiological and whole-genome sequence data across 42 rat strains, identified variants within the congenic regions in Upk3bl, RGD1565131 and AABR06087018.1 that were associated with blood pressure, cardiac mass and insulin sensitivity. Quantitative trait transcript analysis across 29 recombinant inbred strains showed correlation between expression of Hspb1, Zkscan5 and Pdgfrl with adipocyte volume, systolic blood pressure and cardiac mass, respectively. Comparative genome analysis showed a marked enrichment of orthologues for human GWAS-associated genes for insulin resistance within the syntenic regions of both the chromosome 12 and 16 congenic intervals. Our study defines whole-body phenotypes associated with the SHR chromosome 12 and 16 insulin-resistance QTLs, identifies candidate genes for these SHR QTLs and finds human orthologues of rat genes in these regions that associate with related human traits. Further study of these genes in the congenic strains will lead to robust identification of the underlying

  9. Integrative microRNA-gene expression network analysis in genetic hypercalciuric stone-forming rat kidney

    PubMed Central

    Lu, Yuchao; Qin, Baolong; Hu, Henglong; Zhang, Jiaqiao; Wang, Yufeng; Wang, Qing

    2016-01-01

    Background. MicroRNAs (miRNAs) influence a variety of biological functions by regulating gene expression post-transcriptionally. Aberrant miRNA expression has been associated with many human diseases. Urolithiasis is a common disease, and idiopathic hypercalciuria (IH) is an important risk factor for calcium urolithiasis. However, miRNA expression patterns and their biological functions in urolithiasis remain unknown. Methods and Results. A multi-step approach combining microarray miRNA and mRNA expression profile and bioinformatics analysis was adopted to analyze dysregulated miRNAs and genes in genetic hypercalciuric stone-forming (GHS) rat kidneys, using normal Sprague-Dawley (SD) rats as controls. We identified 2418 mRNAs and 19 miRNAs as significantly differentially expressed, over 700 gene ontology (GO) terms and 83 KEGG pathways that were significantly enriched in GHS rats. In addition, we constructed an miRNA-gene network that suggested that rno-miR-674-5p, rno-miR-672-5p, rno-miR-138-5p and rno-miR-21-3p may play important roles in the regulatory network. Furthermore, signal-net analysis suggested that NF-kappa B likely plays a crucial role in hypercalciuria urolithiasis. Conclusions. This study presents a global view of mRNA and miRNA expression in GHS rat kidneys, and suggests that miRNAs may be important in the regulation of hypercalciuria. The data provide valuable insights for future research, which should aim at validating the role of the genes featured here in the pathophysiology of hypercalciuria. PMID:27069814

  10. Treating congenital megacolon by transplanting GDNF and GFRα-1 double genetically modified rat bone marrow mesenchymal stem cells.

    PubMed

    Zhou, C B; Peng, C H; Pang, W B; Zhang, D; Chen, Y J

    2015-08-14

    We studied the survival and gene expression of glial cell line-derived neurotrophic factor (GDNF) and GDNF receptor α-1 (GFRα-1) double-genetically modified rat bone marrow mesenchymal stem cells (BMSCs) transplanted into the intestinal walls of the rat models with congenital megacolon and determine the feasibility of treatment by transplantation of double-genetically modified rat BMSCs. The rat colorectal intestinal wall nerve plexus was treated with the cationic surface active agent benzalkonium chloride to establish an experimental megacolon model. The rat target genes GDNF and GFRα-1 were extracted and ligated into pEGFP-N1. Eukaryotic fluorescent expression vectors carrying the GDNF and GFRα-1 genes were transfected into BMSCs by in vitro culture. We treated congenital megacolon by transplanting double-genetically modified rat bone marrow mesenchymal stem cells. The pEGFP-EGFP-GDNF-GFRα-1 double-gene co-expressing the eukaryotic expression plasmid vector was successfully established. Protein gene protein 9.5 and vasoactive intestinal peptide-positive ganglion cells showed no positive expression in the phosphate-buffered saline transplantation group based on an immunofluorescence test at 1, 2, and 4 weeks after transplantation of BMSCs. Additionally, compared with the phosphate-buffered saline transplantation group, the expression of rearranged during transfection, GDNF, and GFRα-1 mRNA in the stem cell transplantation group increased gradually. The double-genetically modified BMSCs colonized and survived in the intestinal wall of the experimental megacolon rat model and expressed related genes, partially recovering the colonic neuromuscular regulatory functions and thus providing an experimental basis for treating congenital megacolon by cellular transplantation.

  11. Using fine-scale spatial genetics of Norway rats to improve control efforts and reduce leptospirosis risk in urban slum environments.

    PubMed

    Richardson, Jonathan L; Burak, Mary K; Hernandez, Christian; Shirvell, James M; Mariani, Carol; Carvalho-Pereira, Ticiana S A; Pertile, Arsinoê C; Panti-May, Jesus A; Pedra, Gabriel G; Serrano, Soledad; Taylor, Josh; Carvalho, Mayara; Rodrigues, Gorete; Costa, Federico; Childs, James E; Ko, Albert I; Caccone, Adalgisa

    2017-04-01

    The Norway rat (Rattus norvegicus) is a key pest species globally and responsible for seasonal outbreaks of the zoonotic bacterial disease leptospirosis in the tropics. The city of Salvador, Brazil, has seen recent and dramatic increases in human population residing in slums, where conditions foster high rat density and increasing leptospirosis infection rates. Intervention campaigns have been used to drastically reduce rat numbers. In planning these interventions, it is important to define the eradication units - the spatial scale at which rats constitute continuous populations and from where rats are likely recolonizing, post-intervention. To provide this information, we applied spatial genetic analyses to 706 rats collected across Salvador and genotyped at 16 microsatellite loci. We performed spatially explicit analyses and estimated migration levels to identify distinct genetic units and landscape features associated with genetic divergence at different spatial scales, ranging from valleys within a slum community to city-wide analyses. Clear genetic breaks exist between rats not only across Salvador but also between valleys of slums separated by <100 m-well within the dispersal capacity of rats. The genetic data indicate that valleys may be considered separate units and identified high-traffic roads as strong impediments to rat movement. Migration data suggest that most (71-90%) movement is contained within valleys, with no clear source population contributing to migrant rats. We use these data to recommend eradication units and discuss the importance of carrying out individual-based analyses at different spatial scales in urban landscapes.

  12. On-off intermittency in time series of spontaneous paroxysmal activity in rats with genetic absence epilepsy

    SciTech Connect

    Hramov, Alexander; Koronovskii, Alexey A.; Midzyanovskaya, I.S.; Sitnikova, E.; Rijn, C.M. van

    2006-12-15

    In the present paper we consider the on-off intermittency phenomena observed in time series of spontaneous paroxysmal activity in rats with genetic absence epilepsy. The method to register and analyze the electroencephalogram with the help of continuous wavelet transform is also suggested.

  13. Behavioral and genetic effects promoted by sleep deprivation in rats submitted to pilocarpine-induced status epilepticus.

    PubMed

    Matos, Gabriela; Ribeiro, Daniel A; Alvarenga, Tathiana A; Hirotsu, Camila; Scorza, Fulvio A; Le Sueur-Maluf, Luciana; Noguti, Juliana; Cavalheiro, Esper A; Tufik, Sergio; Andersen, Monica L

    2012-05-02

    The interaction between sleep deprivation and epilepsy has been well described in electrophysiological studies, but the mechanisms underlying this association remain unclear. The present study evaluated the effects of sleep deprivation on locomotor activity and genetic damage in the brains of rats treated with saline or pilocarpine-induced status epilepticus (SE). After 50 days of pilocarpine or saline treatment, both groups were assigned randomly to total sleep deprivation (TSD) for 6 h, paradoxical sleep deprivation (PSD) for 24 h, or be kept in their home cages. Locomotor activity was assessed with the open field test followed by resection of brain for quantification of genetic damage by the single cell gel electrophoresis (comet) assay. Status epilepticus induced significant hyperactivity in the open field test and caused genetic damage in the brain. Sleep deprivation procedures (TSD and PSD) did not affect locomotor activity in epileptic or healthy rats, but resulted in significant DNA damage in brain cells. Although PSD had this effect in both vehicle and epileptic groups, TSD caused DNA damage only in epileptic rats. In conclusion, our results revealed that, despite a lack of behavioral effects of sleep deprivation, TSD and PSD induced genetic damage in rats submitted to pilocarpine-induced SE.

  14. Nature and nurture: environmental influences on a genetic rat model of depression

    PubMed Central

    Mehta-Raghavan, N S; Wert, S L; Morley, C; Graf, E N; Redei, E E

    2016-01-01

    In this study, we sought to learn whether adverse events such as chronic restraint stress (CRS), or ‘nurture' in the form of environmental enrichment (EE), could modify depression-like behavior and blood biomarker transcript levels in a genetic rat model of depression. The Wistar Kyoto More Immobile (WMI) is a genetic model of depression that aided in the identification of blood transcriptomic markers, which successfully distinguished adolescent and adult subjects with major depressive disorders from their matched no-disorder controls. Here, we followed the effects of CRS and EE in adult male WMIs and their genetically similar control strain, the Wistar Kyoto Less Immobile (WLI), that does not show depression-like behavior, by measuring the levels of these transcripts in the blood and hippocampus. In WLIs, increased depression-like behavior and transcriptomic changes were present in response to CRS, but in WMIs no behavioral or additive transcriptomic changes occurred. Environmental enrichment decreased both the inherent depression-like behavior in the WMIs and the behavioral difference between WMIs and WLIs, but did not reverse basal transcript level differences between the strains. The inverse behavioral change induced by CRS and EE in the WLIs did not result in parallel inverse expression changes of the transcriptomic markers, suggesting that these behavioral responses to the environment work via separate molecular pathways. In contrast, ‘trait' transcriptomic markers with expression differences inherent and unchanging between the strains regardless of the environment suggest that in our model, environmental and genetic etiologies of depression work through independent molecular mechanisms. PMID:27023176

  15. Dr. Lewis Kitchener Dahl, the Dahl Rats and the ‘Inconvenient truth’ abou the Genetics of Hypertension

    PubMed Central

    Joe, Bina

    2014-01-01

    Synopsis Lewis K. Dahl is regarded as an iconic figure in the field of hypertension research. During the 1960s and 1970s he published several seminal articles in the field that shed light on the relationship between salt and hypertension. Further, the Dahl rat models of hypertension that he developed by a selective breeding strategy are among the most widely used models for hypertension research. To this day, genetic studies using this model are ongoing in our laboratory. While Dr. Dahl is known for his contributions to the field of hypertension, very little, if any, of his personal history is documented. This article details a short biography of Dr. Lewis Dahl, the history behind the development of the Dahl rats and presents an overview of the results obtained through the genetic analysis of the Dahl rat as an experimental model to study the inheritance of hypertension. PMID:25646295

  16. Does genetic BDNF deficiency in rats interact with neurotransmitter control of prepulse inhibition? Implications for schizophrenia.

    PubMed

    van den Buuse, Maarten; Biel, Davina; Radscheit, Kathrin

    2017-04-03

    Several studies have suggested a role of BDNF in the development of schizophrenia. For example, post-mortem studies have shown significantly reduced levels of BDNF protein expression in the brain of schizophrenia patients. We investigated the relationship between reduced levels of BDNF in the brain and the regulation of prepulse inhibition (PPI), a behavioral endophenotype of schizophrenia. We used BDNF heterozygous mutant rats which display a 50% decrease of mature BDNF protein levels. Previously, we observed normal baseline PPI and responses to the dopamine D1/D2 receptor agonist, apomorphine, in these rats. Here, we focused on the effects of the NMDA receptor antagonist, MK-801, its interaction with mGluR2/3 and mGluR5 receptors, and the PPI response to serotonergic drugs. MK-801 administration caused a dose-dependent reduction of PPI and increase of startle amplitudes. Baseline PPI and the effect of 0.02-0.1mg/kg of MK-801 were not significantly altered in male or female BDNF heterozygous rats, although the MK-801-induced increase in startle levels was reduced. Co-treatment with the mGluR2/3 agonist, LY379,268, or the mGluR5 antagonist, MPEP, did not alter the effect of MK-801 on PPI in controls or BDNF mutant rats. Treatment with the serotonin-1A receptor agonist, 8-OH-DPAT, the serotonin-2A receptor agonist, DOI, or the serotonin releaser, fenfluramine, induced differential effects on PPI and startle but these effects were not different between the genotypes. These results show that a significant decrease of BDNF protein expression does not lead to reduced PPI at baseline or changes in the regulation of PPI via NMDA receptors or serotonergic mechanisms. These findings in a genetic rat model of BDNF deficiency do not support a role for similar reductions of BDNF levels in schizophrenia in the disruption of PPI, widely reported as an endophenotype of the illness. The potential implications of these results for our understanding of changes in PPI and BDNF

  17. Differential neural representation of oral ethanol by central taste-sensitive neurons in ethanol-preferring and genetically heterogeneous rats

    PubMed Central

    Wilson, David M.; Brasser, Susan M.

    2011-01-01

    In randomly bred rats, orally applied ethanol stimulates neural substrates for appetitive sweet taste. To study associations between ethanol's oral sensory characteristics and genetically mediated ethanol preference, we made electrophysiological recordings of oral responses (spike density) by taste-sensitive nucleus tractus solitarii neurons in anesthetized selectively bred ethanol-preferring (P) rats and their genetically heterogeneous Wistar (W) control strain. Stimuli (25 total) included ethanol [3%, 5%, 10%, 15%, 25%, and 40% (vol/vol)], a sucrose series (0.01, 0.03, 0.1, 0.3, 0.5, and 1 M), and other sweet, salt, acidic, and bitter stimuli; 50 P and 39 W neurons were sampled. k-means clustering applied to the sucrose response series identified cells showing high (S1) or relatively low (S0) sensitivity to sucrose. A three-way factorial analysis revealed that activity to ethanol was influenced by a neuron's sensitivity to sucrose, ethanol concentration, and rat line (P = 0.01). Ethanol produced concentration-dependent responses in S1 neurons that were larger than those in S0 cells. Although responses to ethanol by S1 cells did not differ between lines, neuronal firing rates to ethanol in S0 cells increased across concentration only in P rats. Correlation and multivariate analyses revealed that ethanol evoked responses in W neurons that were strongly and selectively associated with activity to sweet stimuli, whereas responses to ethanol by P neurons were not easily associated with activity to representative sweet, sodium salt, acidic, or bitter stimuli. These findings show differential central neural representation of oral ethanol between genetically heterogeneous rats and P rats genetically selected to prefer alcohol. PMID:21918002

  18. Genetics

    MedlinePlus

    ... Inheritance; Heterozygous; Inheritance patterns; Heredity and disease; Heritable; Genetic markers ... The chromosomes are made up of strands of genetic information called DNA. Each chromosome contains sections of ...

  19. Safety and risk assessment of the genetically modified Lactococci on rats intestinal bacterial flora.

    PubMed

    Lee, Kai-Chien; Liu, Chin-Feng; Lin, Tzu-Hsing; Pan, Tzu-Ming

    2010-08-15

    The interaction between Lactococcus lactis NZ9000/pNZPNK and intestinal microflora was evaluated as a method to assess safety of genetically modified microorganisms (GMMs). L. lactis NZ9000/pNZPNK is one kind of GMM and able to produce the intracellular subtilisin NAT (nattokinase) under induction with nisin. The host strain L. lactis NZ9000 was a generally recognized as safe (GRAS) microorganism. Six groups of Wistar rats were orally administered with L. lactis NZ9000/pNZPNK and L. lactis NZ9000 for 6 weeks. Fecal and cecal contents were collected to determine the number of L. lactis NZ9000, L. lactis NZ9000/pNZPNK, Lactobacillus, coliform bacteria, beneficial bacteria Bifidobacterium and harmful bacteria Clostridium perfringens. The liver, spleen, kidney and blood were evaluated for the bacterial translocation. After 6 weeks consumption with GM and non-GM Lactococcus, no adverse effects were observed on the rat's body weight, hematological or serum biochemical parameters, or intestinal microflora. The bacterial translocation test showed that L. lactis NZ9000/pNZPNK did not translocate to any organ or blood. Bifidobacterium was significantly increased in feces after administration of both Lactococcus strains (L. lactis NZ9000 and L. lactis NZ9000/pNZPNK), while C. perfringens remained undetectable during the experiment. These results suggested that L. lactis NZ9000/pNZPNK could be safe in animal experiments and monitoring of the interaction between test strains and intestinal microflora might be applied as a method for other GMM safety assessments.

  20. Curcumin enhances wound healing in streptozotocin induced diabetic rats and genetically diabetic mice.

    PubMed

    Sidhu, G S; Mani, H; Gaddipati, J P; Singh, A K; Seth, P; Banaudha, K K; Patnaik, G K; Maheshwari, R K

    1999-01-01

    Tissue repair and wound healing are complex processes that involve inflammation, granulation and tissue remodeling. Interactions of different cells, extracellular matrix proteins and their receptors are involved in wound healing, and are mediated by cytokines and growth factors. Previous studies from our laboratory have shown that curcumin (diferuloylmethane), a natural product obtained from the rhizomes of Curcuma longa, enhanced cutaneous wound healing in rats and guinea pigs. In this study, we have evaluated the efficacy of curcumin treatment by oral and topical applications on impaired wound healing in diabetic rats and genetically diabetic mice using a full thickness cutaneous punch wound model. Wounds of animals treated with curcumin showed earlier re-epithelialization, improved neovascularization, increased migration of various cells including dermal myofibroblasts, fibroblasts, and macrophages into the wound bed, and a higher collagen content. Immunohistochemical localization showed an increase in transforming growth factor-beta1 in curcumin-treated wounds compared to controls. Enhanced transforming growth factor-beta1 mRNA expression in treated wounds was confirmed by in situ hybridization, and laser scan cytometry. A delay in the apoptosis patterns was seen in diabetic wounds compared to curcumin treated wounds as shown by terminal deoxynucleotidyl transferase-mediated deoxyuridyl triphosphate nick end labeling analysis. Curcumin was effective both orally and topically. These results show that curcumin enhanced wound repair in diabetic impaired healing, and could be developed as a pharmacological agent in such clinical settings.

  1. Genetic effects of acute spermatogonial X-irradiation of the laboratory rat.

    PubMed

    Chambers, J R; Chapman, A B

    1977-02-01

    The genetic effects of one generation of spermatogonial X-irradiation in rats, by a single dose of 600r in one experiment and by a fractionated dose of 450r in another, were measured in three generations of their descendants. Estimates of dominant lethal mutation rates--(2 to 3) X 10-4/gamete/r--from litter size differences between irradiated and nonirradiated stock were consistent with previous estimates from rats and mice. Similar consistency was found for estimates of sex-linked recessive mutation rates--(1 to 2) X 10-4 chromosome/r--from male proportions within strains; however, when measured in crossbreds the proportion of males was higher in the irradiated than in the nonirradiated lines. This inconsistency in results is in keeping with the contradictory results reported for recessive sex-linked lethal mutation rates in mice. The effects used to estimate recessive lethal mutation rates which were unusually high--(2 to 14) X 10-4/gamete/r--were not significant. Other factors that could have contributed to the observed effects are postulated.

  2. [The senescence-accelerated oxys rats--a genetic model of premature aging and age-dependent degenerative diseases].

    PubMed

    Kolosova, N G; Stefanova, N A; Korbolina, E E; Fursova, A Zh; Kozhevnikova, O S

    2014-01-01

    The genetic model of accelerated senescence and the associated diseases--the OXYS strain of rats--was created using selection and inbreeding of Wistar rats sensitive to cataractogenic effects of galactose. In the first 5 generations, the development of cataract was induced by galactose overconsumption, and after that, the rats were selected for early spontaneous cataract. Genetically linked with the latter was a set of features of accelerated senescence, which were inherited by the subsequent generations of the animals. At present, we have a 103rd generation of OXYS rats, who at young age develop retinopathy (similar to age-related macular degeneration in humans), osteoporosis, arterial hypertension, accelerated thymus involution, sarcopenia, and neurodegenerative changes in the brain (with the features characteristic of Alzheimer's disease), besides the cataract. This review discusses possible mechanisms of the accelerated senescence: the results of comparison of retinal transcriptomes between OXYS and Wistar(control) rats at different ages, studies of the markers of Alzheimer's disease in the retina and in certain brain regions, and the outcome of the efforts to develop congenic strains of animals via a transfer of several quantitative trait loci (QTLs) of chromosome 1 from OXYS to WAG rats that are associated with the signs of accelerated senescence. The uniqueness of OXYS rats lies in the complex composition of manifestations of the traits; accordingly, this rat model can be used not only for studies of the mechanisms of aging and pathogenesis of the age-related diseases but also for objective evaluation of new methods of treatment and prevention.

  3. Genetic and littermate influences on yawning in two selectively bred strains of rats.

    PubMed

    Moyaho, Alejandro; Barajas, Margarita; Ugarte, Araceli; Eguibar, José R

    2009-04-01

    This study was made to separate genetic from postnatal maternal influences on yawning in two strains of Sprague-Dawley rats selected for high- (HY) and low-yawning frequency (LY). Foster mothers of the two strains reared litters of pups in the four possible combinations and yawning was recorded in a novel environment when the adult offspring were 75-day-old. Yawning frequency of males and females was affected by pup strain but not by the strain of the foster mothers, when litter size was made constant; HY adult offspring yawned more than LY adult offspring. Yawning frequency was higher in HY male offspring than in HY female offspring. An interaction term between pup sex and the strain of the foster mothers revealed that while males reared by LY mothers yawned more than males reared by HY mothers, females reared by HY mothers yawned more than females reared by LY mothers. Mean frequency of yawning increased with the sex ratio of HY litters. These findings indicate that genetic and genotype-correlated littermate effects influence yawning frequency of adult offspring in response to a novel environment. (c) 2008 Wiley Periodicals, Inc.

  4. Genomic regulation of type 2 diabetes endophenotypes: Contribution from genetic studies in the Goto-Kakizaki rat.

    PubMed

    Bihoreau, Marie-Thérèse; Dumas, Marc-Emmanuel; Lathrop, Mark; Gauguier, Dominique

    2017-08-24

    The inbred Goto-Kakizaki (GK) rat strain is a unique model of spontaneous type 2 diabetes mellitus caused by naturally occurring genetic variants that have been selectively isolated from an outbred colony of Wistar rats. Genetic and genomic studies in experimental crosses and congenic strains of the GK have shed light on the complex etiopathogenesis of diabetes phenotypes in this model. Diabetes-related phenotypes in the GK are under polygenic control and distinct genetic loci regulate glucose tolerance, insulin secretion, β-cell mass and plasma lipids. Metabolome and transcriptome profiling data in GK crosses and congenics, combined with GK genome resequencing, have resulted in a comprehensive landscape of genomic regulations of metabolism that can disentangle causal relationships between GK variants and diabetes phenotypes. Application of systems biology and systems genetics in the GK has contributed to improve our understanding of the fundamental mechanisms regulating metabolism. The wealth of physiological, genetic and genomic information in this strain makes it one of the most powerful model systems to improve our understanding of genetic regulations of metabolism and for testing therapeutic solutions for diabetes. Copyright © 2017. Published by Elsevier B.V.

  5. The effects of cocaine self-administration on dendritic spine density in the rat hippocampus are dependent on genetic background.

    PubMed

    Miguéns, Miguel; Kastanauskaite, Asta; Coria, Santiago M; Selvas, Abraham; Ballesteros-Yañez, Inmaculada; DeFelipe, Javier; Ambrosio, Emilio

    2015-01-01

    Chronic exposure to cocaine induces modifications to neurons in the brain regions involved in addiction. Hence, we evaluated cocaine-induced changes in the hippocampal CA1 field in Fischer 344 (F344) and Lewis (LEW) rats, 2 strains that have been widely used to study genetic predisposition to drug addiction, by combining intracellular Lucifer yellow injection with confocal microscopy reconstruction of labeled neurons. Specifically, we examined the effects of cocaine self-administration on the structure, size, and branching complexity of the apical dendrites of CA1 pyramidal neurons. In addition, we quantified spine density in the collaterals of the apical dendritic arbors of these neurons. We found differences between these strains in several morphological parameters. For example, CA1 apical dendrites were more branched and complex in LEW than in F344 rats, while the spine density in the collateral dendrites of the apical dendritic arbors was greater in F344 rats. Interestingly, cocaine self-administration in LEW rats augmented the spine density, an effect that was not observed in the F344 strain. These results reveal significant structural differences in CA1 pyramidal cells between these strains and indicate that cocaine self-administration has a distinct effect on neuron morphology in the hippocampus of rats with different genetic backgrounds. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. The role of the dopamine D1 receptor in social cognition: studies using a novel genetic rat model­

    PubMed Central

    VandenBroeke, Marie; Youn, Jiun; Ellenbroek, Arabella K.; Karel, Peter; Shan, Ling; van Boxtel, Ruben; Ooms, Sharon; Balemans, Monique; Langedijk, Jacqueline; Muller, Mareike; Vriend, Gert; Cools, Alexander R.; Cuppen, Edwin; Ellenbroek, Bart A.

    2016-01-01

    ABSTRACT Social cognition is an endophenotype that is impaired in schizophrenia and several other (comorbid) psychiatric disorders. One of the modulators of social cognition is dopamine, but its role is not clear. The effects of dopamine are mediated through dopamine receptors, including the dopamine D1 receptor (Drd1). Because current Drd1 receptor agonists are not Drd1 selective, pharmacological tools are not sufficient to delineate the role of the Drd1. Here, we describe a novel rat model with a genetic mutation in Drd1 in which we measured basic behavioural phenotypes and social cognition. The I116S mutation was predicted to render the receptor less stable. In line with this computational prediction, this Drd1 mutation led to a decreased transmembrane insertion of Drd1, whereas Drd1 expression, as measured by Drd1 mRNA levels, remained unaffected. Owing to decreased transmembrane Drd1 insertion, the mutant rats displayed normal basic motoric and neurological parameters, as well as locomotor activity and anxiety-like behaviour. However, measures of social cognition like social interaction, scent marking, pup ultrasonic vocalizations and sociability, were strongly reduced in the mutant rats. This profile of the Drd1 mutant rat offers the field of neuroscience a novel genetic rat model to study a series of psychiatric disorders including schizophrenia, autism, depression, bipolar disorder and drug addiction. PMID:27483345

  7. Genetic susceptibility to hypertension-induced renal damage in the rat. Evidence based on kidney-specific genome transfer.

    PubMed Central

    Churchill, P C; Churchill, M C; Bidani, A K; Griffin, K A; Picken, M; Pravenec, M; Kren, V; St Lezin, E; Wang, J M; Wang, N; Kurtz, T W

    1997-01-01

    To test the hypothesis that genetic factors can determine susceptibility to hypertension-induced renal damage, we derived an experimental animal model in which two genetically different yet histocompatible kidneys are chronically and simultaneously exposed to the same blood pressure profile and metabolic environment within the same host. Kidneys from normotensive Brown Norway rats were transplanted into unilaterally nephrectomized spontaneously hypertensive rats (SHR-RT1.N strain) that harbor the major histocompatibility complex of the Brown Norway strain. 25 d after the induction of severe hypertension with deoxycorticosterone acetate and salt, proteinuria, impaired glomerular filtration rate, and extensive vascular and glomerular injury were observed in the Brown Norway donor kidneys, but not in the SHR-RT1.N kidneys. Control experiments demonstrated that the strain differences in kidney damage could not be attributed to effects of transplantation-induced renal injury, immunologic rejection phenomena, or preexisting strain differences in blood pressure. These studies (a) demonstrate that the kidney of the normotensive Brown Norway rat is inherently much more susceptible to hypertension-induced damage than is the kidney of the spontaneously hypertensive rat, and (b) establish the feasibility of using organ-specific genome transplants to map genes expressed in the kidney that determine susceptibility to hypertension-induced renal injury in the rat. PMID:9294102

  8. Cytotoxic effect of aspartame (diet sweet) on the histological and genetic structures of female albino rats and their offspring.

    PubMed

    Abd Elfatah, Azza A M; Ghaly, Inas S; Hanafy, Safaa M

    2012-10-01

    The present study evaluated the effect of aspartame intake on the histological and genetic structures of mother albino rats and their offspring. Sixty adult female albino rats and 180 of their offspring were equally divided into two groups (control and treated), each group divided into three subgroups. Each subgroup consisted of 10 pregnant rats and 30 of their offspring. The experimental design divided into three periods: (1) the gestation period (subgroup one), (2) the gestation period and three weeks after delivery (subgroup two) and (3) animals in the third subgroup treated as subgroup two then left till the end of the ninth week after delivery. Each pregnant rat in the treated subgroups was given a single daily dose of 1 mL aspartame solution (50.4 mg) by gastric gavage throughout the time intervals of experimental design. At the end of each experimental period for control and treated subgroups, the liver of half of both control and treated groups were subjected for histological study while the liver and bone marrow of the other halves were subjected for cytogenetic studies. Body weight of both groups were recorded individually twice weekly in the morning before offering the diet. The results revealed that the rats and their offspring in the subgroups of control animals showed increases in body weight, normal histological sections, low chromosomal aberration and low DNA fragmentation. The treated animals in the three subgroups rats and their offspring revealed decreases in body weight, high histological lesions, increases in the chromosomal aberration and DNA fragmentation compared with control groups. In conclusion, the consumption of aspartame leads to histopathological lesions in the liver and alterations of the genetic system in the liver and bone marrow of mother albino rats and their offspring. These toxicological changes were directly proportional to the duration of its administration and improved after its withdrawal.

  9. Effect of genetically modified corn on the jejunal mucosa of adult male albino rat.

    PubMed

    Ibrahim, Marwa A A; Okasha, Ebtsam F

    2016-11-01

    Genetically modified (GM) plants expressing insecticidal traits offer a new strategy for crop protection. GM-corn contains Bacillus thuringiensis (Bt) genes producing delta endotoxins in the whole plant. Diet can influence the characteristics of the gastrointestinal tract altering its function and structure. The aim of this study was to evaluate the effect of GM-corn on the histological structure of jejunal mucosa of adult male albino rat using different histological, immunohistochemical and morphometrical methods. Twenty adult male albino rats were divided into two equal groups; control and GM-corn fed group administered with 30% GM-corn for 90days. Specimens from the jejunum were processed for light and electron microscopy. Immunohistochemical study was carried out using antibody against proliferating cell nuclear antigen (PCNA). Different morphometrical parameters were assessed. Specimens from GM-corn fed group showed different forms of structural changes. Focal destruction and loss of the villi leaving denuded mucosal surface alternating with stratified areas were observed, while some crypts appeared totally disrupted. Congested blood capillaries and focal infiltration with mononuclear cells were detected. Significant upregulation of PCNA expression, increase in number of goblet cells and a significant increase in both villous height and crypt depth were detected. Marked ultrastructural changes of some enterocytes with focal loss of the microvillous border were observed. Some enterocytes had vacuolated cytoplasm, swollen mitochondria with disrupted cristae and dilated rough endoplasmic reticulum (rER). Some cells had dark irregular nuclei with abnormally clumped chromatin. It could be concluded that consumption of GM-corn profoundly alters the jejunal histological structure. Copyright © 2016 Elsevier GmbH. All rights reserved.

  10. Aluminum phosphide-induced genetic and oxidative damages in rats: attenuation by Laurus nobilis leaf extract.

    PubMed

    Türkez, Hasan; Toğar, Başak

    2013-08-01

    Aluminum phosphide (AlP) is a colorless, flammable, liquefied pesticide that is commonly used to control insects, nematodes, weeds, and pathogens in crops, forests, ornamental nurseries, and wood products. Early investigations of AlP-poisoned mammalian cells led to the proposed involvement of oxidative damage in its toxicity mechanism. Therefore, this study was aimed to evaluate the effect of Laurus nobilis (L) leaf extract (LNE) against AlP-induced genetic and oxidative damages in rats. Selected animals were assigned to four groups (n = 6), namely, group A: control (only distilled water is injected); group B: AlP (4 mg kg(-1) injected intraperitoneally (i.p.)); group C: LNE (200 mg kg(-1) injected i.p.), and group D: AlP plus LNE, respectively. The experimental period lasted for 14 successive days. Chromosomal aberrations (CAs) and micronucleus (MN) assay were used for monitoring genotoxic damage. In addition, biochemical parameters such as total antioxidant capacity (TAC) and total oxidative status (TOS) were examined in serum samples to determine oxidative damage. Our results indicated that AlP caused increase in CA and MN assay rates and alterations in TAC and TOS levels when compared with control group. On the contrary, LNE did not change the rates of both the analyzed cytogenetic end points and led to increase in TAC level. Moreover, we observed that LNE suppressed the genetic damage by AlP to bone marrow cells in vivo. Interestingly AlP-induced oxidative stress was also strongly reduced by LNE. The results of the present study indicated that the protective effect of LNE might be ascribable to its antioxidant and free radical scavenging properties.

  11. Challenging the inbreeding hypothesis in a eusocial mammal: population genetics of the naked mole-rat, Heterocephalus glaber.

    PubMed

    Ingram, Colleen M; Troendle, Nicholas J; Gill, Clare A; Braude, Stanton; Honeycutt, Rodney L

    2015-10-01

    The role of genetic relatedness in the evolution of eusociality has been the topic of much debate, especially when contrasting eusocial insects with vertebrates displaying reproductive altruism. The naked mole-rat, Heterocephalus glaber, was the first described eusocial mammal. Although this discovery was based on an ecological constraints model of eusocial evolution, early genetic studies reported high levels of relatedness in naked mole-rats, providing a compelling argument that low dispersal rates and consanguineous mating (inbreeding as a mating system) are the driving forces for the evolution of this eusocial species. One caveat to accepting this long-held view is that the original genetic studies were based on limited sampling from the species' geographic distribution. A growing body of evidence supports a contrary view, with the original samples not representative of the species-rather reflecting a single founder event, establishing a small population south of the Athi River. Our study is the first to address these competing hypotheses by examining patterns of molecular variation in colonies sampled from north and south of the Athi and Tana rivers, which based on our results, serve to isolate genetically distinct populations of naked mole-rats. Although colonies south of the Athi River share a single mtDNA haplotype and are fixed at most microsatellite loci, populations north of the Athi River are considerably more variable. Our findings support the position that the low variation observed in naked mole-rat populations south of the Athi River reflects a founder event, rather than a consequence of this species' unusual mating system.

  12. Chemosensory responsiveness to ethanol and its individual sensory components in alcohol-preferring, alcohol-nonpreferring and genetically heterogeneous rats.

    PubMed

    Brasser, Susan M; Silbaugh, Bryant C; Ketchum, Myles J; Olney, Jeffrey J; Lemon, Christian H

    2012-03-01

    Alcohol activates orosensory circuits that project to motivationally relevant limbic forebrain areas that control appetite, feeding and drinking. To date, limited data exists regarding the contribution of chemosensory-derived ethanol reinforcement to ethanol preference and consumption. Measures of taste reactivity to intra-orally infused ethanol have not found differences in initial orofacial responses to alcohol between alcohol-preferring (P) and alcohol-non-preferring (NP) genetically selected rat lines. Yet, in voluntary intake tests, P rats prefer highly concentrated ethanol upon initial exposure, suggesting an early sensory-mediated attraction. Here, we directly compared self-initiated chemosensory responding for alcohol and prototypic sweet, bitter and oral trigeminal stimuli among selectively bred P, NP and non-selected Wistar (WI) outbred lines to determine whether differential sensory responsiveness to ethanol and its putative sensory components are phenotypically associated with genetically influenced alcohol preference. Rats were tested for immediate short-term lick responses to alcohol (3-40%), sucrose (0.01-1 M), quinine (0.01-3 mM) and capsaicin (0.003-1 mM) in a brief-access assay designed to index orosensory-guided behavior. P rats exhibited elevated short-term lick responses to both alcohol and sucrose relative to NP and WI lines across a broad range of concentrations of each stimulus and in the absence of blood alcohol levels that would produce significant post-absorptive effects. There was no consistent relationship between genetically mediated alcohol preference and orosensory avoidance of quinine or capsaicin. These data indicate that enhanced initial chemosensory attraction to ethanol and sweet stimuli are phenotypes associated with genetic alcohol preference and are considered within the framework of downstream activation of oral appetitive reward circuits.

  13. Commensal ecology, urban landscapes, and their influence on the genetic characteristics of city-dwelling Norway rats (Rattus norvegicus).

    PubMed

    Gardner-Santana, L C; Norris, D E; Fornadel, C M; Hinson, E R; Klein, S L; Glass, G E

    2009-07-01

    Movement of individuals promotes colonization of new areas, gene flow among local populations, and has implications for the spread of infectious agents and the control of pest species. Wild Norway rats (Rattus norvegicus) are common in highly urbanized areas but surprisingly little is known of their population structure. We sampled individuals from 11 locations within Baltimore, Maryland, to characterize the genetic structure and extent of gene flow between areas within the city. Clustering methods and a neighbour-joining tree based on pairwise genetic distances supported an east-west division in the inner city, and a third cluster comprised of historically more recent sites. Most individuals (approximately 95%) were assigned to their area of capture, indicating strong site fidelity. Moreover, the axial dispersal distance of rats (62 m) fell within typical alley length. Several rats were assigned to areas 2-11.5 km away, indicating some, albeit infrequent, long-distance movement within the city. Although individual movement appears to be limited (30-150 m), locations up to 1.7 km are comprised of relatives. Moderate F(ST), differentiation between identified clusters, and high allelic diversity indicate that regular gene flow, either via recruitment or migration, has prevented isolation. Therefore, ecology of commensal rodents in urban areas and life-history characteristics of Norway rats likely counteract many expected effects of isolation or founder events. An understanding of levels of connectivity of rat populations inhabiting urban areas provides information about the spatial scale at which populations of rats may spread disease, invade new areas, or be eradicated from an existing area without reinvasion.

  14. A 90-Day Toxicology Study of Meat from Genetically Modified Sheep Overexpressing TLR4 in Sprague-Dawley Rats

    PubMed Central

    Hu, Rui; Kan, Tongtong; Li, Yan; Zhang, Xiaosheng; Zhang, Jinlong; Lian, Ling; Han, Hongbing; Lian, Zhengxing

    2015-01-01

    Genetic modification offers alternative strategies to traditional animal breeding. However, the food safety of genetically modified (GM) animals has attracted increasing levels of concern. In this study, we produced GM sheep overexpressing TLR4, and the transgene-positive offsprings (F1) were confirmed using the polymerase chain reaction (PCR) and Southern blot. The expression of TLR4 was 2.5-fold compared with that of the wild-type (WT) sheep samples. During the 90-day safety study, Sprague-Dawley rats were fed with three different dietary concentrations (3.75%, 7.5%, and 15% wt/wt) of GM sheep meat, WT sheep meat or a commercial diet (CD). Blood samples from the rats were collected and analyzed for hematological and biochemical parameters, and then compared with hematological and biochemical reference ranges. Despite a few significant differences among the three groups in some parameters, all other values remained within the normal reference intervals and thus were not considered to be affected by the treatment. No adverse diet-related differences in body weights or relative organ weights were observed. Furthermore, no differences were observed in the gross necropsy findings or microscopic pathology of the rats whose diets contained the GM sheep meat compared with rats whose diets contained the WT sheep meat. Therefore, the present 90-day rat feeding study suggested that the meat of GM sheep overexpressing TLR4 had no adverse effect on Sprague-Dawley rats in comparison with WT sheep meat. These results provide valuable information regarding the safety assessment of meat derived from GM animals. PMID:25874566

  15. A 90-day toxicology study of meat from genetically modified sheep overexpressing TLR4 in Sprague-Dawley rats.

    PubMed

    Bai, Hai; Wang, Zhixian; Hu, Rui; Kan, Tongtong; Li, Yan; Zhang, Xiaosheng; Zhang, Jinlong; Lian, Ling; Han, Hongbing; Lian, Zhengxing

    2015-01-01

    Genetic modification offers alternative strategies to traditional animal breeding. However, the food safety of genetically modified (GM) animals has attracted increasing levels of concern. In this study, we produced GM sheep overexpressing TLR4, and the transgene-positive offsprings (F1) were confirmed using the polymerase chain reaction (PCR) and Southern blot. The expression of TLR4 was 2.5-fold compared with that of the wild-type (WT) sheep samples. During the 90-day safety study, Sprague-Dawley rats were fed with three different dietary concentrations (3.75%, 7.5%, and 15% wt/wt) of GM sheep meat, WT sheep meat or a commercial diet (CD). Blood samples from the rats were collected and analyzed for hematological and biochemical parameters, and then compared with hematological and biochemical reference ranges. Despite a few significant differences among the three groups in some parameters, all other values remained within the normal reference intervals and thus were not considered to be affected by the treatment. No adverse diet-related differences in body weights or relative organ weights were observed. Furthermore, no differences were observed in the gross necropsy findings or microscopic pathology of the rats whose diets contained the GM sheep meat compared with rats whose diets contained the WT sheep meat. Therefore, the present 90-day rat feeding study suggested that the meat of GM sheep overexpressing TLR4 had no adverse effect on Sprague-Dawley rats in comparison with WT sheep meat. These results provide valuable information regarding the safety assessment of meat derived from GM animals.

  16. AFLP genome scan in the black rat (Rattus rattus) from Madagascar: detecting genetic markers undergoing plague-mediated selection.

    PubMed

    Tollenaere, C; Duplantier, J-M; Rahalison, L; Ranjalahy, M; Brouat, C

    2011-03-01

    The black rat (Rattus rattus) is the main reservoir of plague (Yersinia pestis infection) in Madagascar's rural zones. Black rats are highly resistant to plague within the plague focus (central highland), whereas they are susceptible where the disease is absent (low altitude zone). To better understand plague wildlife circulation and host evolution in response to a highly virulent pathogen, we attempted to determine genetic markers associated with plague resistance in this species. To this purpose, we combined a population genomics approach and an association study, both performed on 249 AFLP markers, in Malagasy R. rattus. Simulated distributions of genetic differentiation were compared to observed data in four independent pairs, each consisting of one population from the plague focus and one from the plague-free zone. We found 22 loci (9% of 249) with higher differentiation in at least two independent population pairs or with combining P-values over the four pairs significant. Among the 22 outlier loci, 16 presented significant association with plague zone (plague focus vs. plague-free zone). Population genetic structure inferred from outlier loci was structured by plague zone, whereas the neutral loci dataset revealed structure by geography (eastern vs. western populations). A phenotype association study revealed that two of the 22 loci were significantly associated with differentiation between dying and surviving rats following experimental plague challenge. The 22 outlier loci identified in this study may undergo plague selective pressure either directly or more probably indirectly due to hitchhiking with selected loci. © 2010 Blackwell Publishing Ltd.

  17. Genetically modified Schwann cells producing glial cell line-derived neurotrophic factor inhibit neuronal apoptosis in rat spinal cord injury.

    PubMed

    Liu, Guomin; Wang, Xukai; Shao, Guoxi; Liu, Qinyi

    2014-04-01

    Schwann cells (SCs) are the major cells constituting the peripheral nerve structure and function, and also secret a variety of neurotrophic factors. Schwann cell (SC) transplantation has recently emerged as a promising therapeutic strategy for spinal cord injury (SCI). In the present study, the ability of genetically modified SCs producing high levels of glial cell line‑derived neurotrophic factor (GDNF) to promote spinal cord repair was assessed. The GDNF gene was transduced into SCs. The engineered SCs were characterized by their ability to express and secrete biologically active GDNF, which was shown to inhibit apoptosis of primary rat neurons induced by radiation, and upregulate the expression of B‑cell lymphoma 2 (Bcl‑2) and downregulate the expression of Bcl‑2 associated X protein (Bax) in vitro. Following SC implantation into the spinal cord of adult rats with SCI induced by weight‑drop impact, the survival of rats with transplanted SCs, histology of the spinal cord and expression levels of Bcl‑2 and Bax were examined. Transplantation of unmodified and genetically modified SCs producing GDNF attenuated SCI by inhibiting apoptosis via the Bcl‑2/Bax pathways. The genetically modified SCs demonstrated markedly improved recovery of SCI as compared with unmodified SCs. The present study combined the outgrowth‑promoting property of SCs with the neuroprotective effects of overexpressed GDNF and identified this as a potential novel therapeutic strategy for SCI.

  18. The deafferentation syndrome in genetically blind rats: a model of the painful phantom limb.

    PubMed

    Levitt, M; Heybach, J P

    1981-02-01

    The hypothesis was tested which states that the somatic deafferentation syndrome is a visually prompted response to sensorimotor loss. The dorsal roots, C5-T2, were bilaterally cut in a strain of rats known to be genetically blind. These complete dorsal rhizotomies left the forelimbs totally anesthetic, analgesic and paretic. Contact and visual placing reactions were absent, and responses to pinprick or pinch were absent. Self-mutilation limited to the distal digits appeared on the first or second postoperative days and then progressed proximally. The forelimbs were symmetrically affected, and no other body parts were mutilated. The spatial precision of this syndrome, in the absence of visual as well as peripheral somatosensory information from the affected limb, indicates that controlled guidance of the behavior arises from an existing central representation of the limb and its relationship with the total body; a phantom limb. Consideration of other reports regarding the deafferentation syndrome leads to the view that it is motivated by disturbing abnormal sensations (pain) of central neural origin.

  19. The influence of biocomposites containing genetically modified flax fibers on gene expression in rat skeletal muscle.

    PubMed

    Gredes, Tomasz; Kunert-Keil, Christiane; Dominiak, Marzena; Gedrange, Tomasz; Wróbel-Kwiatkowska, Magdalena; Szopa, Jan

    2010-12-01

    In many studies, natural flax fibers have been proven to be resistant and surgically suitable. Genetically modified flax fibers, derived from transgenic flax expressing three bacterial genes for the synthesis of poly-3-hydroxybutyric acid (PHB), have better mechanical properties than unmodified flax fibers. The aim of this study was to examine the biocompatibility of composites containing flax fibers from transgenic polyhydroxybutyrate producing (M50) and control (wt-NIKE) plants in a polylactide (PLA) matrix in rat Musculus latissimus dorsi. For this purpose, effects of biocomposites on the expression of growth factors and osteogenic differentiation, in particular the mRNA expression of vascular endothelial growth factor, insulin like growth factor 1, insulin like growth factor 2, collagen-1, collagen-2 and myostatin, were analyzed using quantitative RT-PCR. The biocomposites did not show any inflammation response after subcutaneous insertion. The results following subcutaneous insertion of PLA alone and PLA-M50 showed no significant changes on the gene expression of all tested genes, whereas PLA-wt-NIKE reduced the mRNA amount of myostatin, VEGFA and IGF2, respectively. It can be asserted that modified flax membranes with PHB and other organic substances have a good biocompatibility to the muscle and they do not disrupt the muscle function. Furthermore, composites from transgenic flax plants producing PHB did not differ from composites of non-transgenic flax plants.

  20. Ameliorating effect of olive oil on fertility of male rats fed on genetically modified soya bean

    PubMed Central

    El-Kholy, Thanaa A. F.; Al-Abbadi, Hatim A.; Qahwaji, Dina; Al-Ghamdi, Ahmed K.; Shelat, Vishal G.; Sobhy, Hanan M.; Hilal, Mohammad Abu

    2015-01-01

    Background Genetically modified soya bean (GMSB) is a commercialized food. It has been shown to have adverse effects on fertility in animal trials. Extra virgin olive oil (EVOO) has many beneficial effects including anti-oxidant properties. The aim of this study is to elucidate if addition of EVOO ameliorates the adverse effects on reproductive organs of rats fed on GMSB containing diet. Methods Forty adult male albino rats (150–180 g) of Sprague Dawley strain were separated into four groups of 10 rats each: Group 1 – control group fed on basal ration, Group 2 – fed on basal ration mixed with EVOO (30%), Group 3 – fed on basal ration mixed with GMSB (15%), and Group 4 – fed on basal ration mixed with GMSB (15%) and EVOO (30%). This feeding regimen was administered for 65 days. Blood samples were collected to analyze serum zinc, vitamin E, and testosterone levels. Histopathological and weight changes in sex organs were evaluated. Results GMSB diet reduced weight of testis (0.66±0.06 vs. 1.7±0.06, p<0.001), epididymis (0.489±0.03 vs. 0.7±0.03, p<0.001), prostate (0.04±0.009 vs. 0.68±0.04, p<0.001), and seminal vesicles (0.057±0.01 vs. 0.8±0.04, p<0.001). GMSB diet adversely affected sperm count (406±7.1 vs. 610±7.8, p<0.001), motility (p<0.001), and abnormality (p<0.001). GMSB diet also reduced serum zinc (p<0.05), vitamin E (p<0.05), and testosterone (p<0.05) concentrations. EVOO diet had no detrimental effect. Addition of EVOO to GMSB diet increased the serum zinc (p<0.05), vitamin E (p<0.05), and testosterone (p<0.05) levels and also restored the weights of testis (1.35±0.16 vs. 0.66±0.06, p<0.01), epididymis (0.614±0.13 vs. 0.489±0.03, p<0.001), prostate (0.291±0.09 vs. 0.04±0.009, p<0.001), seminal vesicle (0.516±0.18 vs. 0.057±0.01, p<0.001) along with sperm count (516±3.1 vs. 406±7.1, p<0.01), motility (p<0.01), and abnormality (p<0.05). Conclusion EVOO ameliorates the adverse effects of GMSB on reproductive organs in adult male

  1. Gene expression in hippocampus as a function of differential trait anxiety levels in genetically heterogeneous NIH-HS rats.

    PubMed

    Díaz-Morán, Sira; Palència, Marta; Mont-Cardona, Carme; Cañete, Toni; Blázquez, Gloria; Martínez-Membrives, Esther; López-Aumatell, Regina; Sabariego, Marta; Donaire, Rocío; Morón, Ignacio; Torres, Carmen; Martínez-Conejero, José Antonio; Tobeña, Adolf; Esteban, Francisco José; Fernández-Teruel, Alberto

    2013-11-15

    To identify genes involved in the development/expression of anxiety/fear, we analyzed the gene expression profile in the hippocampus of genetically heterogeneous NIH-HS rats. The NIH-HS rat stock is a unique genetic resource for the fine mapping of quantitative trait loci (QTLs) to very small genomic regions, due to the high amount of genetic recombinants accumulated along more than 50 breeding generations, and for the same reason it can be expected that those genetically heterogeneous rats should be especially useful for studying differential gene expression as a function of anxiety, fearfulness or other complex traits. We selected high- and low-anxious NIH-HS rats according to the number of avoidance responses they performed in a single 50-trial session of the two-way active avoidance task. Rats were also tested in unconditioned anxiety/fearfulness tests, i.e. the elevated zero-maze and a "novel-cage activity" test. Three weeks after behavioral testing, the hippocampus was dissected and prepared for the microarray study. There appeared 29 down-regulated and 37 up-regulated SNC-related genes (fold-change>|2.19|, FDR<0.05) in the "Low-anxious" vs. the "High-anxious" group. Regression analyses (stepwise) revealed that differential expression of some genes could be predictive of anxiety/fear responses. Among those genes for which the present results suggest a link with individual differences in trait anxiety, nine relevant genes (Avpr1b, Accn3, Cd74, Ltb, Nrg2, Oprdl1, Slc10a4, Slc5a7 and RT1-EC12), tested for validation through qRT-PCR, have either neuroendocrinological or neuroinmunological/inflammation-related functions, or have been related with the hippocampal cholinergic system, while some of them have also been involved in the modulation of anxiety or stress-related (neurobiological and behavioral) responses (i.e. Avpr1b, Oprdl1). The present work confirms the usefulness of NIH-HS rats as a good animal model for research on the neurogenetic basis or mechanisms

  2. Gene expression in amygdala as a function of differential trait anxiety levels in genetically heterogeneous NIH-HS rats.

    PubMed

    Díaz-Morán, Sira; Palència, Marta; Mont-Cardona, Carme; Cañete, Toni; Blázquez, Gloria; Martínez-Membrives, Esther; López-Aumatell, Regina; Sabariego, Marta; Donaire, Rocío; Morón, Ignacio; Torres, Carmen; Martínez-Conejero, José Antonio; Tobeña, Adolf; Esteban, Francisco José; Fernández-Teruel, Alberto

    2013-09-01

    To identify genes involved in anxiety/fear traits, we analyzed the gene expression profile in the amygdala of genetically heterogeneous NIH-HS rats. The NIH-HS rat stock has revealed to be a unique genetic resource for the fine mapping of Quantitative Trait Loci (QTLs) to very small genomic regions, due to the high amount of genetic recombinants accumulated along more than 50 breeding generations, and for the same reason it can be expected that those genetically heterogeneous rats should be especially useful for studying differential gene expression as a function of anxiety-(or other)-related traits. We selected high- and low-anxious NIH-HS rats differing in their number of avoidances in a single 50-trial session of the two-way active avoidance task. Rats were also tested in unconditioned anxiety tests (e.g., elevated zero-maze). Three weeks after behavioural testing, the amygdala was dissected and prepared for the microarray study. There appeared 6 significantly down-regulated and 28 up-regulated genes (fold-change >|2|, FDR<0.05) between the low- and high-anxious groups, with central nervous system-related functions. Regression analyses (stepwise) revealed that differential expression of some genes could be predictive of anxiety/fear responses. Among those genes for which the present results suggest a link with individual differences in trait anxiety, six relevant genes were examined with qRT-PCR, four of which (Ucn3, Tacr3, H2-M9 and Arr3) were validated. Remarkably, some of them are characterized by sharing known functions related with hormonal HPA-axis responses to (and/or modulation of) stress, anxiety or fear, and putative involvement in related neurobehavioural functions. The results confirm the usefulness of NIH-HS rats as a good animal model for research on the neurogenetic basis of anxiety and fear, while suggesting the involvement of some neuropeptide/neuroendocrine pathways on the development of differential anxiety profiles.

  3. A 90-day subchronic feeding study of genetically modified rice expressing Cry1Ab protein in Sprague-Dawley rats.

    PubMed

    Song, Huan; He, Xiaoyun; Zou, Shiying; Zhang, Teng; Luo, Yunbo; Huang, Kunlun; Zhu, Zhen; Xu, Wentao

    2015-04-01

    Bacillus thuringiensis (Bt) transgenic rice line (mfb-MH86) expressing a synthetic cry1Ab gene can be protected against feeding damage from Lepidopteran insects, including Sesamia inferens, Chilo suppressalis, Tryporyza incertulas and Cnaphalocrocis medinalis. Rice flour from mfb-MH86 and its near-isogenic control MH86 was separately formulated into rodent diets at concentrations of 17.5, 35 and 70 % (w/w) for a 90-day feeding test with rats, and all of the diets were nutritionally balanced. In this study, the responses of rats fed diets containing mfb-MH86 were compared to those of rats fed flour from MH86. Overall health, body weight and food consumption were comparable between groups fed diets containing mfb-MH86 and MH86. Blood samples were collected prior to sacrifice and a few significant differences (p < 0.05) were observed in haematological and biochemical parameters between rats fed genetically modified (GM) and non-GM diets. However, the values of these parameters were within the normal ranges of values for rats of this age and sex, thus not considered treatment related. In addition, upon sacrifice a large number of organs were weighed, macroscopic and histopathological examinations were performed with only minor changes to report. In conclusion, these results demonstrated that no toxic effect was observed in the conditions of the experiment, based on the different parameters assessed. GM rice mfb-MH86 is as safe and nutritious as non-GM rice.

  4. SWI/SNF chromatin remodeling enzymes are associated with cardiac hypertrophy in a genetic rat model of hypertension.

    PubMed

    Mehrotra, Aanchal; Joe, Bina; de la Serna, Ivana L

    2013-12-01

    Pathological cardiac hypertrophy is characterized by a sustained increase in cardiomyocyte size and re-activation of the fetal cardiac gene program. Previous studies implicated SWI/SNF chromatin remodeling enzymes as regulators of the fetal cardiac gene program in surgical models of cardiac hypertrophy. Although hypertension is a common risk factor for developing cardiac hypertrophy, there has not yet been any investigation into the role of SWI/SNF enzymes in cardiac hypertrophy using genetic models of hypertension. In this study, we tested the hypothesis that components of the SWI/SNF complex are activated and recruited to promoters that regulate the fetal cardiac gene program in hearts that become hypertrophic as a result of salt induced hypertension. Utilizing the Dahl salt-sensitive (S) rat model, we found that the protein levels of several SWI/SNF subunits required for heart development, Brg1, Baf180, and Baf60c, are elevated in hypertrophic hearts from S rats fed a high salt diet compared with normotensive hearts from Dahl salt-resistant (R) rats fed the same diet. Furthermore, we detected significantly higher levels of SWI/SNF subunit enrichment as well as evidence of more accessible chromatin structure on two fetal cardiac gene promoters in hearts from S rats compared with R rats. Our data implicate SWI/SNF chromatin remodeling enzymes as regulators of gene expression in cardiac hypertrophy resulting from salt induced hypertension. Thus we provide novel insights into the epigenetic mechanisms by which salt induced hypertension leads to cardiac hypertrophy.

  5. Emotional memory impairments in a genetic rat model of depression: involvement of 5-HT/MEK/Arc signaling in restoration

    PubMed Central

    Eriksson, T M; Delagrange, P; Spedding, M; Popoli, M; Mathé, A A; Ögren, S O; Svenningsson, P

    2012-01-01

    Cognitive dysfunctions are common in major depressive disorder, but have been difficult to recapitulate in animal models. This study shows that Flinders sensitive line (FSL) rats, a genetic rat model of depression, display a pronounced impairment of emotional memory function in the passive avoidance (PA) task, accompanied by reduced transcription of Arc in prefrontal cortex and hippocampus. At the cellular level, FSL rats have selective reductions in levels of NMDA receptor subunits, serotonin 5-HT1A receptors and MEK activity. Treatment with chronic escitalopram, but not with an antidepressant regimen of nortriptyline, restored memory performance and increased Arc transcription in FSL rats. Multiple pharmacological manipulations demonstrated that procognitive effects could also be achieved by either disinhibition of 5-HT1AR/MEK/Arc or stimulation of 5-HT4R/MEK/Arc signaling cascades. Taken together, studies of FSL rats in the PA task revealed reversible deficits in emotional memory processing, providing a potential model with predictive and construct validity for assessments of procognitive actions of antidepressant drug therapies. PMID:21242991

  6. Genetic mapping of Eutr1, a locus controlling E2-induced pyometritis in the Brown Norway rat, to RNO5.

    PubMed

    Gould, Karen A; Pandey, Jyotsna; Lachel, Cynthia M; Murrin, Clare R; Flood, Lisa A; Pennington, Karen L; Schaffer, Beverly S; Tochacek, Martin; McComb, Rodney D; Meza, Jane L; Wendell, Douglas L; Shull, James D

    2005-11-01

    In certain rat strains, chronic estrogen administration can lead to pyometritis, an inflammation of the uterus accompanied by infection and the accumulation of intraluminal pus. In this article, we report that the Brown Norway (BN) rat is highly susceptible to pyometritis induced by 17beta-estradiol (E2). The susceptibility of the BN rat to E2-induced pyometritis appears to segregate as a recessive trait in crosses to the resistant August x Copenhagen Irish (ACI) strain. In a (BN x ACI)F(2) population, we find strong evidence for a major genetic determinant of susceptibility to E2-induced pyometritis on rat chromosome 5 (RNO5). Our data are most consistent with a model in which the BN allele of this locus, designated Eutr1 (Estrogen-induced uterine response 1), acts in an incompletely dominant manner to control E2-induced pyometritis. Furthermore, we have confirmed the contribution of Eutr1 to E2-induced uterine pyometritis using an RNO5 congenic rat strain. In addition to Eutr1, we obtained evidence suggestive of linkage for five additional loci on RNO2, 4, 11, 17, and X that control susceptibility to E2-induced pyometritis in the (BN x ACI)F(2) population.

  7. High performance seizure-monitoring system using a vibration sensor and videotape recording: behavioral analysis of genetically epileptic rats.

    PubMed

    Amano, S; Yokoyama, M; Torii, R; Fukuoka, J; Tanaka, K; Ihara, N; Hazama, F

    1997-06-01

    A new seizure-monitoring apparatus containing a piezoceramic vibration sensor combined with videotape recording was developed. Behavioral analysis of Ihara's genetically epileptic rat (IGER), which is a recently developed novel mutant with spontaneously limbic-like seizures, was performed using this new device. Twenty 8-month-old male IGERs were monitored continuously for 72 h. Abnormal behaviors were detected by use of a vibration recorder, and epileptic seizures were confirmed by videotape recordings taken synchronously with vibration recording. Representative forms of seizures were generalized convulsions and circling seizures. Generalized convulsions were found in 13 rats, and circling seizures in 7 of 20 animals. Two rats had generalized and circling seizures, and two rats did not have seizures. Although there was no apparent circadian rhythm to the generalized seizures, circling seizures occurred mostly between 1800 and 0800 h. A correlation between the sleep-wake cycle and the occurrence of circling seizures seems likely. Without exception, all the seizure actions were recorded by the vibration recorder and the videotape recorder. To eliminate the risk of a false-negative result, investigators scrutinized the information obtained from the vibration sensor and the videotape recorder. The newly developed seizure-monitoring system was found to facilitate detailed analysis of epileptic seizures in rats.

  8. Differential response of rat strains to obesogenic diets underlines the importance of genetic makeup of an individual towards obesity.

    PubMed

    Mn, Muralidhar; Smvk, Prasad; Battula, Kiran Kumar; Nv, Giridharan; Kalashikam, Rajender Rao

    2017-08-22

    Obesity, a multifactorial disorder, results from a chronic imbalance of energy intake vs. expenditure. Apart from excessive consumption of high calorie diet, genetic predisposition also seems to be equally important for the development of obesity. However, the role of genetic predisposition in the etiology of obesity has not been clearly delineated. The present study addresses this problem by selecting three rat strains (WNIN, F-344, SD) with different genetic backgrounds and exposing them to high calorie diets. Rat strains were fed HF, HS, and HFS diets and assessed for physical, metabolic, biochemical, inflammatory responses, and mRNA expression. Under these conditions: significant increase in body weight, visceral adiposity, oxidative stress and systemic pro-inflammatory status; the hallmarks of central obesity were noticed only in WNIN. Further, they developed altered glucose and lipid homeostasis by exhibiting insulin resistance, impaired glucose tolerance, dyslipidemia and fatty liver condition. The present study demonstrates that WNIN is more prone to develop obesity and associated co-morbidities under high calorie environment. It thus underlines the cumulative role of genetics (nature) and diet (nurture) towards the development of obesity, which is critical for understanding this epidemic and devising new strategies to control and manage this modern malady.

  9. Lewis and Fischer 344 rats as a model for genetic differences in spatial learning and memory: Cocaine effects.

    PubMed

    Fole, Alberto; Miguéns, Miguel; Morales, Lidia; González-Martín, Carmen; Ambrosio, Emilio; Del Olmo, Nuria

    2017-06-02

    Lewis (LEW) and Fischer 344 (F344) rats are considered a model of genetic vulnerability to drug addiction. We previously showed important differences in spatial learning and memory between them, but in contrast with previous experiments demonstrating cocaine-induced enhanced learning in Morris water maze (MWM) highly demanding tasks, the eight-arm radial maze (RAM) performance was not modified either in LEW or F344 rats after chronic cocaine treatment. In the present work, chronically cocaine-treated LEW and F344 adult rats have been evaluated in learning and memory performance using the Y-maze, two RAM protocols that differ in difficulty, and a reversal protocol that tests cognitive flexibility. After one of the RAM protocols, we quantified dendritic spine density in hippocampal CA1 neurons and compared it to animals treated with cocaine but not submitted to RAM. LEW cocaine treated rats showed a better performance in the Y maze than their saline counterparts, an effect that was not evident in the F344 strain. F344 rats significantly took more time to learn the RAM task and made a greater number of errors than LEW animals in both protocols tested, whereas cocaine treatment induced deleterious effects in learning and memory in the highly difficult protocol. Moreover, hippocampal spine density was cocaine-modulated in LEW animals whereas no effects were found in F344 rats. We propose that differences in addictive-like behavior between LEW and F344 rats could be related to differences in hippocampal learning and memory processes that could be on the basis of individual vulnerability to cocaine addiction. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Recent demographic bottlenecks are not accompanied by a genetic signature in banner-tailed kangaroo rats (Dipodomys spectabilis).

    PubMed

    Busch, Joseph D; Waser, Peter M; Dewoody, J Andrew

    2007-06-01

    Single-sample methods of bottleneck detection are now routine analyses in studies of wild populations and conservation genetics. Three common approaches to bottleneck detection are the heterozygosity excess, mode-shift, and M-ratio tests. Empirical groundtruthing of these methods is difficult, but their performances are critical for the accurate reconstruction of population demography. We use two banner-tailed kangaroo rat (Dipodomys spectabilis) populations from southeastern Arizona (USA) that are known to have experienced recent demographic reductions to search for genetic bottleneck signals with eight microsatellite loci. Over eight total sample-years, neither population showed a genetic bottleneck signature. M-ratios in both populations were large, stable, and never fell below a critical significance value (Mc). The mode shift test did not detect any distortion of allele frequencies, and tests of heterozygosity excess were not significant in postbottleneck samples when we used standard microsatellite mutation models. The genetic effects of bottlenecks like those experienced by our study populations should be strongly influenced by rates of mutation and migration. We used genetic parentage data to estimate a relatively high mutation rate in D. spectabilis (0.0081 mutants/generation/locus), but mutation alone is unlikely to explain the temporal distribution of rare alleles that we observed. Migration (gene flow) is a more likely explanation, despite prior mark-recapture analysis that estimated very low rates of interpopulation dispersal. We interpret our kangaroo rat data in light of the broader literature and conclude that in natural populations connected by dispersal, demographic bottlenecks may prove difficult to detect using molecular genetic data.

  11. Exploring Genetic, Genomic, and Phenotypic Data at the Rat Genome Database

    PubMed Central

    Laulederkind, Stanley J. F.; Hayman, G. Thomas; Wang, Shur-Jen; Lowry, Timothy F.; Nigam, Rajni; Petri, Victoria; Smith, Jennifer R.; Dwinell, Melinda R.; Jacob, Howard J.; Shimoyama, Mary

    2013-01-01

    The laboratory rat, Rattus norvegicus, is an important model of human health and disease, and experimental findings in the rat have relevance to human physiology and disease. The Rat Genome Database (RGD, http://rgd.mcw.edu) is a model organism database that provides access to a wide variety of curated rat data including disease associations, phenotypes, pathways, molecular functions, biological processes and cellular components for genes, quantitative trait loci, and strains. We present an overview of the database followed by specific examples that can be used to gain experience in employing RGD to explore the wealth of functional data available for the rat. PMID:23255149

  12. Genetic inactivation of glutamate neurons in the rat sublaterodorsal tegmental nucleus recapitulates REM sleep behaviour disorder.

    PubMed

    Valencia Garcia, Sara; Libourel, Paul-Antoine; Lazarus, Michael; Grassi, Daniela; Luppi, Pierre-Hervé; Fort, Patrice

    2017-02-01

    SEE SCHENCK AND MAHOWALD DOI101093/AWW329 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Idiopathic REM sleep behaviour disorder is characterized by the enactment of violent dreams during paradoxical (REM) sleep in the absence of normal muscle atonia. Accumulating clinical and experimental data suggest that REM sleep behaviour disorder might be due to the neurodegeneration of glutamate neurons involved in paradoxical sleep and located within the pontine sublaterodorsal tegmental nucleus. The purpose of the present work was thus to functionally determine first, the role of glutamate sublaterodorsal tegmental nucleus neurons in paradoxical sleep and second, whether their genetic inactivation is sufficient for recapitulating REM sleep behaviour disorder in rats. For this goal, we first injected two retrograde tracers in the intralaminar thalamus and ventral medulla to disentangle neuronal circuits in which sublaterodorsal tegmental nucleus is involved; second we infused bilaterally in sublaterodorsal tegmental nucleus adeno-associated viruses carrying short hairpin RNAs targeting Slc17a6 mRNA [which encodes vesicular glutamate transporter 2 (vGluT2)] to chronically impair glutamate synaptic transmission in sublaterodorsal tegmental nucleus neurons. At the neuroanatomical level, sublaterodorsal tegmental nucleus neurons specifically activated during paradoxical sleep hypersomnia send descending efferents to glycine/GABA neurons within the ventral medulla, but not ascending projections to the intralaminar thalamus. These data suggest a crucial role of sublaterodorsal tegmental nucleus neurons rather in muscle atonia than in paradoxical sleep generation. In line with this hypothesis, 30 days after adeno-associated virus injections into sublaterodorsal tegmental nucleus rats display a decrease of 30% of paradoxical sleep daily quantities, and a significant increase of muscle tone during paradoxical sleep concomitant to a tremendous increase of abnormal motor dream

  13. Comparative safety testing of genetically modified foods in a 90-day rat feeding study design allowing the distinction between primary and secondary effects of the new genetic event.

    PubMed

    Knudsen, Ib; Poulsen, Morten

    2007-10-01

    This article discusses the wider experiences regarding the usefulness of the 90-day rat feeding study for the testing of whole foods from genetically modified (GM) plant based on data from a recent EU-project [Poulsen, M., Schrøder, M., Wilcks, A., Kroghsbo, S., Lindecrona, R.H., Miller, A., Frenzel, T., Danier, J., Rychlik, M., Shu, Q., Emami, K., Taylor, M., Gatehouse, A., Engel, K.-H., Knudsen, I., 2007a. Safety testing of GM-rice expressing PHA-E lectin using a new animal test design. Food Chem. Toxicol. 45, 364-377; Poulsen, M., Kroghsbo, S., Schrøder, M., Wilcks, A., Jacobsen, H., Miller, A., Frenzel, T., Danier, J., Rychlik, M., Shu, Q., Emami, K., Sudhakar, D., Gatehouse, A., Engel, K.-H., Knudsen, I., 2007b. A 90-day safety in Wistar rats fed genetically modified rice expressing snowdrop lectin Galanthus nivalis (GNA). Food Chem. Toxicol. 45, 350-363; Schrøder, M., Poulsen, M., Wilcks, A., Kroghsbo, S., Miller, A., Frenzel, T., Danier, J., Rychlik, M., Emami, K., Gatehouse, A., Shu, Q., Engel, K.-H., Knudsen, I., 2007. A 90-day safety study of genetically modified rice expressing Cry1Ab protein (Bacillus thuringiensis toxin) in Wistar rats. Food Chem. Toxicol. 45, 339-349]. The overall objective of the project has been to develop and validate the scientific methodology necessary for assessing the safety of foods from genetically modified plants in accordance with the present EU regulation. The safety assessment in the project is combining the results of the 90-day rat feeding study on the GM food with and without spiking with the pure novel gene product, with the knowledge about the identity of the genetic change, the compositional data of the GM food, the results from in-vitro/ex-vivo studies as well as the results from the preceding 28-day toxicity study with the novel gene product, before the hazard characterisation is concluded. The results demonstrated the ability of the 90-day rat feeding study to detect the biological/toxicological effects of the

  14. Integrative properties and transfer function of cortical neurons initiating absence seizures in a rat genetic model.

    PubMed

    Williams, Mark S; Altwegg-Boussac, Tristan; Chavez, Mario; Lecas, Sarah; Mahon, Séverine; Charpier, Stéphane

    2016-11-15

    Absence seizures are accompanied by spike-and-wave discharges in cortical electroencephalograms. These complex paroxysmal activities, affecting the thalamocortical networks, profoundly alter cognitive performances and preclude conscious perception. Here, using a well-recognized genetic model of absence epilepsy, we investigated in vivo how information processing was impaired in the ictogenic neurons, i.e. the population of cortical neurons responsible for seizure initiation. In between seizures, ictogenic neurons were more prone to generate bursting activity and their firing response to weak depolarizing events was considerably facilitated compared to control neurons. In the course of seizures, information processing became unstable in ictogenic cells, alternating between an increased and a decreased responsiveness to excitatory inputs, depending on the spike and wave patterns. The state-dependent modulation in the excitability of ictogenic neurons affects their inter-seizure transfer function and their time-to-time responsiveness to incoming inputs during absences. Epileptic seizures result from aberrant cellular and/or synaptic properties that can alter the capacity of neurons to integrate and relay information. During absence seizures, spike-and-wave discharges (SWDs) interfere with incoming sensory inputs and preclude conscious experience. The Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well-established animal model of absence epilepsy, allows exploration of the cellular basis of this impaired information processing. Here, by combining in vivo electrocorticographic and intracellular recordings from GAERS and control animals, we investigated how the pro-ictogenic properties of seizure-initiating cortical neurons modify their integrative properties and input-output operation during inter-ictal periods and during the spike (S-) and wave (W-) cortical patterns alternating during seizures. In addition to a sustained depolarization and an excessive

  15. Prepulse inhibition predicts spatial working memory performance in the inbred Roman high- and low-avoidance rats and in genetically heterogeneous NIH-HS rats: relevance for studying pre-attentive and cognitive anomalies in schizophrenia.

    PubMed

    Oliveras, Ignasi; Río-Álamos, Cristóbal; Cañete, Toni; Blázquez, Gloria; Martínez-Membrives, Esther; Giorgi, Osvaldo; Corda, Maria G; Tobeña, Adolf; Fernández-Teruel, Alberto

    2015-01-01

    Animal models of schizophrenia-relevant symptoms are increasingly important for progress in our understanding of the neurobiological basis of the disorder and for discovering novel and more specific treatments. Prepulse inhibition (PPI) and working memory, which are impaired in schizophrenic patients, are among the symptoms/processes modeled in those animal analogs. We have evaluated whether a genetically-selected rat model, the Roman high-avoidance inbred strain (RHA-I), displays PPI deficits as compared with its Roman low-avoidance (RLA-I) counterpart and the genetically heterogeneous NIH-HS rat stock. We have investigated whether PPI deficits predict spatial working memory impairments (in the Morris water maze; MWM) in these three rat types (Experiment 1), as well as in a separate sample of NIH-HS rats stratified according to their extreme (High, Medium, Low) PPI scores (Experiment 2). The results from Experiment 1 show that RHA-I rats display PPI and spatial working memory deficits compared to both RLA-I and NIH-HS rats. Likewise, in Experiment 2, "Low-PPI" NIH-HS rats present significantly impaired working memory with respect to "Medium-PPI" and "High-PPI" NIH-HS subgroups. Further support to these results comes from correlational, factorial, and multiple regression analyses, which reveal that PPI is positively associated with spatial working memory performance. Conversely, cued learning in the MWM was not associated with PPI. Thus, using genetically-selected and genetically heterogeneous rats, the present study shows, for the first time, that PPI is a positive predictor of performance in a spatial working memory task. These results may have translational value for schizophrenia symptom research in humans, as they suggest that either by psychogenetic selection or by focusing on extreme PPI scores from a genetically heterogeneous rat stock, it is possible to detect a useful (perhaps "at risk") phenotype to study cognitive anomalies linked to schizophrenia.

  16. Prepulse inhibition predicts spatial working memory performance in the inbred Roman high- and low-avoidance rats and in genetically heterogeneous NIH-HS rats: relevance for studying pre-attentive and cognitive anomalies in schizophrenia

    PubMed Central

    Oliveras, Ignasi; Río-Álamos, Cristóbal; Cañete, Toni; Blázquez, Gloria; Martínez-Membrives, Esther; Giorgi, Osvaldo; Corda, Maria G.; Tobeña, Adolf; Fernández-Teruel, Alberto

    2015-01-01

    Animal models of schizophrenia-relevant symptoms are increasingly important for progress in our understanding of the neurobiological basis of the disorder and for discovering novel and more specific treatments. Prepulse inhibition (PPI) and working memory, which are impaired in schizophrenic patients, are among the symptoms/processes modeled in those animal analogs. We have evaluated whether a genetically-selected rat model, the Roman high-avoidance inbred strain (RHA-I), displays PPI deficits as compared with its Roman low-avoidance (RLA-I) counterpart and the genetically heterogeneous NIH-HS rat stock. We have investigated whether PPI deficits predict spatial working memory impairments (in the Morris water maze; MWM) in these three rat types (Experiment 1), as well as in a separate sample of NIH-HS rats stratified according to their extreme (High, Medium, Low) PPI scores (Experiment 2). The results from Experiment 1 show that RHA-I rats display PPI and spatial working memory deficits compared to both RLA-I and NIH-HS rats. Likewise, in Experiment 2, “Low-PPI” NIH-HS rats present significantly impaired working memory with respect to “Medium-PPI” and “High-PPI” NIH-HS subgroups. Further support to these results comes from correlational, factorial, and multiple regression analyses, which reveal that PPI is positively associated with spatial working memory performance. Conversely, cued learning in the MWM was not associated with PPI. Thus, using genetically-selected and genetically heterogeneous rats, the present study shows, for the first time, that PPI is a positive predictor of performance in a spatial working memory task. These results may have translational value for schizophrenia symptom research in humans, as they suggest that either by psychogenetic selection or by focusing on extreme PPI scores from a genetically heterogeneous rat stock, it is possible to detect a useful (perhaps “at risk”) phenotype to study cognitive anomalies linked to

  17. High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model.

    PubMed

    Lo, Chiao-Ling; Lossie, Amy C; Liang, Tiebing; Liu, Yunlong; Xuei, Xiaoling; Lumeng, Lawrence; Zhou, Feng C; Muir, William M

    2016-08-01

    Investigations on the influence of nature vs. nurture on Alcoholism (Alcohol Use Disorder) in human have yet to provide a clear view on potential genomic etiologies. To address this issue, we sequenced a replicated animal model system bidirectionally-selected for alcohol preference (AP). This model is uniquely suited to map genetic effects with high reproducibility, and resolution. The origin of the rat lines (an 8-way cross) resulted in small haplotype blocks (HB) with a corresponding high level of resolution. We sequenced DNAs from 40 samples (10 per line of each replicate) to determine allele frequencies and HB. We achieved ~46X coverage per line and replicate. Excessive differentiation in the genomic architecture between lines, across replicates, termed signatures of selection (SS), were classified according to gene and region. We identified SS in 930 genes associated with AP. The majority (50%) of the SS were confined to single gene regions, the greatest numbers of which were in promoters (284) and intronic regions (169) with the least in exon's (4), suggesting that differences in AP were primarily due to alterations in regulatory regions. We confirmed previously identified genes and found many new genes associated with AP. Of those newly identified genes, several demonstrated neuronal function involved in synaptic memory and reward behavior, e.g. ion channels (Kcnf1, Kcnn3, Scn5a), excitatory receptors (Grin2a, Gria3, Grip1), neurotransmitters (Pomc), and synapses (Snap29). This study not only reveals the polygenic architecture of AP, but also emphasizes the importance of regulatory elements, consistent with other complex traits.

  18. Differential immune and genetic responses in rat models of Crohn's colitis and ulcerative colitis

    PubMed Central

    Shi, Xuan-Zheng; Winston, John H.

    2011-01-01

    Crohn's disease and ulcerative colitis are clinically, immunologically, and morphologically distinct forms of inflammatory bowel disease (IBD). However, smooth muscle function is impaired similarly in both diseases, resulting in diarrhea. We tested the hypothesis that differential cellular, genetic, and immunological mechanisms mediate smooth muscle dysfunction in two animal models believed to represent the two diseases. We used the rat models of trinitrobenzene sulfonic acid (TNBS)- and dextran sodium sulfate (DSS)-induced colonic inflammations, which closely mimic the clinical and morphological features of Crohn's disease and ulcerative colitis, respectively. DSS inflammation induced oxidative stress initially in mucosa/submucosa, which then propagated to the muscularis externa to impair smooth muscle function. The muscularis externa showed no increase of cytokines/chemokines. On the other hand, TNBS inflammation almost simultaneously induced oxidative stress, recruited or activated immune cells, and generated cytokines/chemokines in both mucosa/submucosa and muscularis externa. The generation of cytokines/chemokines did not correlate with the recruitment and activation of immune cells. Consequently, the impairment of smooth muscle function in DSS inflammation was primarily due to oxidative stress, whereas that in TNBS inflammation was due to both oxidative stress and proinflammatory cytokines. The impairment of smooth muscle function in DSS inflammation was due to suppression of Gαq protein of the excitation-contraction coupling. In TNBS inflammation, it was due to suppression of the α1C1b subunit of Cav1.2b channels, CPI-17 and Gαq. TNBS inflammation increased IGF-1 and TGF-β time dependently in the muscularis externa. IGF-1 induced smooth muscle hyperplasia; both IGF-1 and TGF-β induced hypertrophy. In conclusion, both TNBS and DSS induce transmural inflammation, albeit with different types of inflammatory mediators. The recruitment or activation of

  19. High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model

    PubMed Central

    Lo, Chiao-Ling; Liang, Tiebing; Liu, Yunlong; Lumeng, Lawrence; Zhou, Feng C.; Muir, William M.

    2016-01-01

    Investigations on the influence of nature vs. nurture on Alcoholism (Alcohol Use Disorder) in human have yet to provide a clear view on potential genomic etiologies. To address this issue, we sequenced a replicated animal model system bidirectionally-selected for alcohol preference (AP). This model is uniquely suited to map genetic effects with high reproducibility, and resolution. The origin of the rat lines (an 8-way cross) resulted in small haplotype blocks (HB) with a corresponding high level of resolution. We sequenced DNAs from 40 samples (10 per line of each replicate) to determine allele frequencies and HB. We achieved ~46X coverage per line and replicate. Excessive differentiation in the genomic architecture between lines, across replicates, termed signatures of selection (SS), were classified according to gene and region. We identified SS in 930 genes associated with AP. The majority (50%) of the SS were confined to single gene regions, the greatest numbers of which were in promoters (284) and intronic regions (169) with the least in exon's (4), suggesting that differences in AP were primarily due to alterations in regulatory regions. We confirmed previously identified genes and found many new genes associated with AP. Of those newly identified genes, several demonstrated neuronal function involved in synaptic memory and reward behavior, e.g. ion channels (Kcnf1, Kcnn3, Scn5a), excitatory receptors (Grin2a, Gria3, Grip1), neurotransmitters (Pomc), and synapses (Snap29). This study not only reveals the polygenic architecture of AP, but also emphasizes the importance of regulatory elements, consistent with other complex traits. PMID:27490364

  20. Effects of resveratrol on obesity-related inflammation markers in adipose tissue of genetically obese rats.

    PubMed

    Gómez-Zorita, Saioa; Fernández-Quintela, Alfredo; Lasa, Arrate; Hijona, Elizabeth; Bujanda, Luis; Portillo, María P

    2013-01-01

    The aim of this study was to examine whether resveratrol might represent a promising therapeutic tool with which to combat adipose tissue chronic inflammation in a model of genetic obesity and to link its anti-inflammatory activity with its effect on body fat reduction. Twenty 6-wk-old male Zucker (fa/fa) rats were randomly distributed into two experimental groups. Resveratrol (RSV) was given orally (15 mg/kg body weight/d in RSV group) by means of an orogastric catheter for 6 wk. Enzyme activities were measured spectrophotometrically or fluorimetrically. Gene and protein expressions were analyzed by reverse transcriptase polymerase chain reaction and Western blot respectively. Cytokine concentrations and the activity of nuclear factor κ-light-chain-enhancer of activated β cells (NF-κB) were measured by using commercial kits. RSV reduced the weight of internal adipose tissues. In epididymal depot glucose-6P-dehydrogenase, acetyl-CoA carboxylase activities, as well as lipoprotein lipase expression and activity were reduced by RSV. The expression of hormone-sensitive lipase was increased, and that of the cluster of differentiation 36 was reduced. Serum concentrations of tumor necrosis factor-α, monocyte chemoattractant protein 1, and C-reactive protein were lower in the RSV-treated group than in the control group. Protein expression of interleukin-6 and the activity of NF-κB, were decreased by RSV. The present results provide evidence that fatty acid uptake and lipolysis are metabolic pathways involved in the response of adipose tissue to RSV. This polyphenol modulates plasma cytokine levels partially by reducing macrophage infiltration in adipose tissue and inhibiting NF-κB activity. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Genetic threshold hypothesis of neocortical spike-and-wave discharges in the rat: an animal model of petit mal epilepsy.

    PubMed

    Vadász, C; Carpi, D; Jando, G; Kandel, A; Urioste, R; Horváth, Z; Pierre, E; Vadi, D; Fleischer, A; Buzsáki, G

    1995-02-27

    Neocortical high-voltage spike-and-wave discharges (HVS) in the rat are an animal model of petit mal epilepsy. Genetic analysis of total duration of HVS (s/12 hr) in reciprocal F1 and F2 hybrids of F344 and BN rats indicated that the phenotypic variability of HVS cannot be explained by a simple, monogenic Mendelian model. Biometrical analysis suggested the presence of additive, dominance, and sex-linked-epistatic effects, buffering maternal influence, and heterosis. High correlation was observed between average duration (s/episode) and frequency of occurrence of spike-and-wave episodes (n/12 hr) in parental and segregating generations, indicating that common genes affect both duration and frequency of the spike-and-wave pattern. We propose that both genetic and developmental-environmental factors control an underlying quantitative variable, which, above a certain threshold level, precipitates HVS discharges. These findings, together with the recent availability of rat DNA markers for total genome mapping, pave the way to the identification of genes that control the susceptibility of the brain to spike-and-wave discharges.

  2. Genetic threshold hypothesis of neocortical spike-and-wave discharges in the rat: An animal model of petit mal epilepsy

    SciTech Connect

    Vadasz, C.; Fleischer, A.; Carpi, D.; Jando, G.

    1995-02-27

    Neocortical high-voltage spike-and-wave discharges (HVS) in the rat are an animal model of petit mal epilepsy. Genetic analysis of total duration of HVS (s/12 hr) in reciprocal F1 and F2 hybrids of F344 and BN rats indicated that the phenotypic variability of HVS cannot be explained by simple, monogenic Mendelian model. Biometrical analysis suggested the presence of additive, dominance, and sex-linked-epistatic effects, buffering maternal influence, and heterosis. High correlation was observed between average duration (s/episode) and frequency of occurrence of spike-and-wave episodes (n/12 hr) in parental and segregating generations, indicating that common genes affect both duration and frequency of the spike-and-wave pattern. We propose that both genetic and developmental - environmental factors control an underlying quantitative variable, which, above a certain threshold level, precipitates HVS discharges. These findings, together with the recent availability of rat DNA markers for total genome mapping, pave the way to the identification of genes that control the susceptibility of the brain to spike-and-wave discharges. 67 refs., 3 figs., 5 tabs.

  3. [Genetic rat models of type 2 diabetes for evaluation the effectiveness of minor biologically active food substances].

    PubMed

    Mazo, V K; Murashev, A N; Sidorova, Yu S; Zorin, S N; Kochetkova, A A

    2014-01-01

    The purposeful use of plant minor biologically active food substances (with demonstrated evident hypoglycemic, hypocholesterolemic and antioxidant action) in the composition of specialized dietary products can become the inno- vative approach for the dietary treatment of type 2 diabetes mellitus. Clinical testing of minor biologically active food substances of plant origin and their further use in the composition of specialized dietary products should be preceded by the stage of complex physiological and biochemical studies in vivo. It all turns on the question: to which extent the results obtained with the biomodel can be extrapolated on the human body. Hence, this review comparatively evaluates the rat models of type 2 diabetes. In this paper, we overview the most frequently used monogenic models of obesity with the damage of the leptin signaling path- way, when the animal loses control over saturation, hyperphagia and subsequent obesity appear. We describe polygenic models of obesity-related diabetes with fatty rats, which are more approximated to type 2 diabetes mellitus in humans. The characteristic of the type 2 diabetes model without obesity is given in the article: the SDT (Spontaneously Diabetic Torii) rats are genetically predisposed to glucose intolerance. Spontaneously Diabetic Torii-fa/fa (SDT fatty) rat is a new model of obese type 2 diabetes. Both male and female SDT fatty rats show overt obesity, and hyperglycemia and hyperlipidemia are observed at a younger age as compared with SDTrats. In conclusion, the SDT fatty rats are useful as a model for the development of new drugs and/or specialized dietary products to reduce body fat mass.

  4. Genetic Deletion of the Nociceptin/Orphanin FQ Receptor in the Rat Confers Resilience to the Development of Drug Addiction.

    PubMed

    Kallupi, Marsida; Scuppa, Giulia; de Guglielmo, Giordano; Calò, Girolamo; Weiss, Friedbert; Statnick, Michael A; Rorick-Kehn, Linda M; Ciccocioppo, Roberto

    2017-02-01

    The nociceptin (NOP) receptor is a G-protein-coupled receptor whose natural ligand is the NOP/orphanin FQ (N/OFQ) peptide. Evidence from pharmacological studies suggests that the N/OFQ system is implicated in the regulation of several addiction-related phenomena, such as drug intake, withdrawal, and relapse. Here, to further explore the role of NOP system in addiction, we used NOP (-/-) rats to study the motivation for cocaine, heroin, and alcohol self-administration in the absence of N/OFQ function. Conditioned place preference (CPP) and saccharin (0.2% w/v) self-administration were also investigated. Results showed that NOP (-/-) rats self-administer less cocaine (0.25, 0.125, or 0.5 mg/infusion) both under a fixed ratio 1 and a progressive ratio schedule of reinforcement compared with wild-type (Wt) controls. Consistently, cocaine (10 mg/kg, i.p.) was able to induce CPP in Wt but not in NOP (-/-). When NOP (-/-) rats were tested for heroin (20 μg/infusion) and ethanol (10% v/v) self-administration, they showed significantly lower drug intake compared with Wt. Conversely, saccharin self-administration was not affected by NOP deletion, excluding the possibility of nonspecific learning deficits or generalized disruption of reward mechanisms in NOP (-/-) rats. These findings were confirmed with pharmacological experiments using two selective NOP antagonists, SB-612111 and LY2817412. Both drugs attenuated alcohol self-administration in Wt rats but not in NOP (-/-) rats. In conclusion, our results demonstrate that genetic deletion of NOP receptors confers resilience to drug abuse and support a role for NOP receptor antagonism as a potential treatment option for drug addiction.

  5. Dehydroepiandrosterone decreases serum tumor necrosis factor-alpha and restores insulin sensitivity: independent effect from secondary weight reduction in genetically obese Zucker fatty rats.

    PubMed

    Kimura, M; Tanaka, S; Yamada, Y; Kiuchi, Y; Yamakawa, T; Sekihara, H

    1998-07-01

    Dehydroepiandrosterone (DHEA) and its sulfate ester are the most abundant circulating adrenal steroids in humans. Administration of DHEA has been reported to have beneficial effects on obesity, hyperlipidemia, diabetes, and atherosclerosis in obese rodents, although its effects on insulin resistance have not been fully elucidated. In this study, the effects of DHEA treatment on insulin sensitivity were investigated in genetically obese Zucker rats, an animal model of insulin resistance, using the euglycemic clamp technique. After 0.4% DHEA was administered for 10 days to female obese Zucker rats aged 16 weeks, body weight and plasma insulin decreased and glucose disposal rate (GDR), which was normally reduced in obese rats, rose significantly compared with age- and sex-matched control obese rats. On the other hand, although the pair-fed obese rats also showed levels of weight reduction similar to those of DHEA-treated rats, the increase in GDR of DHEA-treated rats was significantly greater than in pair-fed rats, suggesting a direct ameliorating effect of DHEA on insulin sensitivity of obese rats. Serum concentration of tumor necrosis factor (TNF)-alpha, one of cytokines causing insulin resistance, was also reduced significantly in DHEA-treated, but not in pair-fed obese rats. In conclusion, our results suggest that DHEA treatment reduces body weight and serum TNF-alpha independently, and that both may ameliorate insulin resistance in obese Zucker fatty rats.

  6. Dissecting the genetic components of a quantitative trait locus for blood pressure and renal pathology on rat chromosome 3

    PubMed Central

    Koh-Tan, H.H. Caline; Dashti, Mohammed; Wang, Ting; Beattie, Wendy; Mcclure, John; Young, Barbara; Dominiczak, Anna F.; McBride, Martin W.; Graham, Delyth

    2017-01-01

    Background: We have previously confirmed the importance of rat chromosome 3 (RNO3) genetic loci on blood pressure elevation, pulse pressure (PP) variability and renal pathology during salt challenge in the stroke-prone spontaneously hypertensive (SHRSP) rat. The aims of this study were to generate a panel of RNO3 congenic sub-strains to genetically dissect the implicated loci and identify positional candidate genes by microarray expression profiling and analysis of next-generation sequencing data. Method and results: A panel of congenic sub-strains were generated containing Wistar–Kyoto (WKY)-introgressed segments of varying size on the SHRSP genetic background, focused within the first 50 Mbp of RNO3. Haemodynamic profiling during salt challenge demonstrated significantly reduced systolic blood pressure, diastolic blood pressure and PP variability in SP.WKYGla3a, SP.WKYGla3c, SP.WKYGla3d and SP.WKYGla3e sub-strains. Only SBP and DBP were significantly reduced during salt challenge in SP.WKYGla3b and SP.WKYGla3f sub-strains, whereas SP.WKYGla3g rats did not differ in haemodynamic response to SHRSP. Those sub-strains demonstrating significantly reduced PP variability during salt challenge also demonstrated significantly reduced renal pathology and proteinuria. Microarray expression profiling prioritized two candidate genes for blood pressure regulation (Dnm1, Tor1b), localized within the common congenic interval shared by SP.WKYGla3d and SP.WKYGla3f strains, and one candidate gene for salt-induced PP variability and renal pathology (Rabgap1), located within the region unique to the SP.WKYGla3d strain. Comparison of next-generation sequencing data identified variants within additional positional genes that are likely to affect protein function. Conclusion: This study has identified distinct intervals on RNO3-containing genes that may be important for blood pressure regulation and renal pathology during salt challenge. PMID:27755386

  7. Chronic caffeine administration exacerbates renovascular, but not genetic, hypertension in rats.

    PubMed Central

    Ohnishi, A; Branch, R A; Jackson, K; Hamilton, R; Biaggioni, I; Deray, G; Jackson, E K

    1986-01-01

    The purpose of this study was to determine whether or not caffeine would exacerbate renovascular hypertension. Therefore, we examined the effects of chronic caffeine administration on arterial blood pressure in rats subjected to either unilateral renal artery clipping (2K-1C rats) or sham-operation. Animals in each group were randomly assigned to receive either 0.1% caffeine in their drinking water or normal drinking water, and systolic blood pressure was monitored for 6 wk. Caffeine markedly exacerbated the severity of hypertension in 2K-1C rats and caused histological changes consistent with malignant hypertension. 6 wk after surgery, systolic blood pressure, plasma renin activity, and creatinine clearance in control 2K-1C rats were 169 +/- 5 mmHg (mean +/- SEM), 4.4 +/- 0.5 ng AI X ml-1 X h-1, and 2.9 +/- 0.2 ml/min, respectively; as compared with 219 +/- 4 mmHg, 31.8 +/- 7.8 ng AI X ml-1 X h-1, and 1.4 +/- 0.3 ml/min, respectively, in 2K-1C rats receiving caffeine (all values were significantly different compared with control 2K-1C). Chronic caffeine administration did not alter systolic blood pressure, plasma renin activity, or creatinine clearance in sham-operated rats or spontaneously hypertensive rats. Chronic treatment with enalapril (a converting enzyme inhibitor) prevented the development of hypertension in control 2K-1C rats and caffeine-treated 2K-1C rats; however, withdrawal of enalapril precipitated a rapid rise in systolic blood pressure in caffeine-treated 2K-1C rats, but not in control 2K-1C rats. These experiments indicate that caffeine specifically exacerbates experimental renovascular hypertension and might worsen the hypertensive process in patients with renovascular hypertension. PMID:3020089

  8. Genetic damage and the expression of behavioral abnormalities in the progeny of male rats exposed to ionizing radiation

    SciTech Connect

    Lowery, M.C.

    1987-01-01

    To determine the possible genetic nature of behavioral anomalies, an identifiable genetic endpoint, inherited chromosome translocations in the offspring, was selected to evaluate the relationship to behavior. Young adult male Fischer 344 rats were exposed to 50-300 rads of ionizing radiation. Two weeks following their irradiation, the males were mated with four virgin females for one week. During this time, fertilizing sperm were derived from post-meiotic spermatids, the stage of the spermatogenic cycle most sensitive to the mutagenic effects of radiation. Behavioral analyses of the resulting 390 offspring consisted of both motor reflex and motor coordination measurements as well as learning and retention parameters. Significant differences in performance were seen in several of the motor reflex measurements in progeny of males exposed to some of the higher doses of irradiation. A similar phenomenon was observed in the performance of a single learned behavior.

  9. Transcriptome Profiling in Rat Inbred Strains and Experimental Cross Reveals Discrepant Genetic Architecture of Genome-Wide Gene Expression

    PubMed Central

    Kaisaki, Pamela J.; Otto, Georg W.; Argoud, Karène; Collins, Stephan C.; Wallis, Robert H.; Wilder, Steven P.; Yau, Anthony C. Y.; Hue, Christophe; Calderari, Sophie; Bihoreau, Marie-Thérèse; Cazier, Jean-Baptiste; Mott, Richard; Gauguier, Dominique

    2016-01-01

    To test the impact of genetic heterogeneity on cis- and trans-mediated mechanisms of gene expression regulation, we profiled the transcriptome of adipose tissue in 20 inbred congenic strains derived from diabetic Goto–Kakizaki (GK) rats and Brown–Norway (BN) controls, which contain well-defined blocks (1–183 Mb) of genetic polymorphisms, and in 123 genetically heterogeneous rats of an (GK × BN)F2 offspring. Within each congenic we identified 73–1351 differentially expressed genes (DEGs), only 7.7% of which mapped within the congenic blocks, and which may be regulated in cis. The remainder localized outside the blocks, and therefore must be regulated in trans. Most trans-regulated genes exhibited approximately twofold expression changes, consistent with monoallelic expression. Altered biological pathways were replicated between congenic strains sharing blocks of genetic polymorphisms, but polymorphisms at different loci also had redundant effects on transcription of common distant genes and pathways. We mapped 2735 expression quantitative trait loci (eQTL) in the F2 cross, including 26% predominantly cis-regulated genes, which validated DEGs in congenic strains. A hotspot of >300 eQTL in a 10 cM region of chromosome 1 was enriched in DEGs in a congenic strain. However, many DEGs among GK, BN and congenic strains did not replicate as eQTL in F2 hybrids, demonstrating distinct mechanisms of gene expression when alleles segregate in an outbred population or are fixed homozygous across the entire genome or in short genomic regions. Our analysis provides conceptual advances in our understanding of the complex architecture of genome expression and pathway regulation, and suggests a prominent impact of epistasis and monoallelic expression on gene transcription. PMID:27646706

  10. Genetic Analysis of a Rat Model of Aerobic Capacity and Metabolic Fitness

    PubMed Central

    Ren, Yu-yu; Overmyer, Katherine A.; Qi, Nathan R.; Treutelaar, Mary K.; Heckenkamp, Lori; Kalahar, Molly; Koch, Lauren G.; Britton, Steven L.; Burant, Charles F.; Li, Jun Z.

    2013-01-01

    Aerobic capacity is a strong predictor of all-cause mortality and can influence many complex traits. To explore the biological basis underlying this connection, we developed via artificial selection two rat lines that diverge for intrinsic (i.e. inborn) aerobic capacity and differ in risk for complex disease traits. Here we conduct the first in-depth pedigree and molecular genetic analysis of these lines, the high capacity runners (HCR) and low capacity runners (LCR). Our results show that both HCR and LCR lines maintain considerable narrow-sense heritability (h2) for the running capacity phenotype over 28 generations (h2 = 0.47 ± 0.02 and 0.43 ± 0.02, respectively). To minimize inbreeding, the lines were maintained by rotational mating. Pedigree records predict that the inbreeding coefficient increases at a rate of <1% per generation, ~37-38% slower than expected for random mating. Genome-wide 10K SNP genotype data for generations 5, 14, and 26 demonstrate substantial genomic evolution: between-line differentiation increased progressively, while within-line diversity deceased. Genome-wide average heterozygosity decreased at a rate of <1% per generation, consistent with pedigree-based predictions and confirming the effectiveness of rotational breeding. Linkage disequilibrium index r2 decreases to 0.3 at ~3 Mb, suggesting that the resolution for mapping quantitative trait loci (QTL) can be as high as 2-3 cM. To establish a test population for QTL mapping, we conducted an HCR-LCR intercross. Running capacity of the F1 population (n=176) was intermediate of the HCR and LCR parentals (28 pairs); and the F2 population (n=645) showed a wider range of phenotypic distribution. Importantly, heritability in the F0-F2 pedigree remained high (h2~0.6). These results suggest that the HCR-LCR lines can serve as a valuable system for studying genomic evolution, and a powerful resource for mapping QTL for a host of characters relevant to human health. PMID:24147032

  11. Genetics

    USDA-ARS?s Scientific Manuscript database

    The genus Capsicum represents one of several well characterized Solanaceous genera. A wealth of classical and molecular genetics research is available for the genus. Information gleaned from its cultivated relatives, tomato and potato, provide further insight for basic and applied studies. Early ...

  12. Genetics

    USDA-ARS?s Scientific Manuscript database

    Maintaining genetic variation in wild populations of Arctic organisms is fundamental to the long-term persistence of high latitude biodiversity. Variability is important because it provides options for species to respond to changing environmental conditions and novel challenges such as emerging path...

  13. Serum lipids, lipoprotein composition and liver cholesterol in genetically obese Zucker rats fed semipurified diets containing either casein or soy protein.

    PubMed

    Terpstra, A H; van Tintelen, G; West, C E

    1983-01-01

    The effect of semipurified diets containing either casein or soy protein on serum lipids, lipoprotein composition and liver cholesterol was studied in genetically obese Zucker rats. The ingestion of a cholesterol-enriched semipurified diet containing casein resulted in elevated levels of serum cholesterol and phospholipids compared to the feeding of a soy protein diet. No differences in serum triglycerides were observed. Differences in serum cholesterol and phospholipids were mainly reflected in the very low density lipoproteins and low density lipoproteins and to a minor extent in the high density lipoproteins. Liver cholesterol paralleled the levels of cholesterol in the serum, the rats fed casein exhibited markedly higher levels of liver cholesterol than those fed soy protein. Furthermore, the rats fed casein also had enlarged livers. Thus, this study clearly shows the differential cholesterolemic effect of dietary casein and soy protein in genetically obese Zucker rats.

  14. Genetically engineered rat gliomas: PDGF-driven tumor initiation and progression in tv-a transgenic rats recreate key features of human brain cancer.

    PubMed

    Connolly, Nina P; Stokum, Jesse A; Schneider, Craig S; Ozawa, Tatsuya; Xu, Su; Galisteo, Rebeca; Castellani, Rudolph J; Kim, Anthony J; Simard, J Marc; Winkles, Jeffrey A; Holland, Eric C; Woodworth, Graeme F

    2017-01-01

    Previously rodent preclinical research in gliomas frequently involved implantation of cell lines such as C6 and 9L into the rat brain. More recently, mouse models have taken over, the genetic manipulability of the mouse allowing the creation of genetically accurate models outweighed the disadvantage of its smaller brain size that limited time allowed for tumor progression. Here we illustrate a method that allows glioma formation in the rat using the replication competent avian-like sarcoma (RCAS) virus / tumor virus receptor-A (tv-a) transgenic system of post-natal cell type-specific gene transfer. The RCAS/tv-a model has emerged as a particularly versatile and accurate modeling technology by enabling spatial, temporal, and cell type-specific control of individual gene transformations and providing de novo formed glial tumors with distinct molecular subtypes mirroring human GBM. Nestin promoter-driven tv-a (Ntv-a) transgenic Sprague-Dawley rat founder lines were created and RCAS PDGFA and p53 shRNA constructs were used to initiate intracranial brain tumor formation. Tumor formation and progression were confirmed and visualized by magnetic resonance imaging (MRI) and spectroscopy. The tumors were analyzed using histopathological and immunofluorescent techniques. All experimental animals developed large, heterogeneous brain tumors that closely resembled human GBM. Median survival was 92 days from tumor initiation and 62 days from the first point of tumor visualization on MRI. Each tumor-bearing animal showed time dependent evidence of malignant progression to high-grade glioma by MRI and neurological examination. Post-mortem tumor analysis demonstrated the presence of several key characteristics of human GBM, including high levels of tumor cell proliferation, pseudopalisading necrosis, microvascular proliferation, invasion of tumor cells into surrounding tissues, peri-tumoral reactive astrogliosis, lymphocyte infiltration, presence of numerous tumor

  15. Genetically engineered rat gliomas: PDGF-driven tumor initiation and progression in tv-a transgenic rats recreate key features of human brain cancer

    PubMed Central

    Stokum, Jesse A.; Schneider, Craig S.; Ozawa, Tatsuya; Xu, Su; Galisteo, Rebeca; Castellani, Rudolph J.; Kim, Anthony J.; Simard, J. Marc; Winkles, Jeffrey A.; Holland, Eric C.; Woodworth, Graeme F.

    2017-01-01

    Previously rodent preclinical research in gliomas frequently involved implantation of cell lines such as C6 and 9L into the rat brain. More recently, mouse models have taken over, the genetic manipulability of the mouse allowing the creation of genetically accurate models outweighed the disadvantage of its smaller brain size that limited time allowed for tumor progression. Here we illustrate a method that allows glioma formation in the rat using the replication competent avian-like sarcoma (RCAS) virus / tumor virus receptor-A (tv-a) transgenic system of post-natal cell type-specific gene transfer. The RCAS/tv-a model has emerged as a particularly versatile and accurate modeling technology by enabling spatial, temporal, and cell type-specific control of individual gene transformations and providing de novo formed glial tumors with distinct molecular subtypes mirroring human GBM. Nestin promoter-driven tv-a (Ntv-a) transgenic Sprague-Dawley rat founder lines were created and RCAS PDGFA and p53 shRNA constructs were used to initiate intracranial brain tumor formation. Tumor formation and progression were confirmed and visualized by magnetic resonance imaging (MRI) and spectroscopy. The tumors were analyzed using histopathological and immunofluorescent techniques. All experimental animals developed large, heterogeneous brain tumors that closely resembled human GBM. Median survival was 92 days from tumor initiation and 62 days from the first point of tumor visualization on MRI. Each tumor-bearing animal showed time dependent evidence of malignant progression to high-grade glioma by MRI and neurological examination. Post-mortem tumor analysis demonstrated the presence of several key characteristics of human GBM, including high levels of tumor cell proliferation, pseudopalisading necrosis, microvascular proliferation, invasion of tumor cells into surrounding tissues, peri-tumoral reactive astrogliosis, lymphocyte infiltration, presence of numerous tumor

  16. Maternal care affects EEG properties of spike-wave seizures (including pre- and post ictal periods) in adult WAG/Rij rats with genetic predisposition to absence epilepsy.

    PubMed

    Sitnikova, Evgenia; Rutskova, Elizaveta M; Raevsky, Vladimir V

    2016-10-01

    WAG/Rij rats have a genetic predisposition to absence epilepsy and develop spontaneous spike-wave discharges in EEG during late ontogenesis (SWD, EEG manifestation of absence epilepsy). Changes in an environment during early postnatal ontogenesis can influence the genetically predetermined absence epilepsy. Here we examined the effect of maternal environment during weaning period on the EEG manifestation of absence epilepsy in adulthood. Experiments were performed in the offspring of WAG/Rij and Wistar rats. The newborn pups were fostered to dams of the same (in-fostering) or another strain (cross-fostering). Age-matched control WAG/Rij and Wistar rats were reared by their biological mothers. Absence seizures were uncommon in Wistar and were not aggravated in both in- and cross-fostered groups. In WAG/Rij rats, fewer SWD were found in the cross-fostered as compared to the in-fostered group. The cross-fostered WAG/Rij rats showed higher percentage of short-lasting SWD with duration <2s. The mean frequency of EEG at the beginning of SWD in the cross-fostered WAG/Rij rats was lower than in control (8.82 vs 9.25Hz), but it was higher in a period of 1.5s before and after SWD. It was concluded that a healthier maternal environment is able to alleviate genetically predetermined absence seizures in adulthood through changes in EEG rhythmic activity. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Fatty acid composition of brown adipose tissue in genetically heat-tolerant FOK rats

    NASA Astrophysics Data System (ADS)

    Ohno, T.; Furuyama, F.; Kuroshima, A.

    The phospholipid fatty acid composition of brown adipose tissue (BAT) was examined in inbred heat-tolerant FOK rats and compared with that in conventional Wistar rats not previously exposed to heat. The FOK rats showed higher unsaturation states, as indicated by higher levels of polyunsaturated fatty acids and a higher unsaturation index and polyunsaturated fatty acids/saturated fatty acids ratio. This higher level of unsaturation was characterized by the higher amount of polyunsaturated fatty acids such as linoleic acid, arachidonic acid and docosahexaenoic acid. It may be concluded that the increased docosahexaenoic acid level in BAT phospholipids brings about the hyperplasia of BAT, causing an enhancement of its in vivo thermogernic activity as well as the systemic non-shivering thermogenesis observed in heat-tolerant FOK rats.

  18. Safety assessment of genetically modified milk containing human beta-defensin-3 on rats by a 90-day feeding study.

    PubMed

    Chen, Xin; Gao, Ming-Qing; Liang, Dong; Yin, Songna; Yao, Kezhen; Zhang, Yong

    2017-02-01

    In recent years, transgenic technology has been widely applied in many fields. There is concern about the safety of genetically modified (GM) products with the increased prevalence of GM products. In order to prevent mastitis in dairy cows, our group produced transgenic cattle expressing human beta-defensin-3 (HBD3) in their mammary glands, which confers resistance to the bacteria that cause mastitis. The milk derived from these transgenic cattle thus contained HBD3. The objective of the present study was to analyze the nutritional composition of HBD3 milk and conduct a 90-day feeding study on rats. Rats were divided into 5 groups which consumed either an AIN93G diet (growth purified diet for rodents recommended by the American Institute of Nutrition) with the addition of 10% or 30% HBD3 milk, an AIN93G diet with the addition of 10% or 30% conventional milk, or an AIN93G diet alone. The results showed that there was no difference in the nutritional composition of HBD3 and conventional milk. Furthermore, body weight, food consumption, blood biochemistry, relative organ weight, and histopathology were normal in those rats that consumed diets containing HBD3. No adverse effects were observed between groups that could be attributed to varying diets or gender.

  19. Effects of NMDA glutamate receptor antagonist drugs on the volitional consumption of ethanol by a genetic drinking rat.

    PubMed

    McMillen, Brian A; Joyner, Paul W; Parmar, Chandresh A; Tyer, Will E; Williams, Helen L

    2004-09-30

    The ability of drugs that reduce NMDA receptor activity on the volitional consumption of ethanol in the genetic drinking rat, mHEP line, was investigated. After the consumption of ethanol solutions and water by each male or female mHEP rat had stabilized on its preferred concentration, different doses of LY 274614, a competitive NMDA antagonist, MK 801, a non-competitive NMDA antagonist, (+)-HA-966 or ACPC (1-aminocyclopropane-1-carboxylic acid), antagonists of the glycine site were administered daily for three days. The dose of 3.0 mg/kg i.p. LY 274614 reduced the consumption of ethanol by 64% compared to the pre-treatment baseline, while 0.3 mg/kg of MK 801 reduced consumption by 44%, 20 mg/kg (+)-HA-966 reduced consumption by 47% and 300 mg/kg of ACPC reduced consumption by 30%. These doses of LY 274614 and MK 801 reduced the ability of Sprague-Dawley rats to walk on a rotorod. Effects of these drugs on food intake were small except for the 20 mg/kg dose of (+)-HA-966. Therefore, the drugs did not have an anti-caloric effect and manipulations of the glutamatergic system through NMDA receptors may modify the consumption of ethanol. This interaction should be explored further for its therapeutic potential and to better understand the control by central neuronal systems of the consumption of ethanol.

  20. Effects of levetiracetam, a novel antiepileptic drug, on convulsant activity in two genetic rat models of epilepsy.

    PubMed

    Gower, A J; Hirsch, E; Boehrer, A; Noyer, M; Marescaux, C

    1995-11-01

    The anticonvulsant effects of levetiracetam were assessed in two genetic rat models. In the audiogenic-seizure prone rat, levetiracetam, 5.4 to 96 mg/kg i.p. dose-dependently inhibited both wild running and tonic-clonic convulsions. In the GAERS model of petit mal epilepsy, levetiracetam markedly suppressed spontaneous spike-and-wave discharge (SWD) but left the underlying EEG trace normal. The effects were already marked at 5.4 mg/kg and did not increase significantly up to 170 mg/kg although more animals were completely protected. Levetiracetam produced no observable effects on behaviour apart from slight reversible sedation at 170 mg/kg. In contrast, piracetam, a structural analogue of levetiracetam, significantly and consistently suppressed SWD in GAERS rats only at the high dose of 1000 mg/kg with some slight effects at lower doses. The effect of piracetam appeared to be due to increased sleeping rather than to a direct antiepileptic effect. The results with levetiracetam argue for a clinical application in both petit mal, absence epilepsy and in treating generalised tonic-clonic and partial seizures.

  1. Antidepressant efficacy of high and low frequency transcranial magnetic stimulation in the FSL/FRL genetic rat model of depression.

    PubMed

    Hesselberg, Marie Louise; Wegener, Gregers; Buchholtz, Poul Erik

    2016-11-01

    Repetitive Magnetic Stimulation (rTMS) has appeared to be a potential non-invasive antidepressant method, which implies non-convulsive focal stimulation of the brain through a time varying magnetic field. The antidepressant potential of rTMS has been supported by animal studies showing a number of interesting similarities between magnetic stimulation and electroconvulsive stimulation (ECS). Despite these positive results, this method still contains many unknown issues. Importantly, there are fundamental uncertainties concerning the optimal combination of stimulus parameters (frequency, intensity, duration, and number of pulses) to obtain an antidepressant effect. Therefore, the present study aimed to qualify the choice of rTMS stimulus frequency in a well-validated genetic animal model of depression, the FSL/FRL rats. We compared the antidepressant effect of low frequency, high frequency rTMS and ECS to sham treatment in FRL and FSL rats using 6 parallel groups. We used the Forced Swim Test and the Open Field Test to screen the depression-like state in rats. We found that both the high frequency and the low frequency rTMS resulted in a significant antidepressant effect. However, this effect was inferior to the effect of ECS. The low frequency and high frequency groups, which received the same total impulse load and stimulus intensity, did not differ with respect to antidepressant efficacy in this study. In conclusion, this study provides robust evidence that both rTMS interventions are efficacious, although not as efficient as ECS.

  2. Increased wheel-running activity in the genetically skeletal muscle fast-twitch fiber-dominant rats.

    PubMed

    Suwa, Masataka; Nakano, Hiroshi; Higaki, Yasuki; Nakamura, Tomohiro; Katsuta, Shigeru; Kumagai, Shuzo

    2003-01-01

    The purpose of the present study was to investigate whether genetic differences in muscle histochemical characteristics were related to the voluntary wheel-running activity level by using genetically fast-twitch fiber-dominant rats (FFDR) and control rats (CR). The rats were divided into four groups; sedentary CR (Sed-CR), wheel-running CR (WR-CR), sedentary FFDR (Sed-FFDR), and wheel-running FFDR (WR-FFDR). Wheel access was started at age 9 wk and lasted for 7 days. The FFDR showed a lower percentage of type I fibers of the deep portion of gastrocnemius and soleus muscles and a higher percentage of both type IIX fibers of the gastrocnemius muscle and type IIA fibers of the soleus muscle compared with CR. A higher capillary density and smaller fiber cross-sectional area were also observed in FFDR. The daily running distance in WR-FFDR was higher than in WR-CR for each 7 days. The total running distance for 7 days in WR-FFDR was 3.2-fold higher than in WR-CR. On day 7 of the 7-day test, the total number of active 1-min intervals for 24 h, the average rpm when they were active, and the maximum rpm for any single 1-min period in the WR-FFDR were significantly higher than in the WR-CR (1.5-, 2.9-, and 2.0-fold, respectively). These results suggest that mechanical or physiological muscle characteristics may thus affect the wheel-running activity level.

  3. Comparison of cortical epileptic afterdischarges in immature genetic absence epilepsy WAG/Rij rats with those in two other strains (ACI and Wistar).

    PubMed

    Mares, Pavel; Tolmacheva, Elena

    2007-01-01

    The aim of this study was to examine the development of cortical epileptic afterdischarges (ADs) in genetic absence epilepsy WAG/Rij rats, and to compare them with two strains with minimal incidence of spike-and-wave (SW) episodes (ACI and Wistar). Epileptic ADs were elicited by stimulation of sensorimotor cortex in 12-, 18-, and 25-day-old rats of the three strains. The threshold current intensities were established for movements accompanying stimulation, for ADs of the SW type and accompanying clonic seizures and for transition into limbic type of ADs (characterized by behavioral automatisms). Individual groups were formed by 7-12 rats. There were no differences among the three strains in the thresholds for elicitation of stimulation-bound movements. In contrast, WAG/Rij and ACI rats exhibited easier elicitation of SW ADs than Wistar rats at the age of 18 and 25 days. There was no difference among the three strains in transition into the limbic type of ADs in 18- and 25-day-old rats. Lower thresholds for SW ADs in 18- and 25-day-old WAG/Rij and ACI rats in comparison with Wistar rats are in agreement with our data from adult animals as well as with development of pharmacologically induced models of absence seizures. The failure to find a specific difference between WAG/Rij rats and the other two strains might indicate a difference in generation of SW episodes and SW cortical AD.

  4. Genetic microsurgery by laser: establishment of a clonal population of rat kangaroo cells (PTK2) with a directed deficiency in a chromosomal nucleolar organizer.

    PubMed

    Berns, M W; Chong, L K; Hammer-Wilson, M; Miller, K; Siemens, A

    1979-06-21

    An ultraviolet laser beam was focused to a submicron spot on one of the nucleolar organizer regions of mitotic chromosomes of rat kangaroo cells in tissue culture. The daughter cells were isolated and cloned into a viable population that maintained the directed nucleolar deficiency. It is concluded that the laser can be used to delete preselected genetic regions and the genetic deletion is maintained as a heritable deficiency in subsequent daughter cells.

  5. Sex differences in the blood antioxidant defense system in juvenile rats with various genetic predispositions to hypertension.

    PubMed

    Horvathova, Martina; Zitnanova, Ingrid; Kralovicova, Zuzana; Balis, Peter; Puzserova, Angelika; Muchova, Jana; Kluknavsky, Michal; Durackova, Zdenka; Bernatova, Iveta

    2016-02-01

    This study investigated the contribution of blood oxidative stress (OS) to the development of hypertension, as well as sex differences in the antioxidant defense system (ADS) in genetic models of hypertension. Nine-week-old normotensive Wistar-Kyoto (WKY) rats, borderline hypertensive rats (BHR) and spontaneously hypertensive rats (SHR) of both sexes were used. Systolic blood pressure (SBP) was determined by tail-cuff plethysmography, the trolox equivalent antioxidant capacity (TEAC) and the concentration of lipid peroxides (LP) were determined in plasma. The activity of the antioxidant enzymes Cu/Zn-superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) was determined in erythrocytes. SBP was significantly elevated in BHR and SHR in both sexes. BHR and SHR males had a higher SBP than the respective females. Sex-dependent differences in the ADS were found only in SHR, in which TEAC, SOD and CAT were significantly higher in males than in females. No differences in TEAC, SOD, CAT and GPx were observed between BHR (males and females) and WKY controls. LP levels were similar in all the groups investigated. Significant positive correlations were observed between SBP and both SOD and CAT. TEAC correlated positively with SOD and LP. As no signs of oxidative damage to lipids were found in young BHR and SHR of either sex, OS in the blood does not seem to be causatively related to the development of hypertension in these rats. However, despite activated antioxidant defenses, the positive correlation between plasma TEAC and LP suggests that oxidative damage is progressing slowly and therefore it seems to be a consequence rather than the cause of hypertension.

  6. Differential interaction with the serotonin system by S-ketamine, vortioxetine, and fluoxetine in a genetic rat model of depression.

    PubMed

    du Jardin, Kristian Gaarn; Liebenberg, Nico; Müller, Heidi Kaastrup; Elfving, Betina; Sanchez, Connie; Wegener, Gregers

    2016-07-01

    The mechanisms mediating ketamine's antidepressant effect have only been partly resolved. Recent preclinical reports implicate serotonin (5-hydroxytryptamine; 5-HT) in the antidepressant-like action of ketamine. Vortioxetine is a multimodal-acting antidepressant that is hypothesized to exert its therapeutic activity through 5-HT reuptake inhibition and modulation of several 5-HT receptors. The objective of this study was to evaluate the therapeutic-like profiles of S-ketamine, vortioxetine, and the serotonin reuptake inhibitor fluoxetine in response to manipulation of 5-HT tone. Flinders Sensitive Line (FSL) rats, a genetic model of depression, were depleted of 5-HT by repeated administration of 4-chloro-DL-phenylalanine methyl ester HCl (pCPA). Using pCPA-pretreated and control FSL rats, we investigated the acute and sustained effects of S-ketamine (15 mg/kg), fluoxetine (10 mg/kg), or vortioxetine (10 mg/kg) on recognition memory and depression-like behavior in the object recognition task (ORT) and forced swim test (FST), respectively. The behavioral phenotype of FSL rats was unaffected by 5-HT depletion. Vortioxetine, but not fluoxetine or S-ketamine, acutely ameliorated the memory deficits of FSL rats in the ORT irrespective of 5-HT tone. No sustained effects were observed in the ORT. In the FST, all three drugs demonstrated acute antidepressant-like activity but only S-ketamine had sustained effects. Unlike vortioxetine, the antidepressant-like responses of fluoxetine and S-ketamine were abolished by 5-HT depletion. These observations suggest that the acute and sustained antidepressant-like effects of S-ketamine depend on endogenous stimulation of 5-HT receptors. In contrast, the acute therapeutic-like effects of vortioxetine on memory and depression-like behavior may be mediated by direct activity at 5-HT receptors.

  7. Sociability impairments in Genetic Absence Epilepsy Rats from Strasbourg: Reversal by the T-type calcium channel antagonist Z944.

    PubMed

    Henbid, Mark T; Marks, Wendie N; Collins, Madeline J; Cain, Stuart M; Snutch, Terrance P; Howland, John G

    2017-10-01

    Childhood absence epilepsy (CAE) is associated with interictal co-morbid symptoms including abnormalities in social behaviour. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) is a model of CAE that exhibits physiological and behavioural alterations characteristic of the human disorder. However, it is unknown if GAERS display the social deficits often observed in CAE. Sociability in rodents is thought to be mediated by neural circuits densely populated with T-type calcium channels and GAERS contain a missense mutation in the Cav3.2 T-type calcium channel gene. Thus, the objective of this study was to examine the effects of the clinical stage pan-T-type calcium channel blocker, Z944, on sociability behaviour in male and female GAERS and non-epileptic control (NEC) animals. Female GAERS showed reduced sociability in a three-chamber sociability task whereas male GAERS, male NECs, and female NECs all showed a preference for the chamber containing a stranger rat. In drug trials, pre-treatment with 5mg/kg of Z944 normalized sociability in female GAERS. In contrast, female NECs showed impaired sociability following Z944 treatment. Dose-dependent decreases in locomotor activity were noted following Z944 treatment in both strains. Treatment with 10mg/kg of Z944 altered exploration such that only 8 of the 16 rats tested explored both sides of the testing chamber. In those that explored the chamber, significant preference for the stranger rat was observed in GAERS but not NECs. Overall, the data suggest that T-type calcium channels are critical in regulating sociability in both GAERS and NEC animals. Future research should focus on T-type calcium channels in the treatment of sociability deficits observed in disorders such as CAE. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Characterisation of peroxisome proliferator-activated receptor signalling in the midbrain periaqueductal grey of rats genetically prone to heightened stress, negative affect and hyperalgesia.

    PubMed

    Okine, Bright N; Gaspar, Jessica C; Madasu, Manish K; Olango, Weredeselam M; Harhen, Brendan; Roche, Michelle; Finn, David P

    2017-02-15

    The stress-hyperresponsive Wistar-Kyoto (WKY) rat strain exhibits a hyperalgesic phenotype and is a useful genetic model for studying stress-pain interactions. Peroxisome proliferator-activated receptor (PPAR) signalling in the midbrain periaqueductal grey (PAG) modulates pain. This study characterised PPAR signalling in the PAG of WKY rats exposed to the formalin test of inflammatory pain, versus Sprague-Dawley (SD) controls. Formalin injection reduced levels of the endogenous PPAR ligands N-palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA) in the lateral(l) PAG of SD rats, but not WKY rats which exhibited higher levels of these analytes compared with formalin-injected SD counterparts. Levels of mRNA coding for fatty acid amide hydrolase (FAAH; catabolises PEA and OEA) were lower in the lPAG of WKY versus SD rats. PPARγ mRNA and protein levels in the lPAG were higher in saline-treated WKY rats, with PPARγ protein levels reduced by formalin treatment in WKY rats only. In the dorsolateral(dl) or ventrolateral(vl) PAG, there were no effects of formalin injection on PEA or OEA levels but there were some differences in levels of these analytes between saline-treated WKY and SD rats and some formalin-evoked alterations in levels of PPARα, PPARγ or FAAH mRNA in WKY and/or SD rats. Pharmacological blockade of PPARγ in the lPAG enhanced formalin-evoked nociceptive behaviour in WKY, but not SD, rats. These data indicate differences in the PPAR signalling system in the PAG of WKY versus SD rats and suggest that enhanced PEA/OEA-mediated tone at PPARγ in the lPAG may represent an adaptive mechanism to lower hyperalgesia in WKY rats. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Grafting fibroblasts genetically modified to produce L-dopa in a rat model of Parkinson disease

    SciTech Connect

    Wolff, J.A.; Fisher, L.J.; Xu, L.; Jinnah, H.A.; Rosenberg, M.B.; Shimohama, S.; Gage, F.H. ); Langlais, P.J. School of Medicine and Veterans Administration Medical Center, La Jolla San Diego State Univ., CA ); Iuvone, P.M. ); O'Malley, K.L. )

    1989-11-01

    Rat fibroblasts were infected with a retroviral vector containing the cDNA for rat tyrosine hydroxylase. A TH-positive clone was identified by biochemical assay and immunohistochemical staining. When supplemented in vitro with pterin cofactors required for TH activity, these cells produced L-dopa and released it into the cell cultured medium. Uninfected control cells and fibroblasts infected with the TH vector were grafted separately to the caudate of rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway. Only grafts containing TH-expressing fibroblasts were found to reduce rotational asymmetry. These results have general implications for the application of gene therapy to human neurological disease and specific implications for Parkinson disease.

  10. Geographic patterns of genetic differentiation within the restricted range of the endangered Stephens' kangaroo rat Dipodomys stephensi.

    PubMed

    Metcalf, A E; Nunney, L; Hyman, B C

    2001-06-01

    Using mtDNA variation in the kangaroo rat Dipodomys stephensi, we found no support for the hypothesis that a species with an historically restricted range will exhibit low levels of genetic polymorphism and little genetic structure. Dipodomys stephensi has long been restricted to a few interior coastal valleys in southern California encompassing an area of approximately 70 x 40 km; however, we found high levels of genetic variation over much of its range and significant genetic structure both within and between regions. We also found evidence for a recent range expansion. Dipodomys stephensi is a federally endangered species that is separated from D. panamintinus, its presumed sister taxon, by a mountain range to the north. We assessed genetic variation by sequencing 645 bases of the mitochondrial d-loop from 61 individuals sampled from 16 locations across the species range and rooted their relationship using two D. panamintinus individuals. Despite its limited geographic range, the level of mtDNA variation in D. stephensi is comparable to that of other rodents, including that of the more widely distributed D. panamintinus. This variation revealed significant regional differentiation. The northern, central, and southern regions of the range differ in both the level and the distribution of genetic variation. Phylogenetic analysis revealed that the center of the range contains the most diversity of lineages, including the most basal. In this region and in the north, most haplotypes were found at only a single location (25/29), or at a pair of nearby locations (3/29). In addition, related haplotypes clustered geographically. These results are consistent with long-term demographic stability characterized by limited dispersal and high local effective population size. Further support for this conclusion is the finding of unique diversity in two northern peripheral populations, Norco and Potrero Creek (PC). However, in sharp contrast, one haplotype (CC) was found at five

  11. COMPARATIVE EVALUATION OF RISK FACTORS FOR CARDIOVASCULAR DISEASE (CVD) IN GENETICALLY PREDISPOSED RATS

    EPA Science Inventory

    Rodent CVD models are increasingly used for understanding individual differences in susceptibility to environmental stressors such as air pollution. We characterized pathologies and a number of known human risk factors of CVD in genetically predisposed, male young adult Spontaneo...

  12. COMPARATIVE EVALUATION OF RISK FACTORS FOR CARDIOVASCULAR DISEASE (CVD) IN GENETICALLY PREDISPOSED RATS

    EPA Science Inventory

    Rodent CVD models are increasingly used for understanding individual differences in susceptibility to environmental stressors such as air pollution. We characterized pathologies and a number of known human risk factors of CVD in genetically predisposed, male young adult Spontaneo...

  13. Virus-induced autoimmune diabetes in the LEW.1WR1 rat requires Iddm14 and a genetic locus proximal to the major histocompatibility complex.

    PubMed

    Blankenhorn, Elizabeth P; Cort, Laura; Greiner, Dale L; Guberski, Dennis L; Mordes, John P

    2009-12-01

    To identify genes that confer susceptibility to autoimmune diabetes following viral infection in the LEW.1WR1 rat. About 2% of LEW.1WR1 rats develop spontaneous autoimmune diabetes. Immunological perturbants including viral infection increase both the frequency and tempo of diabetes onset. To identify diabetes susceptibility genes (LEW.1WR1 x WF), F2 rats were infected with Kilham rat virus following brief pretreatment with polyinosinic:polycytidylic acid. This treatment induces diabetes in 100% of parental LEW.1WR1 rats and 0% of parental WF rats. Linkage to diabetes was analyzed by genome-wide scanning. Among 182 F2 rats, 57 (31%) developed autoimmune diabetes after a mean latency of 16 days. All diabetic animals and approximately 20% of nondiabetic animals exhibited pancreatic insulitis. Genome-wide scanning revealed a requirement for the Iddm14 locus, long known to be required for diabetes in the BB rat. In addition, a new locus near the RT1 major histocompatibility complex (MHC) was found to be a major determinant of disease susceptibility. Interestingly, one gene linked to autoimmune diabetes in mouse and human, UBD, lies within this region. The Iddm14 diabetes locus in the rat is a powerful determinant of disease penetrance in the LEW.1WR1 rat following viral infection. In addition, a locus near the MHC (Iddm37) conditions diabetes susceptibility in these animals. Other, as-yet-unidentified genes are required to convert latent susceptibility to overt diabetes. These data provide insight into the polygenic nature of autoimmune diabetes in the rat and the interplay of genetic and environmental factors underlying disease expression.

  14. Genetically determined inflammatory-response related cytokine and chemokine transcript profiles between mammary carcinoma resistant and susceptible rat strains

    PubMed Central

    Devapatla, Bharat; Sanders, Jennifer; Samuelson, David J.

    2012-01-01

    Multiple human breast and rat mammary carcinoma susceptibility (Mcs) alleles have been identified. Wistar Kyoto (WKY) rats are resistant to developing mammary carcinomas, while Wistar Furth (WF) females are susceptible. Gene transcripts at Mcs5a1, Mcs5a2, and Mcs5c are differentially expressed between resistant WKY and susceptible WF alleles in immune-system tissues. We hypothesized that immune-related gene transcript profiles are genetically determined in mammary carcinoma resistant and susceptible mammary glands. Low-density QPCR arrays were used to compare inflammation related genes between mammary carcinoma resistant WKY and susceptible WF females. Mammary gland gene transcript levels predicted to be different based on arrays were tested in independent samples. In total, twenty females per strain were exposed to 7,12-dimethylbenz(a)anthracene (DMBA) to induce mammary carcinogenesis. Twelve age-matched controls per strain without DMBA were included to determine main effects of DMBA-exposure. Significant (ANOVA P ≤ 0.01) effects of strain on mammary gland transcript level were observed for Cx3cl1, Il11ra, Il4, C3, Ccl20, Ccl11, Itgb2, Cxcl12, and Cxcr7. Significant effects of DMBA-exposure were observed for Cx3cl1, Il11ra, Cxcr4, Il4ra, and Il4. Strain and DMBA-exposure interaction effects were significant for Cx3cl1. Transcript levels of Cxcr7 relative to Cxcr4 were modified differently by DMBA in mammary carcinoma resistant and susceptible strains. In conclusion, several genetically-determined differences in cytokine, chemokine, and receptor gene transcript levels were identified between mammary carcinoma susceptible and resistant mammary glands, which may be indicative of cell populations and activities that suppress mammary carcinogenesis in resistant genotypes. PMID:22609213

  15. Genetic control of estrogen action in the rat: mapping of QTLs that impact pituitary lactotroph hyperplasia in a BN x ACI intercross.

    PubMed

    Shull, James D; Lachel, Cynthia M; Murrin, Clare R; Pennington, Karen L; Schaffer, Beverly S; Strecker, Tracy E; Gould, Karen A

    2007-09-01

    Estrogens are important regulators of growth and development and contribute to the etiology of several types of cancer. Different inbred rat strains exhibit marked, cell-type-specific differences in responsiveness to estrogens as well as differences in susceptibility to estrogen-induced tumorigenesis. Regulation of pituitary lactotroph homeostasis is one estrogen-regulated response that differs dramatically between different inbred rat strains. In this article we demonstrate that the growth response of the anterior pituitary gland of female ACI rats to 17beta-estradiol (E2) markedly exceeds that of identically treated female Brown Norway (BN) rats. We further demonstrate that pituitary mass, a surrogate indicator of absolute lactotroph number, behaves as a quantitative trait in E2-treated F(2) progeny generated in a genetic cross originating with BN females and ACI males. Composite interval mapping analyses of the (BNxACI)F(2) population revealed quantitative trait loci (QTLs) that exert significant effects on E2-induced pituitary growth on rat chromosome 4 (RNO4) (Ept5) and RNO7 (Ept7). Continuous treatment with E2 rapidly induces mammary cancer in female ACI rats but not BN rats, and QTLs that impact susceptibility to E2-induced mammary cancer in the (BNxACI)F(2) population described here have been mapped to RNO3 (Emca5), RNO4 (Emca6), RNO5 (Emca8), RNO6 (Emca7), and RNO7 (Emca4). Ept5 and Emca6 map to distinct regions of RNO4. However, Ept7 and Emca4 map to the same region of RNO7. No correlation between pituitary mass and mammary cancer number at necropsy was observed within the (BNxACI)F(2) population. This observation, together with the QTL mapping data, indicate that with the exception of the Ept7/Emca4 locus on RNO7, the genetic determinants of E2-induced pituitary growth differ from the genetic determinants of susceptibility to E2-induced mammary cancer.

  16. Genetic bases of estrogen-induced tumorigenesis in the rat: mapping of loci controlling susceptibility to mammary cancer in a Brown Norway x ACI intercross.

    PubMed

    Schaffer, Beverly S; Lachel, Cynthia M; Pennington, Karen L; Murrin, Clare R; Strecker, Tracy E; Tochacek, Martin; Gould, Karen A; Meza, Jane L; McComb, Rodney D; Shull, James D

    2006-08-01

    Exposure to estrogens is associated with an increased risk of breast cancer. Our laboratory has shown that the ACI rat is uniquely susceptible to 17beta-estradiol (E2)-induced mammary cancer. We previously mapped two loci, Emca1 and Emca2 (estrogen-induced mammary cancer), that act independently to determine susceptibility to E2-induced mammary cancer in crosses between the susceptible ACI rat strain and the genetically related, but resistant, Copenhagen (COP) rat strain. In this study, we evaluate susceptibility to E2-induced mammary cancer in a cross between the ACI strain and the unrelated Brown Norway (BN) rat strain. Whereas nearly 100% of the ACI rats developed mammary cancer when treated continuously with E2, BN rats did not develop palpable mammary cancer during the 196-day course of E2 treatment. Susceptibility to E2-induced mammary cancer segregated as a dominant or incompletely dominant trait in a cross between BN females and ACI males. In a population of 251 female (BN x ACI)F(2) rats, we observed evidence for a total of five genetic determinants of susceptibility. Two loci, Emca4 and Emca5, were identified when mammary cancer status at sacrifice was evaluated as the phenotype, and three additional loci, Emca6, Emca7, and Emca8, were identified when mammary cancer number was evaluated as the phenotype. A total of three genetic interactions were identified. These data indicate that susceptibility to E2-induced mammary cancer in the BN x ACI cross behaves as a complex trait controlled by at least five loci and multiple gene-gene interactions.

  17. Antidepressant-like properties of phosphodiesterase type 5 inhibitors and cholinergic dependency in a genetic rat model of depression.

    PubMed

    Liebenberg, Nico; Harvey, Brian H; Brand, Linda; Brink, Christiaan B

    2010-09-01

    We explored the antidepressant-like properties of two phosphodiesterase type 5 (PDE5) inhibitors in a genetic animal model of depression, namely Flinders sensitive line rats. We investigated the dose-dependency of the antidepressant-like action of sildenafil, and its interaction with the cholinergic system and behavioural correlates of monoaminergic neurotransmission, in the forced swim test. Antidepressant-like properties of tadalafil (a structurally distinct PDE5 inhibitor) were also evaluated. Flinders sensitive line rats were treated for 14 days with vehicle, fluoxetine, atropine or PDE5 inhibitors+/-atropine. Immobility, swimming and climbing behaviours were assessed in the forced swim test. In combination with atropine (1 mg/kg), both sildenafil (10, 20 mg/kg) and tadalafil (10 mg/kg) decreased immobility while increasing swimming (serotonergic) and climbing (noradrenergic) behaviours. Interestingly, sildenafil (3 mg/kg) decreased immobility while selectively increasing climbing behaviour in the absence of atropine. These results suggest that the antidepressant-like activity of PDE5 inhibitors involve alterations in monoaminergic neurotransmission, but involve a dependence on inherent cholinergic tone so that the final response is determined by the relative extent of activation of these systems. Furthermore, the behavioural profile of sildenafil alone, and its observed antidepressant-like properties, shows strict dose-dependency, with only higher doses showing an interaction with the cholinergic system.

  18. New analysis of a rat feeding study with a genetically modified maize reveals signs of hepatorenal toxicity.

    PubMed

    Séralini, Gilles-Eric; Cellier, Dominique; de Vendomois, Joël Spiroux

    2007-05-01

    Health risk assessment of genetically modified organisms (GMOs) cultivated for food or feed is under debate throughout the world, and very little data have been published on mid- or long-term toxicological studies with mammals. One of these studies performed under the responsibility of Monsanto Company with a transgenic corn MON863 has been subjected to questions from regulatory reviewers in Europe, where it was finally approved in 2005. This necessitated a new assessment of kidney pathological findings, and the results remained controversial. An Appeal Court action in Germany (Münster) allowed public access in June 2005 to all the crude data from this 90-day rat-feeding study. We independently re-analyzed these data. Appropriate statistics were added, such as a multivariate analysis of the growth curves, and for biochemical parameters comparisons between GMO-treated rats and the controls fed with an equivalent normal diet, and separately with six reference diets with different compositions. We observed that after the consumption of MON863, rats showed slight but dose-related significant variations in growth for both sexes, resulting in 3.3% decrease in weight for males and 3.7% increase for females. Chemistry measurements reveal signs of hepatorenal toxicity, marked also by differential sensitivities in males and females. Triglycerides increased by 24-40% in females (either at week 14, dose 11% or at week 5, dose 33%, respectively); urine phosphorus and sodium excretions diminished in males by 31-35% (week 14, dose 33%) for the most important results significantly linked to the treatment in comparison to seven diets tested. Longer experiments are essential in order to indicate the real nature and extent of the possible pathology; with the present data it cannot be concluded that GM corn MON863 is a safe product.

  19. Low-voltage-activated calcium channel subunit expression in a genetic model of absence epilepsy in the rat.

    PubMed

    Talley, E M; Solórzano, G; Depaulis, A; Perez-Reyes, E; Bayliss, D A

    2000-01-10

    The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are an inbred strain of rats that display many of the characteristics of human absence epilepsy. In these rats, reciprocal thalamocortical projections play a critical role in the generation of spike-and-wave discharges that characterize absence seizures. When compared to those of the non-epileptic control strain, juvenile animals of the GAERS strain reportedly possess higher-amplitude T-type calcium currents in neurons of the thalamic reticular nucleus (nRt). We hypothesized that differences in calcium currents seen between GAERS and controls result from differences in expression of genes for low-voltage-activated calcium channels. Quantitative in situ hybridization was used to compare expression of alpha1G, alpha1H, alpha1I, and alpha1E calcium channel subunit mRNAs from adult and juvenile animals of the two strains. We found higher levels of alpha1H mRNA expression in nRt neurons of juvenile animals (34.9+/-2. 3 vs. 28.4+/-1.8 grains/10(3) pixels, p<0.05), perhaps accounting in part for earlier reports of elevated T-type current amplitude in those cells. In adult GAERS animals, we found elevated levels of alpha1G mRNA in neurons of the ventral posterior thalamic relay nuclei (64.8+/-3.5 vs. 53.5+/-1.7 grains/10(3) pixels, p<0.05), as well as higher levels of alpha1H mRNA in nRt neurons (32.6+/-0.8 vs. 28.2+/-1.6 grains/10(3) pixels, p<0.05). These results suggest that the epileptic phenotype apparent in adult GAERS may result in part from these significant, albeit small ( approximately 15-25%), elevations in T-type calcium channel mRNA levels.

  20. Impact of genetic strain on body fat loss, food consumption, metabolism, ventilation, and motor activity in free running female rats.

    PubMed

    Gordon, C J; Phillips, P M; Johnstone, A F M

    2016-01-01

    Chronic exercise is considered as one of the most effective means of countering symptoms of the metabolic syndrome (MS) such as obesity and hyperglycemia. Rodent models of forced or voluntary exercise are often used to study the mechanisms of MS and type 2 diabetes. However, there is little known on the impact of genetic strain on the metabolic response to exercise. We studied the effects of housing rats with running wheels (RW) for 65 days compared to sedentary (SED) housing in five female rat strains: Sprague-Dawley (SD), Long-Evans (LE), Wistar (WIS), spontaneously hypertensive (SHR), and Wistar-Kyoto (WKY). Key parameters measured were total distance run, body composition, food consumption, motor activity, ventilatory responses by plethysmography, and resting metabolic rate (MR). WKY and SHR ran significantly more than the WIS, LE, and SD strains. Running-induced reduction in body fat was affected by strain but not by distance run. LE's lost 6% fat after 21 d of running whereas WKY's lost 2% fat but ran 40% more than LE's. LE and WIS lost body weight while the SHR and WKY strains gained weight during running. Food intake with RW was markedly increased in SHR, WIS, and WKY while LE and SD showed modest increases. Exploratory motor activity was reduced sharply by RW in all but the SD strain. Ventilatory parameters were primarily altered by RW in the SHR, WKY, and WIS strains. MR was unaffected by RW. In an overall ranking of physiological and behavioral responses to RW, the SD strain was considered the least responsive whereas the WIS was scored as most responsive. In terms of RW-induced fat loss, the LE strain appears to be the most ideal. These results should be useful in the future selection of rat models to study benefits of volitional exercise.

  1. Genetic Influences on Survival Time After Severe Hemorrhage in Inbred Rat Strains

    DTIC Science & Technology

    2011-04-12

    adrenergic receptors (32) are associated with differences in mortality. In the current series of studies, experiment 3 evolved be- cause the absence of... opioid receptor -mediated G-protein activation in rat brain. Brain Res Bull 60: 201–208, 2003. 36. Shoemaker WC, Montgomery ES, Kaplan E, Elwyn DH...biological effects such as an ability to increase activity of calcium-dependent potassium channels associated with hyper- polarization and a decrease in

  2. Propolis prevents aluminium-induced genetic and hepatic damages in rat liver.

    PubMed

    Türkez, Hasan; Yousef, Mokhtar I; Geyikoglu, Fatime

    2010-10-01

    Aluminium is present in several manufactured foods and medicines and is also used in water purification. Therefore, the present experiment was undertaken to determine the effectiveness of propolis in modulating the aluminium chloride (AlCl(3)) induced genotoxicity and hepatotoxicity in liver of rats. Animals were assigned to 1 of 4 groups: control; 34 mg AlCl(3)/kg bw; 50mg propolis/kg bw; AlCl(3) (34 mg/kg bw) plus propolis (50mg/kg bw), respectively. Rats were orally administered their respective doses daily for 30 days. At the end of the experiment, rats were anesthetized and hepatocytes (HEP) were isolated for counting the number of micronucleated hepatocytes (MNHEPs). In addition, the levels of serum enzymes and histological alterations in liver were investigated. AlCl(3) caused a significant increase in MNHEPs, alkaline phosphatase, transaminases (AST and ALT) and lactate dehydrogenase (LDH). Furthermore, severe pathological damages such as: sinusoidal dilatation, congestion of central vein, lipid accumulation and lymphocyte infiltration were established in liver. On the contrary, treatment with propolis alone did not cause any adverse effect on above parameters. Moreover, simultaneous treatments with propolis significantly modulated the toxic effects of AlCl(3). It can be concluded that propolis has beneficial influences and could be able to antagonize AlCl(3) toxicity. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  3. Argan oil reduces oxidative stress, genetic damage and emperipolesis in rats treated with acrylamide.

    PubMed

    Şekeroğlu, Zülal Atlı; Aydın, Birsen; Şekeroğlu, Vedat

    2017-10-01

    Acrylamide (AA), a well-known toxicant, is present in high-temperature-processed foods in heated foods. Argan oil (AO), a natural vegetable oil, is receiving increasing attention due to its powerful biological properties. However, limited information is available about its effects in lymphoid organs and bone marrow. The aim of this study is to investigate the effects of AO on hematological parameters, 8-hydroxydeoxyguanosine (8-OHdG), thiobarbituric acid reactive substances (TBARs), protein carbonyl (PCO), glutathione (GSH), myeloperoxidase (MPO) levels, the formation of micronucleus (MN) and megakaryocytic emperipolesis (ME) against AA-induced toxicity in rats. The animals were treated with AA (50mg/kg/day), AO (6ml/kg/day per day) and AA+AO (50mg+6ml/kg/day) for 30days. Treatment of rats with AA significantly decreased the hematological parameters, GSH and MPO activity and PCEs ratio while it increased TBARs, PCOs and 8-OHdG levels and formation of MN and ME. No significant differences were observed in the animals received the AO alone. Co-treatment with AA+AO ameliorated almost all of the alterations caused by AA and exhibited protective effect in rats. Based on the obtained results, we suggest that integration of AO in diet or using its supplements may be a good strategy for improving tissue injury in many diseases. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Ingestion of milk fermented by genetically modified Lactococcus lactis improves the riboflavin status of deficient rats.

    PubMed

    LeBlanc, J G; Burgess, C; Sesma, F; Savoy de Giori, G; van Sinderen, D

    2005-10-01

    Riboflavin deficiency is common in many parts of the world, particularly in developing countries. The use of riboflavin-producing strains in the production of dairy products such as fermented milks, yogurts, and cheeses is feasible and economically attractive because it would decrease the costs involved during conventional vitamin fortification and satisfy consumer demands for healthier foods. The present study was conducted to assess in a rat bioassay the response of administration of milk fermented by modified Lactococcus lactis on the riboflavin status of deficient rats. Rats were fed a riboflavin-deficient diet during 21 d after which this same diet was supplemented with milk fermented by Lactoccus lactis pNZGBAH, a strain that overproduces riboflavin during fermentation. The novel fermented product, with increased levels of riboflavin, was able to eliminate most physiological manifestations of ariboflavinosis, such as stunted growth, elevated erythrocyte glutathione reductase activation coefficient values and hepatomegaly, that were observed using a riboflavin depletion-repletion model, whereas a product fermented with a nonriboflavin-producing strain did not show similar results. A safety assessment of this modified strain was performed by feeding rodents with the modified strain daily for 4 wk. This strain caused no detectable secondary effects. These results pave the way for analyzing the effect of similar riboflavin-overproducing lactic acid bacteria in human trials. The regular consumption of products with increased levels of riboflavin could help prevent deficiencies of this essential vitamin.

  5. Markedly elevated specific renin levels in the adrenal in genetically hypertensive rats.

    PubMed Central

    Naruse, M; Inagami, T

    1982-01-01

    The specific renin (EC 3.4.99.19) activity in the adrenal of spontaneously hypertensive rats was determined by a method that is capable of distinguishing renin from nonspecific renin-like activity of proteases by using specific antibody to renin. The renin level in the adrenals of adult spontaneously hypertensive rats with established hypertension was found to be 6-8 times as high as that of the normotensive control Wistar-Kyoto strain. The large difference in the adrenal renin level was observed even in 3-wk-old rats in which hypertension has not yet developed. The adrenal renin level was increased by bilateral nephrectomy in both the hypertensive and normotensive strains. A larger quantity of renin was found in the adrenal cortex than in the medulla, and the difference between the hypertensive strain and the normotensive strain was more prominent in the cortex than in the medulla. These results suggest possible involvement of adrenal renin in the development and in the early maintenance phase of hypertension in this animal mode of human essential hypertension by affecting the adrenocortical or adrenomedullary activity, or both. PMID:7048303

  6. Genetic Signatures for Enhanced Olfaction in the African Mole-Rats

    PubMed Central

    Stathopoulos, Sofia; Bishop, Jacqueline M.; O’Ryan, Colleen

    2014-01-01

    The Olfactory Receptor (OR) superfamily, the largest in the vertebrate genome, is responsible for vertebrate olfaction and is traditionally subdivided into 17 OR families. Recent studies characterising whole-OR subgenomes revealed a ‘birth and death’ model of evolution for a range of species, however little is known about fine-scale evolutionary dynamics within single-OR families. This study reports the first assessment of fine-scale OR evolution and variation in African mole-rats (Bathyergidae), a family of subterranean rodents endemic to sub-Saharan Africa. Because of the selective pressures of life underground, enhanced olfaction is proposed to be fundamental to the evolutionary success of the Bathyergidae, resulting in a highly diversified OR gene-repertoire. Using a PCR-sequencing approach, we analysed variation in the OR7 family across 14 extant bathyergid species, which revealed enhanced levels of functional polymorphisms concentrated across the receptors’ ligand-binding region. We propose that mole-rats are able to recognise a broad range of odorants and that this diversity is reflected throughout their OR7 gene repertoire. Using both classic tests and tree-based methods to test for signals of selection, we investigate evolutionary forces across the mole-rat OR7 gene tree. Four well-supported clades emerged in the OR phylogeny, with varying signals of selection; from neutrality to positive and purifying selection. Bathyergid life-history traits and environmental niche-specialisation are explored as possible drivers of adaptive OR evolution, emerging as non-exclusive contributors to the positive selection observed at OR7 genes. Our results reveal unexpected complexity of evolutionary mechanisms acting within a single OR family, providing insightful perspectives into OR evolutionary dynamics. PMID:24699281

  7. Genetic signatures for enhanced olfaction in the African mole-rats.

    PubMed

    Stathopoulos, Sofia; Bishop, Jacqueline M; O'Ryan, Colleen

    2014-01-01

    The Olfactory Receptor (OR) superfamily, the largest in the vertebrate genome, is responsible for vertebrate olfaction and is traditionally subdivided into 17 OR families. Recent studies characterising whole-OR subgenomes revealed a 'birth and death' model of evolution for a range of species, however little is known about fine-scale evolutionary dynamics within single-OR families. This study reports the first assessment of fine-scale OR evolution and variation in African mole-rats (Bathyergidae), a family of subterranean rodents endemic to sub-Saharan Africa. Because of the selective pressures of life underground, enhanced olfaction is proposed to be fundamental to the evolutionary success of the Bathyergidae, resulting in a highly diversified OR gene-repertoire. Using a PCR-sequencing approach, we analysed variation in the OR7 family across 14 extant bathyergid species, which revealed enhanced levels of functional polymorphisms concentrated across the receptors' ligand-binding region. We propose that mole-rats are able to recognise a broad range of odorants and that this diversity is reflected throughout their OR7 gene repertoire. Using both classic tests and tree-based methods to test for signals of selection, we investigate evolutionary forces across the mole-rat OR7 gene tree. Four well-supported clades emerged in the OR phylogeny, with varying signals of selection; from neutrality to positive and purifying selection. Bathyergid life-history traits and environmental niche-specialisation are explored as possible drivers of adaptive OR evolution, emerging as non-exclusive contributors to the positive selection observed at OR7 genes. Our results reveal unexpected complexity of evolutionary mechanisms acting within a single OR family, providing insightful perspectives into OR evolutionary dynamics.

  8. Alterations in the α2 δ ligand, thrombospondin-1, in a rat model of spontaneous absence epilepsy and in patients with idiopathic/genetic generalized epilepsies.

    PubMed

    Santolini, Ines; Celli, Roberta; Cannella, Milena; Imbriglio, Tiziana; Guiducci, Michela; Parisi, Pasquale; Schubert, Julian; Iacomino, Michele; Zara, Federico; Lerche, Holger; Moyanova, Slavianka; Ngomba, Richard Teke; van Luijtelaar, Gilles; Battaglia, Giuseppe; Bruno, Valeria; Striano, Pasquale; Nicoletti, Ferdinando

    2017-09-15

    Thrombospondins, which are known to interact with the α2 δ subunit of voltage-sensitive calcium channels to stimulate the formation of excitatory synapses, have recently been implicated in the process of epileptogenesis. No studies have been so far performed on thrombospondins in models of absence epilepsy. We examined whether expression of the gene encoding for thrombospondin-1 was altered in the brain of WAG/Rij rats, which model absence epilepsy in humans. In addition, we examined the frequency of genetic variants of THBS1 in a large cohort of children affected by idiopathic/genetic generalized epilepsies (IGE/GGEs). We measured the transcripts of thrombospondin-1 and α2 δ subunit, and protein levels of α2 δ, Rab3A, and the vesicular glutamate transporter, VGLUT1, in the somatosensory cortex and ventrobasal thalamus of presymptomatic and symptomatic WAG/Rij rats and in two control strains by real-time polymerase chain reaction (PCR) and immunoblotting. We examined the genetic variants of THBS1 and CACNA2D1 in two independent cohorts of patients affected by IGE/GGE recruited through the Genetic Commission of the Italian League Against Epilepsy (LICE) and the EuroEPINOMICS-CoGIE Consortium. Thrombospondin-1 messenger RNA (mRNA) levels were largely reduced in the ventrobasal thalamus of both presymptomatic and symptomatic WAG/Rij rats, whereas levels in the somatosensory cortex were unchanged. VGLUT1 protein levels were also reduced in the ventrobasal thalamus of WAG/Rij rats. Genetic variants of THBS1 were significantly more frequent in patients affected by IGE/GGE than in nonepileptic controls, whereas the frequency of CACNA2D1 was unchanged. These findings suggest that thrombospondin-1 may have a role in the pathogenesis of IGE/GGEs. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

  9. A high-fat diet exacerbates depressive-like behavior in the Flinders Sensitive Line (FSL) rat, a genetic model of depression.

    PubMed

    Abildgaard, Anders; Solskov, Lasse; Volke, Vallo; Harvey, Brian H; Lund, Sten; Wegener, Gregers

    2011-06-01

    Major depressive disorder (MDD) and diabetes mellitus type II (T2DM) are two of the major health challenges of our time. It has been shown that MDD and T2DM are highly co-morbid, and recent work has proposed a bi-directional connection between the diseases. The aim of the current study was to investigate the effect of a high-fat diet (HFD) on behavior and metabolism in a genetic rat model of depression, the Flinders Sensitive and Resistant Line (FSL/FRL) rats. Age and weight matched rats were fed a HFD or control diet for 10 weeks and subjected to behavioral testing and metabolic assessment. We found that HFD exacerbated the depressive-like behavior of the FSL rat in the Forced Swim Test (FST), a depression screening tool, although it did not affect the non-depressed FRL rat despite a higher caloric intake. Moreover, the depressive-like phenotype was associated with reduced anxiety and impairment in novel object recognition memory, while HFD consumption led to diminished object recognition memory as well. In both strains HFD increased insulin levels during an oral glucose tolerance test, although fasting blood glucose levels were only significantly increased by HFD in the FSL rat, suggesting a greater metabolic susceptibility in this rat strain. We conclude that compared with the FRL rat, the FSL rat is more susceptible to developing aberrant behaviors related to depression following metabolic stress induced by HFD. Further studies with a mechanistic focus could potentially lead to a better understanding of a possible pathophysiological link between T2DM and MDD.

  10. Adolescent Rats Differ by Genetic Strain in Response to Nicotine Withdrawal

    DTIC Science & Technology

    2007-11-01

    are sex and genetic differences in withdrawal effects of nicotine to design optimal smoking cessation strategies. The current research examined...tobacco inhibits the enzyme monoamine oxidase, which breaks down dopamine. Because dopamine is thought to stimulate pleasure in the brain, the excess...levels produced by the absence of monoamine oxidase may stimulate further drug-seeking behavior for drugs of abuse such as alcohol, cocaine, and heroin

  11. Caerulin-induced pancreatitis in rats: Histological and genetic expression changes from acute phase to recuperation

    PubMed Central

    Magaña-Gómez, Javier; López-Cervantes, Guillermo; de la Barca, Ana María Calderón

    2006-01-01

    AIM: To study the histological and pancreatitis-associated protein mRNA accumulation changes of pancreas from acute phase of caerulin-induced pancreatitis to recuperation in rats. METHODS: Acute pancreatitis was induced by caerulein in male Wistar rats and followed up for 90 d by histological and mRNA analyses of pancreas. Pancreases were dissected at 0, 9, 24 h and 3, 5, 15, 30, 60, 90 d post-induction. Edema (E), polymorphonuclear neutrophil (PMN) infiltration, cytoplasmic vacuolization (V), zymogen granule depletion (ZD) and acinar disorganization (AD) were microscopically evaluated. Accumulation of pancreatitis-associated protein (PAP) and L13A mRNAs were quantified by real-time PCR. RESULTS: The main histological changes appeared at 9 h post-induction for PMN infiltration and cytoplasmic V, while at 24 h and 3 d for E and ZD, respectively. All the parameters were recovered after 5 d, except for ZD which delayed more than 30 d. The main AD was observed after 15 d and values returned to normal after 30 d. Similarly to histological changes, accumulation of the PAP mRNA was increased at 9 h with the highest accumulation at 24 h and differences disappeared after 5 d. CONCLUSION: From the acute phase to recuperation of pancreatitis, regeneration and re-differentiation of pancreas occur and PAP expression is exclusively an acute response of pancreatitis. PMID:16810747

  12. Effects of genetically modified T2A-1 rice on faecal microflora of rats during 90 day supplementation.

    PubMed

    Yuan, Yanfang; Xu, Wentao; Luo, Yunbo; Liu, Haiyan; Lu, Jiao; Su, Chunyuan; Huang, Kunlun

    2011-08-30

    Many animal studies have been performed on products with the Bacillus thuringiensis insecticidal toxin-encoding gene (Bt products), but less have focused on its effects on intestinal microflora owing to difficulties in culturing. This 90 day study was designed to assess unintended effects of genetically modified T2A-1 rice (GMR) on selected intestinal bacteria (Lactobacillus group, Bifidobacterium genus, Escherichia coli subgroup, Enterococcus genus and Clostridium perfringens) of rats by the real-time polymerase chain reaction (PCR) method. During the whole experiment, no statistically significant differences in the numbers of specific bacteria and total bacteria were found between the GMR group and its parental group. At all stages of the experiment the two main probiotics (Lactobacillus group and Bifidobacterium genus) in faeces accounted for 11-23% of the total bacteria, whereas the conditional pathogens (E. coli subgroup, Enterococcus genus and C. perfringens) made up less than 1% of the total bacteria. B/E (log(10) copies of Bifidobacterium genome g(-1) faeces/log(10) copies of E. coli genome g(-1) faeces) ratios from 1.19 to 1.34 were obtained. Furthermore, significant correlations (P < 0.01) between the real-time PCR method and the plate count method were found, with r values ranging from 0.60 to 0.75. No adverse effects on the numbers of specific bacteria in rat faeces were observed as a result of GMR feeding. The real-time PCR method is recommended in further studies on the composition and dynamics of the intestinal bacteria community for better safety assessment of GM materials. Copyright © 2011 Society of Chemical Industry.

  13. Effects of Crocetin Esters and Crocetin from Crocus sativus L. on Aortic Contractility in Rat Genetic Hypertension.

    PubMed

    Llorens, Silvia; Mancini, Andrea; Serrano-Díaz, Jessica; D'Alessandro, Anna Maria; Nava, Eduardo; Alonso, Gonzalo Luis; Carmona, Manuel

    2015-09-22

    Endothelial dysfunction, characterized by an enhancement in vasoconstriction, is clearly associated with hypertension. Saffron (Crocus sativus L.) bioactive compounds have been recognized to have hypotensive properties. Recently, we have reported that crocetin exhibits potent vasodilator effects on isolated aortic rings from hypertensive rats. In this work, we have aimed to analyze the anticontractile ability of crocetin or crocetin esters pool (crocins) isolated from saffron. Thus, we have studied the effects of saffron carotenoids on endothelium-dependent and -independent regulation of smooth muscle contractility in genetic hypertension. We have measured the isometric responses of aortic segments with or without endothelium obtained from spontaneously hypertensive rats. The effects of carotenoids were studied by assessing the endothelial modulation of phenylephrine-induced contractions (10(-9)-10(-5) M) in the presence or absence of crocetin or crocins. The role of nitric oxide and prostanoids was analyzed by performing the experiments with L-NAME (NG-nitro-l-arginine methyl ester) or indomethacin (both 10(-5) M), respectively. Crocetin, and to a minor extent crocins, diminished the maximum contractility of phenylephrine in intact rings, while crocins, but not crocetin, increased this contractility in de-endothelizated vessels. In the intact vessels, the effect of crocetin on contractility was unaffected by indomethacin but was abolished by L-NAME. However, crocetin but not crocins, lowered the already increased contractility caused by L-NAME. Saffron compounds, but especially crocetin have endothelium-dependent prorelaxing actions. Crocins have procontractile actions that take place via smooth muscle cell mechanisms. These results suggest that crocetin and crocins activate different mechanisms involved in the vasoconstriction pathway in hypertension.

  14. Exposure to PM2.5 causes genetic changes in fetal rat cerebral cortex and hippocampus.

    PubMed

    Chao, Ming-Wei; Yang, Chin-Hua; Lin, Po-Ting; Yang, Yu-Hsiu; Chuang, Yu-Chen; Chung, Meng-Chi; Tseng, Chia-Yi

    2016-08-19

    PM2.5 travels along the respiratory tract and enters systemic blood circulation. Studies have shown that PM2.5 increases the incidence of various diseases not only in adults but also in newborn infants. It causes chronic inflammation in pregnant women and retards fetal development. In this study, pregnant rats were exposed to PM2.5 for extended periods of time and it was found that PM2.5 exposure increased immune cells in mother rats. In addition, cytokines and free radicals rapidly accumulated in the amniotic fluid and indirectly affected the fetuses. The authors collected cerebral cortex and hippocampus samples at E18 and analyzed changes of miRNA levels. Expression levels of cortical miR-6315, miR-3588, and miR-466b-5p were upregulated, and positively correlated with the genes Pkn2 (astrocyte migration), Gorab (neuritogenesis), and Mobp (allergic encephalomyelitis). In contrast, PM2.5 decreased expression of miR-338-5p and let-7e-5p, both related to mental development. Further, PM2.5 exposure increased miR-3560 and let-7b-5p in the hippocampus, two proteins that regulate genes Oxct1 and Lin28b that control ketogenesis and glycosylation, and neural cell differentiation, respectively. miR-99b-5p, miR-92b-5p, and miR-99a-5p were decreased, leading to reduced expression of Kbtbd8 and Adam11 which reduced cell mitosis, migration, and differentiation, and inhibited learning abilities and motor coordination of the fetus. © 2016 Wiley Periodicals, Inc. Environ Toxicol, 2016.

  15. Genetic resistance to the induction of experimental allergic encephalomyelitis in Lewis rats. I. Genetic analysis of an apparent mutant strain with phenotypic resistance to experimental allergic encephalomyelitis.

    PubMed

    Waxman, F J; Perryman, L E; Hinrichs, D J; Coe, J E

    1981-01-01

    Clinical resistance to the induction of experimental allergic encephalomyelitis was observed in a closed colony of Lewis (designated Le-R) rats. Disease susceptibility in randomly bred animals appeared to increase with increasing age. In the small group of young Le-R rats, which were susceptible, disease onset was delayed, severity of symptoms was reduced, and duration of clinical signs was abbreviated compared to conventional Lewis rats. The severity of histologic neural tissue lesions correlated with clinical observations. Breeding experiments indicated that most Le-R rats were resistant to disease induction regardless of whether their ancestors had been selected for susceptibility or resistance. The F3 generation of resistant lineage was uniformly resistant at all ages tested. Virtually all (Lewis X Le-R)F1 rats of either sex were resistant when challenged at 7-8 wk of age indicating that resistance was a dominant autosomal trait. Approximately half of (F1 X Lewis) backcross rats developed paralytic EAE whereas one-fourth were entirely resistant, suggesting that disease resistance may be mediated by one or two genes. Le-R rats shared at least some of the Lewis rat major histocompatibility antigens. Resistance apparently did not reflect a nonspecific impairment of cellular immune responsiveness. Le-R rats, which had been challenged with myelin basic protein, developed antigen-reactive cells specific for basic protein or its encephalitogenic fragment. Spleen cells obtained from basic protein-sensitized Le-R rats did not adoptively transfer disease into Lewis rats. In contrast, spleen cells obtained from basic protein-sensitized Lewis rats readily transferred disease into both Lewis and Le-R recipients. These data suggest that disease resistance may be a result of an immunologic deficit (or suppressor cell activity) expressed during the differentiation of antigen-reactive cells into disease-inducing effector cells.

  16. RBE and genetic susceptibility of mouse and rat spermatogonial stem cells to protons, heavy charged particles and 1.5 MeV neutrons

    NASA Astrophysics Data System (ADS)

    Vaglenov, A.; Fedorenko, B.; Kaltenboeck, B.

    The main purpose of the present study is to provide data on RBE and genetic susceptibility in the mouse and the rat when exposed to protons, HZE particles and neutrons. Genetic damage from exposure to 50 MeV and 9 GeV protons, 4 GeV/nucleon helium ions, 4 GeV/nucleon carbon ions and 1.5 MeV neutrons was studied in adult (CBA × C57Bl/6J) F1 mice. Damage from 9 GeV protons and 4 GeV helium ions was studied in adult Wistar rats. The incidence of reciprocal translocations (RT) induced in the spermatogonial stem cells of each species was recorded. RBE values were derived by comparing linear regression coefficients from dose-responses within the same dose-range for each of the radiation types tested and 60Co γ-rays or by means of a direct nonparametric method. RT yields measured after mouse and rat spermatogonial irradiation with protons, heavy charged particles and neutrons fit the linear model of the dose-response relationship. Relative to 60Co γ-rays, RBE values are as follows for mouse spermatogonia: 0.9 for 50 MeV protons; 1.3 for 9 GeV protons; 0.7 for 4 GeV helium ions; and 1.3 for 4 GeV carbon ions. For rat spermatogonia, values were: 1.7 for 9 GeV protons and 1.3 for helium ions. Compared to mice irradiated using the same experimental design, rats were more susceptible to high-LET radiations, with susceptibility assessed by genetic damage to their spermatogonial stem cells. The RBE of 1.5 MeV neutron is about 6.6.

  17. Retargeting of rat parvovirus H-1PV to cancer cells through genetic engineering of the viral capsid.

    PubMed

    Allaume, Xavier; El-Andaloussi, Nazim; Leuchs, Barbara; Bonifati, Serena; Kulkarni, Amit; Marttila, Tiina; Kaufmann, Johanna K; Nettelbeck, Dirk M; Kleinschmidt, Jürgen; Rommelaere, Jean; Marchini, Antonio

    2012-04-01

    The rat parvovirus H-1PV is a promising anticancer agent given its oncosuppressive properties and the absence of known side effects in humans. H-1PV replicates preferentially in transformed cells, but the virus can enter both normal and cancer cells. Uptake by normal cells sequesters a significant portion of the administered viral dose away from the tumor target. Hence, targeting H-1PV entry specifically to tumor cells is important to increase the efficacy of parvovirus-based treatments. In this study, we first found that sialic acid plays a key role in H-1PV entry. We then genetically engineered the H-1PV capsid to improve its affinity for human tumor cells. By analogy with the resolved crystal structure of the closely related parvovirus minute virus of mice, we developed an in silico three-dimensional (3D) model of the H-1PV wild-type capsid. Based on this model, we identified putative amino acids involved in cell membrane recognition and virus entry at the level of the 2-fold axis of symmetry of the capsid, within the so-called dimple region. In situ mutagenesis of these residues significantly reduced the binding and entry of H-1PV into permissive cells. We then engineered an entry-deficient viral capsid and inserted a cyclic RGD-4C peptide at the level of its 3-fold axis spike. This peptide binds α(v)β(3) and α(v)β(5) integrins, which are overexpressed in cancer cells and growing blood vessels. The insertion of the peptide rescued viral infectivity toward cells overexpressing α(v)β(5) integrins, resulting in the efficient killing of these cells by the reengineered virus. This work demonstrates that H-1PV can be genetically retargeted through the modification of its capsid, showing great promise for a more efficient use of this virus in cancer therapy.

  18. Angiopoietin-1-expressing adipose stem cells genetically modified with baculovirus nanocomplex: investigation in rat heart with acute infarction.

    PubMed

    Paul, Arghya; Nayan, Madhur; Khan, Afshan Afsar; Shum-Tim, Dominique; Prakash, Satya

    2012-01-01

    The objective of this study was to develop angiopoietin-1 (Ang1)-expressing genetically modified human adipose tissue derived stem cells (hASCs) for myocardial therapy. For this, an efficient gene delivery system using recombinant baculovirus complexed with cell penetrating transactivating transcriptional activator TAT peptide/deoxyribonucleic acid nanoparticles (Bac-NP), through ionic interactions, was used. It was hypothesized that the hybrid Bac- NP(Ang1) system can efficiently transduce hASCs and induces favorable therapeutic effects when transplanted in vivo. To evaluate this hypothesis, a rat model with acute myocardial infarction and intramyocardially transplanted Ang1-expressing hASCs (hASC-Ang1), genetically modified by Bac-NP(Ang1), was used. Ang1 is a crucial pro-angiogenic factor for vascular maturation and neovasculogenesis. The released hAng1 from hASC-Ang1 demonstrated profound mitotic and anti-apoptotic activities on endothelial cells and cardiomyocytes. The transplanted hASC-Ang1 group showed higher cell retention compared to hASC and control groups. A significant increase in capillary density and reduction in infarct sizes were noted in the infarcted hearts with hASC-Ang1 treatment compared to infarcted hearts treated with hASC or the untreated group. Furthermore, the hASC-Ang1 group showed significantly higher cardiac performance in echocardiography (ejection fraction 46.28% ± 6.3%, P < 0.001 versus control, n = 8) than the hASC group (36.35% ± 5.7%, P < 0.01, n = 8), 28 days post-infarction. The study identified Bac-NP complex as an advanced gene delivery vehicle for stem cells and demonstrated its potential to treat ischemic heart disease with high therapeutic index for combined stem cell-gene therapy strategy.

  19. Retargeting of Rat Parvovirus H-1PV to Cancer Cells through Genetic Engineering of the Viral Capsid

    PubMed Central

    Allaume, Xavier; El-Andaloussi, Nazim; Leuchs, Barbara; Bonifati, Serena; Kulkarni, Amit; Marttila, Tiina; Kaufmann, Johanna K.; Nettelbeck, Dirk M.; Kleinschmidt, Jürgen; Rommelaere, Jean

    2012-01-01

    The rat parvovirus H-1PV is a promising anticancer agent given its oncosuppressive properties and the absence of known side effects in humans. H-1PV replicates preferentially in transformed cells, but the virus can enter both normal and cancer cells. Uptake by normal cells sequesters a significant portion of the administered viral dose away from the tumor target. Hence, targeting H-1PV entry specifically to tumor cells is important to increase the efficacy of parvovirus-based treatments. In this study, we first found that sialic acid plays a key role in H-1PV entry. We then genetically engineered the H-1PV capsid to improve its affinity for human tumor cells. By analogy with the resolved crystal structure of the closely related parvovirus minute virus of mice, we developed an in silico three-dimensional (3D) model of the H-1PV wild-type capsid. Based on this model, we identified putative amino acids involved in cell membrane recognition and virus entry at the level of the 2-fold axis of symmetry of the capsid, within the so-called dimple region. In situ mutagenesis of these residues significantly reduced the binding and entry of H-1PV into permissive cells. We then engineered an entry-deficient viral capsid and inserted a cyclic RGD-4C peptide at the level of its 3-fold axis spike. This peptide binds αvβ3 and αvβ5 integrins, which are overexpressed in cancer cells and growing blood vessels. The insertion of the peptide rescued viral infectivity toward cells overexpressing αvβ5 integrins, resulting in the efficient killing of these cells by the reengineered virus. This work demonstrates that H-1PV can be genetically retargeted through the modification of its capsid, showing great promise for a more efficient use of this virus in cancer therapy. PMID:22258256

  20. Neuropeptide S alters anxiety, but not depression-like behaviour in Flinders Sensitive Line rats: a genetic animal model of depression.

    PubMed

    Wegener, Gregers; Finger, Beate C; Elfving, Betina; Keller, Kirsten; Liebenberg, Nico; Fischer, Christina W; Singewald, Nicolas; Slattery, David A; Neumann, Inga D; Mathé, Aleksander A

    2012-04-01

    Neuropeptide S (NPS) and its receptor (NPSR) have been implicated in the mediation of anxiolytic-like behaviour in rodents. However, little knowledge is available regarding the NPS system in depression-related behaviours, and whether NPS also exerts anxiolytic effects in an animal model of psychopathology. Therefore, the aim of this work was to characterize the effects of NPS on depression- and anxiety-related parameters, using male and female rats in a well-validated animal model of depression: the Flinders Sensitive Line (FSL), their controls, the Flinders Resistant Line (FRL), and Sprague-Dawley (SD) rats. We found that FSL showed greater immobility in the forced swim test (FST) than FRL, confirming their phenotype. However, NPS did not affect depression-related behaviour in any rat line. No significant differences in baseline anxiety levels between the FSL and FRL strains were observed, but FSL and FRL rats displayed less anxiety-like behaviour compared to SD rats. NPS decreased anxiety-like behaviour on the elevated plus-maze in all strains. The expression of the NPSR in the amygdala, periventricular hypothalamic nucleus, and hippocampus was equal in all male strains, although a trend towards reduced expression within the amygdala was observed in FSL rats compared to SD rats. In conclusion, NPS had a marked anxiolytic effect in FSL, FRL and SD rats, but did not modify the depression-related behaviour in any strain, in spite of the significant differences in innate level between the strains. These findings suggest that NPS specifically modifies anxiety behaviour but cannot overcome/reverse a genetically mediated depression phenotype.

  1. No increases in biomarkers of genetic damage or pathological changes in heart and brain tissues in male rats administered methylphenidate hydrochloride (Ritalin) for 28 days.

    PubMed

    Witt, Kristine L; Malarkey, David E; Hobbs, Cheryl A; Davis, Jeffrey P; Kissling, Grace E; Caspary, William; Travlos, Gregory; Recio, Leslie

    2010-01-01

    Following a 2005 report of chromosomal damage in children with attention deficit/hyperactivity disorder (ADHD) who were treated with the commonly prescribed medication methylphenidate (MPH), numerous studies have been conducted to clarify the risk for MPH-induced genetic damage. Although most of these studies reported no changes in genetic damage endpoints associated with exposure to MPH, one recent study (Andreazza et al. [2007]: Prog Neuropsychopharmacol Biol Psychiatry 31:1282-1288) reported an increase in DNA damage detected by the Comet assay in blood and brain cells of Wistar rats treated by intraperitoneal injection with 1, 2, or 10 mg/kg MPH; no increases in micronucleated lymphocyte frequencies were observed in these rats. To clarify these findings, we treated adult male Wistar Han rats with 0, 2, 10, or 25 mg/kg MPH by gavage once daily for 28 consecutive days and measured micronucleated reticulocyte (MN-RET) frequencies in blood, and DNA damage in blood, brain, and liver cells 4 hr after final dosing. Flow cytometric evaluation of blood revealed no significant increases in MN-RET. Comet assay evaluations of blood leukocytes and cells of the liver, as well as of the striatum, hippocampus, and frontal cortex of the brain showed no increases in DNA damage in MPH-treated rats in any of the three treatment groups. Thus, the previously reported observations of DNA damage in blood and brain tissue of rats exposed to MPH for 28 days were not confirmed in this study. Additionally, no histopathological changes in brain or heart, or elevated serum biomarkers of cardiac injury were observed in these MPH-exposed rats.

  2. No Increases in Biomarkers of Genetic Damage or Pathological Changes in Heart and Brain Tissues in Male Rats Administered Methylphenidate Hydrochloride (Ritalin) for 28 Days

    PubMed Central

    Witt, Kristine L.; Malarkey, David E.; Hobbs, Cheryl A.; Davis, Jeffrey P.; Kissling, Grace E.; Caspary, William; Travlos, Gregory; Recio, Leslie

    2009-01-01

    Following a 2005 report of chromosomal damage in children with attention deficit/hyperactivity disorder (ADHD) who were treated with the commonly prescribed medication methylphenidate (MPH), numerous studies have been conducted to clarify the risk for MPH-induced genetic damage. Although most of these studies reported no changes in genetic damage endpoints associated with exposure to MPH, one recent study (Andreazza et al. 2007) reported an increase in DNA damage detected by the Comet assay in blood and brain cells of Wistar rats treated by intraperitoneal injection with 1, 2, or 10 mg/kg MPH; no increases in micronucleated lymphocyte frequencies were observed in these rats. To clarify these findings, we treated adult male Wistar Han rats with 0, 2, 10, or 25 mg/kg MPH by gavage once daily for 28 consecutive days and measured micronucleated reticulocyte (MN-RET) frequencies in blood, and DNA damage in blood, brain, and liver cells 4 hr after final dosing. Flow cytometric evaluation of blood revealed no significant increases in MN-RET. Comet assay evaluations of blood leukocytes and cells of the liver, as well as of the striatum, hippocampus, and frontal cortex of the brain showed no increases in DNA damage in MPH-treated rats in any of the three treatment groups. Thus, the previously reported observations of DNA damage in blood and brain tissue of rats exposed to MPH for 28 days were not confirmed in this study. Additionally, no histopathological changes in brain or heart, or elevated serum biomarkers of cardiac injury were observed in these MPH-exposed rats. PMID:19634155

  3. Genetic determination of susceptibility to estrogen-induced mammary cancer in the ACI rat: mapping of Emca1 and Emca2 to chromosomes 5 and 18.

    PubMed

    Gould, Karen A; Tochacek, Martin; Schaffer, Beverly S; Reindl, Tanya M; Murrin, Clare R; Lachel, Cynthia M; VanderWoude, Eric A; Pennington, Karen L; Flood, Lisa A; Bynote, Kimberly K; Meza, Jane L; Newton, Michael A; Shull, James D

    2004-12-01

    Hormonal, genetic, and environmental factors play major roles in the complex etiology of breast cancer. When treated continuously with 17beta-estradiol (E2), the ACI rat exhibits a genetically conferred propensity to develop mammary cancer. The susceptibility of the ACI rat to E2-induced mammary cancer appears to segregate as an incompletely dominant trait in crosses to the resistant Copenhagen (COP) strain. In both (ACI x COP)F(2) and (COP x ACI)F(2) populations, we find strong evidence for a major genetic determinant of susceptibility to E2-induced mammary cancer on distal rat chromosome 5. Our data are most consistent with a model in which the ACI allele of this locus, termed Emca1 (estrogen-induced mammary cancer 1), acts in an incompletely dominant manner to increase both tumor incidence and tumor multiplicity as well as to reduce tumor latency in these populations. We also find evidence suggestive of a second locus, Emca2, on chromosome 18 in the (ACI x COP)F(2) population. The ACI allele of Emca2 acts in a dominant manner to increase incidence and decrease latency. Together, Emca1 and Emca2 act independently to modify susceptibility to E2-induced mammary cancer.

  4. Highly impulsive rats: modelling an endophenotype to determine the neurobiological, genetic and environmental mechanisms of addiction

    PubMed Central

    Jupp, Bianca; Caprioli, Daniele; Dalley, Jeffrey W.

    2013-01-01

    Impulsivity describes the tendency of an individual to act prematurely without foresight and is associated with a number of neuropsychiatric co-morbidities, including drug addiction. As such, there is increasing interest in the neurobiological mechanisms of impulsivity, as well as the genetic and environmental influences that govern the expression of this behaviour. Tests used on rodent models of impulsivity share strong parallels with tasks used to assess this trait in humans, and studies in both suggest a crucial role of monoaminergic corticostriatal systems in the expression of this behavioural trait. Furthermore, rodent models have enabled investigation of the causal relationship between drug abuse and impulsivity. Here, we review the use of rodent models of impulsivity for investigating the mechanisms involved in this trait, and how these mechanisms could contribute to the pathogenesis of addiction. PMID:23355644

  5. Genetic variants on rat chromosome 8 exhibit profound effects on hypertension severity and survival during nitric oxide inhibition in spontaneously hypertensive rats.

    PubMed

    Schulz, Angela; Schütten-Faber, Sabrina; Schulte, Leonard; Unland, Johannes; Kossmehl, Peter; Kreutz, Reinhold

    2014-03-01

    Hypertension and mortality is aggravated by nitric oxide inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME) in spontaneously hypertensive rats (SHRs) but not in Munich Wistar Frömter (MWF) rats. MWF rats carry major albuminuria quantitative trait loci on rat chromosome (RNO) 6 and RNO8; susceptibility of SHRs to L-NAME is enhanced by transfer of RNO6 from MWF rats into the SHR background. Here, we tested whether the sensitivity to L-NAME in SHRs is affected by transfer of RNO8 from MWF rats in consomic SHR-8(MWF) rats. In study 1, we analyzed survival in male SHR and SHR-8(MWF) rats in response to 18 weeks of treatment with either normal drinking water (vehicle-treated) or water containing 20mg/L L-NAME. In study 2, we analyzed blood pressure and renal damage in both strains in response to 6 weeks of treatment with L-NAME compared with vehicle-treated groups. In study 1, starting after 6 weeks of treatment with L-NAME, mortality reached 90% in SHRs in contrast with the group of L-NAME treated SHR-8(MWF) rats (P < 0.0001) in which all rats survived similar to vehicle-treated rats. In study 2, L-NAME resulted in a more pronounced increase in mean arterial blood pressures in SHRs compared with SHR-8(MWF) rats (216 ± 6 vs. 180 ± 11 mm Hg; P < 0.05). In contrast, tubulointerstitial kidney damage was even lower in SHRs compared with SHR-8(MWF) rats after L-NAME treatment (P < 0.05), whereas albuminuria was not different between strains. The blood pressure increase and impaired survival of SHRs in response to nitric oxide inhibition is profoundly influenced by genes on RNO8.

  6. Does arousal interfere with operant conditioning of spike-wave discharges in genetic epileptic rats?

    PubMed

    Osterhagen, Lasse; Breteler, Marinus; van Luijtelaar, Gilles

    2010-06-01

    One of the ways in which brain computer interfaces can be used is neurofeedback (NF). Subjects use their brain activation to control an external device, and with this technique it is also possible to learn to control aspects of the brain activity by operant conditioning. Beneficial effects of NF training on seizure occurrence have been described in epileptic patients. Little research has been done about differentiating NF effectiveness by type of epilepsy, particularly, whether idiopathic generalized seizures are susceptible to NF. In this experiment, seizures that manifest themselves as spike-wave discharges (SWDs) in the EEG were reinforced during 10 sessions in 6 rats of the WAG/Rij strain, an animal model for absence epilepsy. EEG's were recorded before and after the training sessions. Reinforcing SWDs let to decreased SWD occurrences during training; however, the changes during training were not persistent in the post-training sessions. Because behavioural states are known to have an influence on the occurrence of SWDs, it is proposed that the reinforcement situation increased arousal which resulted in fewer SWDs. Additional tests supported this hypothesis. The outcomes have implications for the possibility to train SWDs with operant learning techniques. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  7. Genetically mediated resistance to naturally occurring aortic sclerosis in spontaneously hypertensive as against Sprague-Dawley and Wistar-Kyoto breeder rats.

    PubMed Central

    Wexler, B. C.; McMurtry, J. P.

    1982-01-01

    Male and female, normotensive, Sprague-Dawley (S-D), Wistar-Kyoto (WKy), and spontaneously hypertensive rats (SHR) were bred repeatedly until the females had given birth to and nursed 6 litters of pups. At the close of the 2nd, 4th and 6th breeding, breeder males and females, along with celibate males and females of equal age, were killed. S-D and WKy breeder rats manifested progressively increasing adiposity and high blood pressure with each successive breeding; breeder SHR showed mild exacerbation of their pre-existing high blood pressure. Adrenocortical hyperplasia and thymus-gland involution suggested increasing pituitary-adrenal activity in breeder rats. Circulating aldosterone levels decreased with repeated breeding in parallel with increased deoxycorticosterone and corticosterone secretion. The repeatedly bred normotensive rats manifested worsening aortic sclerosis as against little or no aortic sclerosis in the repeatedly bred SHR. Breeder SHR developed fibrinohyalin intimal lesions limited exclusively to the arterioles of the testis and ovary. Virgin rats did not develop any vascular disease. It is suggested that a diverse spectrum of adrenal steroids in breeder HSR combined with genetic direction control the morphogenesis of arterial disease in breeder SHR. Images Fig. 8 Fig. 9 Fig. 6 Fig. 7 Fig. 10 Fig. 11 Fig. 12 PMID:7066185

  8. The importance of genetic background on pain behaviours and pharmacological sensitivity in the rat spared serve injury model of peripheral neuropathic pain.

    PubMed

    Rode, Frederik; Thomsen, Mads; Broløs, Tine; Jensen, Dorthe G; Blackburn-Munro, Gordon; Bjerrum, Ole J

    2007-06-14

    Neuropathic pain conditions can encompass a diverse constellation of signs and symptoms consisting of sensory deficits, allodynia and hyperalgesia. Animal models of neuropathic pain have enabled the identification of key pathophysiological changes occurring within nociceptive pathways as a result of injury, and serve an invaluable role for preclinical screening of novel analgesic candidates. We have produced the first systematic description of the development and maintenance, and the pharmacological sensitivity of nociceptive behaviours in four rat strains with different genetic background (outbred Sprague-Dawley and inbred Brown Norway, Lewis and Fischer 344 rats), using the spared nerve injury model of peripheral neuropathic pain. Hindpaw mechanical hypersensitivity was evident from 7 to 30 days post-injury in all four strains, developing most quickly and severely in Fischer 344 rats; Lewis rats were least affected. Morphine (6 but not 3 mg/kg, s.c.) and gabapentin (100 but not 50 mg/kg, s.c.) had significant antiallodynic and antihyperalgesic actions in all four strains after spared nerve injury, although marked differences in potency across strains were observed. Two strains (Fischer 344 rats and Lewis) were insensitive to the antihyperalgesic properties of gaboxadol (15 mg/kg) whereas gaboxadol (6 mg/kg) was equipotent to morphine (6 mg/kg) in two other strains (Sprague-Dawley and Brown Norway). The observed pharmacogenetic variations have important implications for the preclinical testing of drugs, and provide a basis for development of pharmacogenomics in neuropathic pain.

  9. Population genetics of Escherichia coli in a natural population of native Australian rats.

    PubMed

    Pupo, G M; Lan, R; Reeves, P R; Baverstock, P R

    2000-12-01

    Escherichia coli, a normal inhabitant of the intestinal tract of mammals and birds, is a diverse species. Most studies on E. coli populations involve organisms from humans or human-associated animals. In this study, we undertook a survey of E. coli from native Australian mammals, predominantly Rattus tunneyi, living in a relatively pristine environment in the Bundjalung National Park. The genetic diversity was assessed and compared by multilocus enzyme electrophoresis (MLEE), sequence analysis of the mdh (malate dehydrogenase) gene and biotyping using seven sugars. Ninety-nine electrophoretic types were identified from the 242 isolates analysed by MLEE and 15 sequences from the mdh genes sequenced from 21 representative strains. The Bundjalung isolates extend the diversity represented by the E. coli reference (ECOR) set, with new MLEE alleles found in six out of 10 loci. Many of the Bundjalung isolates fell into a discrete group in MLEE. Other Bundjalung strains fell into the recognized E. coli ECOR set groups, but tended to be at the base of both the MLEE and mdh gene trees, implying that these strains are derived independently from ancestral forms of the ECOR groups and that ECOR strains represent only a subset of E. coli adapted to humans and human-associated animals. Linkage disequilibrium analysis showed that the Bundjalung population has an 'epidemic' population structure. The Bundjalung isolates were able to utilize more sugars than the ECOR strains, suggesting that diet plays a prominent role in adaptation of E. coli.

  10. Transplants of cells genetically modified to express neurotrophin-3 rescue axotomized Clarke's nucleus neurons after spinal cord hemisection in adult rats.

    PubMed

    Himes, B T; Liu, Y; Solowska, J M; Snyder, E Y; Fischer, I; Tessler, A

    2001-09-15

    To test the idea that genetically engineered cells can rescue axotomized neurons, we transplanted fibroblasts and immortalized neural stem cells (NSCs) modified to express neurotrophic factors into the injured spinal cord. The neurotrophin-3 (NT-3) or nerve growth factor (NGF) transgene was introduced into these cells using recombinant retroviral vectors containing an internal ribosome entry site (IRES) sequence and the beta-galactosidase or alkaline phosphatase reporter gene. Bioassay confirmed biological activity of the secreted neurotrophic factors. Clarke's nucleus (CN) axons, which project to the rostral spinal cord and cerebellum, were cut unilaterally in adult rats by T8 hemisection. Rats received transplants of fibroblasts or NSCs genetically modified to express NT-3 or NGF and a reporter gene, only a reporter gene, or no transplant. Two months postoperatively, grafted cells survived at the hemisection site. Grafted fibroblasts and NSCs expressed a reporter gene and immunoreactivity for the NGF or NT-3 transgene. Rats receiving no transplant or a transplant expressing only a reporter gene showed a 30% loss of CN neurons in the L1 segment on the lesioned side. NGF-expressing transplants produced partial rescue compared with hemisection alone. There was no significant neuron loss in rats receiving grafts of either fibroblasts or NSCs engineered to express NT-3. We postulate that NT-3 mediates survival of CN neurons through interaction with trkC receptors, which are expressed on CN neurons. These results support the idea that NT-3 contributes to long-term survival of axotomized CN neurons and show that genetically modified cells rescue axotomized neurons as efficiently as fetal CNS transplants.

  11. Genetic Variation in Renal Expression of Folate Receptor 1 (Folr1) Gene Predisposes Spontaneously Hypertensive Rats to Metabolic Syndrome.

    PubMed

    Pravenec, Michal; Kožich, Viktor; Krijt, Jakub; Sokolová, Jitka; Zídek, Václav; Landa, Vladimír; Mlejnek, Petr; Šilhavý, Jan; Šimáková, Miroslava; Škop, Vojtěch; Trnovská, Jaroslava; Kazdová, Ludmila; Kajiya, Takashi; Wang, Jiaming; Kurtz, Theodore W

    2016-02-01

    Metabolism of homocysteine and other sulfur amino acids is closely associated with metabolism of folates. In this study, we analyzed the possible role of folates and sulfur amino acids in the development of features of the metabolic syndrome in the BXH/HXB recombinant inbred strains derived from the spontaneously hypertensive rat (SHR) and Brown Norway progenitors. We mapped a quantitative trait locus for cysteine concentrations to a region of chromosome 1 that contains a cis-acting expression quantitative trait locus regulating mRNA levels of folate receptor 1 (Folr1) in the kidney. Sequence analysis revealed a deletion variant in the Folr1 promoter region of the SHR. Transfection studies demonstrated that the SHR-promoter region of Folr1 is less effective in driving luciferase reporter gene expression than the Brown Norway promoter region of Folr1. Results in the SHR.BN-chr.1 congenic strain confirmed that the SHR variant in Folr1 cosegregates with markedly reduced renal expression of Folr1 and renal folate reabsorption, decreased serum levels of folate, increased serum levels of cysteine and homocysteine, increased adiposity, ectopic fat accumulation in liver and muscle, reduced muscle insulin sensitivity, and increased blood pressure. Transgenic rescue experiments performed by expressing a Folr1 transgene in the SHR ameliorated most of the metabolic disturbances. These findings are consistent with the hypothesis that inherited variation in the expression of Folr1 in the kidney influences the development of the metabolic syndrome and constitutes a previously unrecognized genetic mechanism that may contribute to increased risk for diabetes mellitus and cardiovascular disease.

  12. Will Climate Change, Genetic and Demographic Variation or Rat Predation Pose the Greatest Risk for Persistence of an Altitudinally Distributed Island Endemic?

    PubMed Central

    Simmons, Catherine Laura; Auld, Tony D.; Hutton, Ian; Baker, William J.; Shapcott, Alison

    2012-01-01

    Species endemic to mountains on oceanic islands are subject to a number of existing threats (in particular, invasive species) along with the impacts of a rapidly changing climate. The Lord Howe Island endemic palm Hedyscepe canterburyana is restricted to two mountains above 300 m altitude. Predation by the introduced Black Rat (Rattus rattus) is known to significantly reduce seedling recruitment. We examined the variation in Hedyscepe in terms of genetic variation, morphology, reproductive output and demographic structure, across an altitudinal gradient. We used demographic data to model population persistence under climate change predictions of upward range contraction incorporating long-term climatic records for Lord Howe Island. We also accounted for alternative levels of rat predation into the model to reflect management options for control. We found that Lord Howe Island is getting warmer and drier and quantified the degree of temperature change with altitude (0.9 °C per 100 m). For H. canterburyana, differences in development rates, population structure, reproductive output and population growth rate were identified between altitudes. In contrast, genetic variation was high and did not vary with altitude. There is no evidence of an upward range contraction as was predicted and recruitment was greatest at lower altitudes. Our models predicted slow population decline in the species and that the highest altitude populations are under greatest threat of extinction. Removal of rat predation would significantly enhance future persistence of this species. PMID:24832517

  13. The ketogenic diet has no effect on the expression of spike-and-wave discharges and nutrient transporters in genetic absence epilepsy rats from Strasbourg.

    PubMed

    Nehlig, Astrid; Dufour, Franck; Klinger, Marianne; Willing, Lisa B; Simpson, Ian A; Vannucci, Susan J

    2009-05-01

    The genetic absence epilepsy rat from Strasbourg is considered an isomorphic, predictive, and homologous model of typical childhood absence epilepsy. It is characterized by the expression of spike-and-wave discharges (SWDs) in the thalamus and cortex. The ketogenic diet (KD) is successfully used in humans and animals with various types of seizures, but was not effective in children with intractable atypical absence epilepsy. Here, we studied its potential impact on the occurrence of SWDs in genetic absence epilepsy rat from Strasbourg. Rats were fed the KD for 3 weeks during which they were regularly subjected to the electroencephalographic recording of SWDs. The KD did not influence the number and duration of SWDs despite a 15-22% decrease in plasma glucose levels and a large increase in beta-hydroxybutyrate levels. Likewise, the KD did not affect the level of expression of the blood-brain barrier glucose transporter GLUT1 or of the monocarboxylate transporters, MCT1 and MCT2. This report extends the observation in humans that the KD does not appear to show effectiveness in intractable atypical absence epilepsy to this model of typical childhood absence epilepsy which responds to specific antiepileptic drugs.

  14. Plasmid-based genetic modification of human bone marrow-derived stromal cells: analysis of cell survival and transgene expression after transplantation in rat spinal cord.

    PubMed

    Ronsyn, Mark W; Daans, Jasmijn; Spaepen, Gie; Chatterjee, Shyama; Vermeulen, Katrien; D'Haese, Patrick; Van Tendeloo, Viggo Fi; Van Marck, Eric; Ysebaert, Dirk; Berneman, Zwi N; Jorens, Philippe G; Ponsaerts, Peter

    2007-12-14

    Bone marrow-derived stromal cells (MSC) are attractive targets for ex vivo cell and gene therapy. In this context, we investigated the feasibility of a plasmid-based strategy for genetic modification of human (h)MSC with enhanced green fluorescent protein (EGFP) and neurotrophin (NT)3. Three genetically modified hMSC lines (EGFP, NT3, NT3-EGFP) were established and used to study cell survival and transgene expression following transplantation in rat spinal cord. First, we demonstrate long-term survival of transplanted hMSC-EGFP cells in rat spinal cord under, but not without, appropriate immune suppression. Next, we examined the stability of EGFP or NT3 transgene expression following transplantation of hMSC-EGFP, hMSC-NT3 and hMSC-NT3-EGFP in rat spinal cord. While in vivo EGFP mRNA and protein expression by transplanted hMSC-EGFP cells was readily detectable at different time points post-transplantation, in vivo NT3 mRNA expression by hMSC-NT3 cells and in vivo EGFP protein expression by hMSC-NT3-EGFP cells was, respectively, undetectable or declined rapidly between day 1 and 7 post-transplantation. Further investigation revealed that the observed in vivo decline of EGFP protein expression by hMSC-NT3-EGFP cells: (i) was associated with a decrease in transgenic NT3-EGFP mRNA expression as suggested following laser capture micro-dissection analysis of hMSC-NT3-EGFP cell transplants at day 1 and day 7 post-transplantation, (ii) did not occur when hMSC-NT3-EGFP cells were transplanted subcutaneously, and (iii) was reversed upon re-establishment of hMSC-NT3-EGFP cell cultures at 2 weeks post-transplantation. Finally, because we observed a slowly progressing tumour growth following transplantation of all our hMSC cell transplants, we here demonstrate that omitting immune suppressive therapy is sufficient to prevent further tumour growth and to eradicate malignant xenogeneic cell transplants. In this study, we demonstrate that genetically modified hMSC lines can survive

  15. Plasmid-based genetic modification of human bone marrow-derived stromal cells: analysis of cell survival and transgene expression after transplantation in rat spinal cord

    PubMed Central

    Ronsyn, Mark W; Daans, Jasmijn; Spaepen, Gie; Chatterjee, Shyama; Vermeulen, Katrien; D'Haese, Patrick; Van Tendeloo, Viggo FI; Van Marck, Eric; Ysebaert, Dirk; Berneman, Zwi N; Jorens, Philippe G; Ponsaerts, Peter

    2007-01-01

    Background Bone marrow-derived stromal cells (MSC) are attractive targets for ex vivo cell and gene therapy. In this context, we investigated the feasibility of a plasmid-based strategy for genetic modification of human (h)MSC with enhanced green fluorescent protein (EGFP) and neurotrophin (NT)3. Three genetically modified hMSC lines (EGFP, NT3, NT3-EGFP) were established and used to study cell survival and transgene expression following transplantation in rat spinal cord. Results First, we demonstrate long-term survival of transplanted hMSC-EGFP cells in rat spinal cord under, but not without, appropriate immune suppression. Next, we examined the stability of EGFP or NT3 transgene expression following transplantation of hMSC-EGFP, hMSC-NT3 and hMSC-NT3-EGFP in rat spinal cord. While in vivo EGFP mRNA and protein expression by transplanted hMSC-EGFP cells was readily detectable at different time points post-transplantation, in vivo NT3 mRNA expression by hMSC-NT3 cells and in vivo EGFP protein expression by hMSC-NT3-EGFP cells was, respectively, undetectable or declined rapidly between day 1 and 7 post-transplantation. Further investigation revealed that the observed in vivo decline of EGFP protein expression by hMSC-NT3-EGFP cells: (i) was associated with a decrease in transgenic NT3-EGFP mRNA expression as suggested following laser capture micro-dissection analysis of hMSC-NT3-EGFP cell transplants at day 1 and day 7 post-transplantation, (ii) did not occur when hMSC-NT3-EGFP cells were transplanted subcutaneously, and (iii) was reversed upon re-establishment of hMSC-NT3-EGFP cell cultures at 2 weeks post-transplantation. Finally, because we observed a slowly progressing tumour growth following transplantation of all our hMSC cell transplants, we here demonstrate that omitting immune suppressive therapy is sufficient to prevent further tumour growth and to eradicate malignant xenogeneic cell transplants. Conclusion In this study, we demonstrate that genetically

  16. Augmented agonist-induced Ca(2+)-sensitization of coronary artery contraction in genetically hypertensive rats. Evidence for altered signal transduction in the coronary smooth muscle cells.

    PubMed Central

    Satoh, S; Kreutz, R; Wilm, C; Ganten, D; Pfitzer, G

    1994-01-01

    The Ca2+ responsiveness of vascular smooth muscle myofilaments is not unique: it is increased during neuro-humoral activation and decreased during beta-adrenergic stimulation. In this study we tested whether an augmented Ca2+ responsiveness of smooth muscle myofilaments may contribute to the increased coronary tone observed in hypertension using beta-escin-permeabilized coronary arteries from 3-mo-old stroke-prone spontaneously hypertensive rats (SHRSP) and their age matched normotensive reference strain (WKY rats). In intact coronary arteries, the response to 5-hydroxytryptamine (5-HT) but not to KCl was larger in SHRSP than in WKY rats. In beta-escin permeabilized coronary arteries in which the receptor effector coupling is still intact, 5-HT enhanced force at constant submaximal (Ca2+) (pCa 6.38) to a greater extent in SHRSP. The Ca2+ sensitizing effect of 5-HT was mimicked by GTP gamma S (0.01-10 microM); again this effect was larger in SHRSP. In the absence of 5-HT or GTP gamma S the Ca2+ force relation was similar in both groups. Forskolin induced relaxation at constant submaximal (Ca2+). This desensitizing effect was smaller in SHRSP than in WKY rats. In conclusion, this study shows that intracellular signalling pathways involved in modulating the Ca2+ responsiveness of coronary smooth muscle myofilaments are altered in the genetically hypertensive animals favoring a hypercontractile state in the coronary circulation. PMID:7929815

  17. Genetic obestiy: estrogenic influences on the body weight and food intake of lean and obese adult Zucker (fa/fa) rats.

    PubMed

    Gale, S K; Van Itallie, T B

    1979-07-01

    The effects of chronic estrogen withdrawal and subsequent hormone replacement on the feeding and body weight of adult lean and genetically obese Zucker rats were investigated. Following confirmation of a delay in the vaginal canalization of the fatty rat, subgroups of each genotype received either ovariectomy or sham surgery (Experiment 1). One hundred days later all subjects were injected subcutaneously (SC) with 1.0 microgram of estradiol benzoate (EB) daily for 16 treatment days (Experiment 2A). A second series of daily 2.0 microgram EB injections was administered intraperitoneally (IP) for 1 week (Experiment 2B). The first experiment revealed that ovariectomy produced overeating and similar weight gains in both genotypes. In the second experiment, SC hormone treatment completely reversed ovarian obesity in lean animals but failed to alter the food intake or weight gain of fatty rats. IP administration of EB depressed the feeding of fatty and lean animals to a comparable degree but a reduction in weight gain was observed only in the lean rats. These findings are discussed in light of current theories of estrogenic modulation of energy balance.

  18. Positional cloning of the nude locus: Genetic, physical, and transcription maps of the region and mutations in the mouse and rat

    SciTech Connect

    Segre, J.A.; Lander, E.S. |; Taylor, B.A.

    1995-08-10

    Mutations in the nude locus in mice and rats produce the pleiotropic phenotype of hairlessness and athymia, resulting in severely compromised immune system. To identify the causative gene, we utilized modern tools and techniques of positional cloning. Specifically, spanning the region in which the nude locus resides, we constructed a genetic map of polymorphic markers, a physical map of yeast artificial chromosomes and bacteriophage P1 clones, and a transcription map of genes obtained by direct cDNA selection and exon trapping. We identified seven novel transcripts with similarity to genes from Drosophila, Caenorhabditis elegans, rat or human and three previously identified mouse genes. Based on our transcription mapping results, we present a novel approach to estimate that the nude locus resides in a region approximately threefold enriched for genes. We confirm a recently published report that the nude phenotype is caused by mutations in a gene encoding a novel winged helix or fork head domain transcription factor, whn. We report as well as the mutations in the rat rnu allele and the complete coding sequence of the rat whn mRNA. 42 refs., 4 figs., 1 tab.

  19. Antinociceptive Effect of Intrathecal Injection of Genetically Engineered Human Bone Marrow Stem Cells Expressing the Human Proenkephalin Gene in a Rat Model of Bone Cancer Pain

    PubMed Central

    Tian, Yuke; Li, Haifeng; Zhang, Dengwen; Sun, Qiang

    2017-01-01

    Background. This study aimed to investigate the use of human bone marrow mesenchymal stem cells (hBMSCs) genetically engineered with the human proenkephalin (hPPE) gene to treat bone cancer pain (BCP) in a rat model. Methods. Primary cultured hBMSCs were passaged and modified with hPPE, and the cell suspensions (6 × 106) were then intrathecally injected into a rat model of BCP. Paw mechanical withdrawal threshold (PMWT) was measured before and after BCP. The effects of hPPE gene transfer on hBMSC bioactivity were analyzed in vitro and in vivo. Results. No changes were observed in the surface phenotypes and differentiation of hBMSCs after gene transfer. The hPPE-hBMSC group showed improved PMWT values on the ipsilateral side of rats with BCP from day 12 postoperatively, and the analgesic effect was reversed by naloxone. The levels of proinflammatory cytokines such as IL-1β and IL-6 were ameliorated, and leucine-enkephalin (L-EK) secretion was augmented, in the hPPE-engineered hBMSC group. Conclusion. The intrathecal administration of BMSCs modified with the hPPE gene can effectively relieve pain caused by bone cancer in rats and might be a potentially therapeutic tool for cancer-related pain in humans. PMID:28286408

  20. The Genetic Absence Epilepsy Rats from Strasbourg model of absence epilepsy exhibits alterations in fear conditioning and latent inhibition consistent with psychiatric comorbidities in humans.

    PubMed

    Marks, Wendie N; Cavanagh, Mary E; Greba, Quentin; Cain, Stuart M; Snutch, Terrance P; Howland, John G

    2016-01-01

    Behavioural, neurological, and genetic similarities exist in epilepsies, their psychiatric comorbidities, and various psychiatric illnesses, suggesting common aetiological factors. Rodent models of epilepsy are used to characterize the comorbid symptoms apparent in epilepsy and their neurobiological mechanisms. The present study was designed to assess Pavlovian fear conditioning and latent inhibition in a polygenetic rat model of absence epilepsy, i.e. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and the non-epileptic control (NEC) strain. Electrophysiological recordings confirmed the presence of spike-wave discharges in young adult GAERS but not NEC rats. A series of behavioural tests designed to assess anxiety-like behaviour (elevated plus maze, open field, acoustic startle response) and cognition (Pavlovian conditioning and latent inhibition) was subsequently conducted on male and female offspring. Results showed that GAERS exhibited significantly higher anxiety-like behaviour, a characteristic reported previously. In addition, using two protocols that differed in shock intensity, we found that both sexes of GAERS displayed exaggerated cued and contextual Pavlovian fear conditioning and impaired fear extinction. Fear reinstatement to the conditioned stimuli following unsignalled footshocks did not differ between the strains. Male GAERS also showed impaired latent inhibition in a paradigm using Pavlovian fear conditioning, suggesting that they may have altered attention, particularly related to previously irrelevant stimuli in the environment. Neither the female GAERS nor NEC rats showed evidence of latent inhibition in our paradigm. Together, the results suggest that GAERS may be a particularly useful model for assessing therapeutics designed to improve the emotional and cognitive disturbances associated with absence epilepsy.

  1. The effect of lentivirus-mediated TH and GDNF genetic engineering mesenchymal stem cells on Parkinson's disease rat model.

    PubMed

    Shi, Dezhi; Chen, Gong; Lv, Li; Li, Lixin; Wei, Dong; Gu, Peiyuan; Gao, Juemin; Miao, Yi; Hu, Weixing

    2011-02-01

    This study was designed to assess the potential therapeutic efficacy of gene-modified mesenchymal stem cells (MSCs), MSCs-TH and MSCs-GDNF, in PD rats. Fifty-nine PD rat models were divided into five groups and then the gene-modified MSCs were transplanted into the striatum of rats according to the design. Apomorphine-induced rotational behavior in rats was observed weekly; rats which received both MSCs-TH and MSCs-GDNF showed the most significant improvement compared with those in other groups (P < 0.01). Three weeks later, immunohistochemistry analysis found TH-positive cells and GDNF-positive cells in striatal. Eight weeks later, PD rats were killed. HPLC and ELISA results showed DA and GDNF content in striatum of rats which received both MSCs-TH, and MSCs-GDNF was considerably higher compared with those of other groups (P < 0.01),respectively. In conclusion, our results suggest that combined transplantation of MSCs expressing TH and GDNF can lead to remarkable therapeutic effects in a rat model of PD.

  2. Varenicline decreases nicotine but not alcohol self-administration in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats

    PubMed Central

    Scuppa, Giulia; Cippitelli, Andrea; Toll, Lawrence; Ciccocioppo, Roberto; Ubaldi, Massimo

    2015-01-01

    Background Alcohol and nicotine are largely co-abused. Here, we investigated whether concurrent exposure to both addictive drugs influences each other’s consumption and whether varenicline attenuates alcohol consumption in the presence of nicotine. Methods Marchigian Sardinian alcohol-preferring (msP) rats trained to simultaneously self-administer oral alcohol (10% v/v) and intravenous nicotine (30 μg/kg/inf.) were used. Additional groups of rats were trained to self-administer either alcohol or nicotine. Further, msP rats were also trained to self-administer nicotine followed by 22-h/day access to alcohol and water in a two bottle free choice paradigm or water alone. The effects of varenicline (0.0, 0.3, 1.0, 3.0 mg/kg, p.o.) on alcohol and nicotine consumption was tested. Results In a self-administration paradigm, msP rats showed a significantly high levels of alcohol and nicotine intake when the drugs were administered alone. However, when access to both drugs occurred concomitantly, the number of nicotine infusions self-administered was significantly decreased. Nicotine self-administration was markedly reduced by varenicline regardless of whether it was self-administered alone or concurrently with alcohol. In a two bottle choice test, varenicline significantly decreased nicotine self-administration but had no influence on alcohol consumption. Conclusion Varenicline is highly efficacious in decreaasing nicotine self-administration either alone or in combination with alcohol. However, varenicline failed to influence both operant responding for alcohol and home-cage alcohol drinking in msP animals. Taken together, our findings suggest that the effects of varenicline could be specific to nicotine under conditions where excessive alcohol drinking is facilitated by genetic factors as in msP rats. PMID:26383997

  3. 1,25(OH)₂D₃-enhanced hypercalciuria in genetic hypercalciuric stone-forming rats fed a low-calcium diet.

    PubMed

    Frick, Kevin K; Asplin, John R; Krieger, Nancy S; Culbertson, Christopher D; Asplin, Daniel M; Bushinsky, David A

    2013-10-15

    The inbred genetic hypercalciuric stone-forming (GHS) rats exhibit many features of human idiopathic hypercalciuria and have elevated levels of vitamin D receptors (VDR) in calcium (Ca)-transporting organs. On a normal-Ca diet, 1,25(OH)2D3 (1,25D) increases urine (U) Ca to a greater extent in GHS than in controls [Sprague-Dawley (SD)]. The additional UCa may result from an increase in intestinal Ca absorption and/or bone resorption. To determine the source, we asked whether 1,25D would increase UCa in GHS fed a low-Ca (0.02%) diet (LCD). With 1,25D, UCa in SD increased from 1.2 ± 0.1 to 9.3 ± 0.9 mg/day and increased more in GHS from 4.7 ± 0.3 to 21.5 ± 0.9 mg/day (P < 0.001). In GHS rats on LCD with or without 1,25D, UCa far exceeded daily Ca intake (2.6 mg/day). While the greater excess in UCa in GHS rats must be derived from bone mineral, there may also be a 1,25D-mediated decrease in renal tubular Ca reabsorption. RNA expression of the components of renal Ca transport indicated that 1,25D administration results in a suppression of klotho, an activator of the renal Ca reabsorption channel TRPV5, in both SD and GHS rats. This fall in klotho would decrease tubular reabsorption of the 1,25D-induced bone Ca release. Thus, the greater increase in UCa with 1,25D in GHS fed LCD strongly suggests that the additional UCa results from an increase in bone resorption, likely due to the increased number of VDR in the GHS rat bone cells, with a possible component of decreased renal tubular calcium reabsorption.

  4. Systems-level approaches reveal conservation of trans-regulated genes in the rat and genetic determinants of blood pressure in humans

    PubMed Central

    Langley, Sarah R.; Bottolo, Leonardo; Kunes, Jaroslav; Zicha, Josef; Zidek, Vaclav; Hubner, Norbert; Cook, Stuart A.; Pravenec, Michal; Aitman, Timothy J.; Petretto, Enrico

    2013-01-01

    Aims Human genome-wide association studies (GWAS) of hypertension identified only few susceptibility loci with large effect that were replicated across populations. The vast majority of genes detected by GWAS has small effect and the regulatory mechanisms through which these genetic variants cause disease remain mostly unclear. Here, we used comparative genomics between human and an established rat model of hypertension to explore the transcriptional mechanisms mediating the effect of genes identified in 15 hypertension GWAS. Methods and results Time series analysis of radiotelemetric blood pressure (BP) was performed to assess 11 parameters of BP variation in recombinant inbred strains derived from the spontaneously hypertensive rat. BP data were integrated with ∼27 000 expression quantative trait loci (eQTLs) mapped across seven tissues, detecting >8000 significant associations between eQTL genes and BP variation in the rat. We then compiled a large catalogue of human genes from GWAS of hypertension and identified a subset of 2292 rat–human orthologous genes. Expression levels for 795 (34%) of these genes correlated with BP variation across rat tissues: 51 genes were cis-regulated, whereas 459 were trans-regulated and enriched for ‘calcium signalling pathway’ (P = 9.6 × 10−6) and ‘ion channel’ genes (P = 3.5 × 10−7), which are important determinants of hypertension. We identified 158 clusters of trans-eQTLs, annotated the underlying ‘master regulator’ genes and found significant over-representation in the human hypertension gene set (enrichment P = 5 × 10−4). Conclusion We showed extensive conservation of trans-regulated genes and their master regulators between rat and human hypertension. These findings reveal that small-effect genes associated with hypertension by human GWAS are likely to exert their action through coordinate regulation of pathogenic pathways. PMID:23118132

  5. A developmental study of glutamatergic neuron populations in the ventrobasal and the lateral geniculate nucleus of the thalamus: Comparing Genetic Absence Rats from Strasbourg (GAERS) and normal control wistar rats.

    PubMed

    Kirazlı, Özlem; Çavdar, Safiye; Yıldızel, Sercan; Onat, Filiz; Kaptanoğlu, Erkan

    2017-02-01

    An imbalance of GABAergic inhibition and glutamatergic excitation is suspected to be the cause of absence epileptic seizures. Absence seizures are known to be generated in thalamocortical circuitry. In the present study we used light microscopy immunohistochemistry to quantify the density of glutamate+ve neurons at two developmental stages (P10 and P60) in two thalamic nuclei, the ventrobasal (VB) and lateral geniculate nucleus (LGN) in Wistar rats and compared the results with similar data obtained from genetic absence epilepsy rats from Strasbourg (GAERS). Rats were perfused transcardially with glutaraldehyde and paraformaldehyde fixative, then samples from VB and LGN were removed from each animal and sectioned. The glutamatergic neurons were labelled using light-microscopic glutamate immunohistochemistry. The disector method was used to quantify the glutamate+ve neurons in VB and LGN of GAERS and Wistar rats. The data were statistically analyzed. The distribution of the glutamate+ve neurons in the VB thalamic nucleus showed a significant reduction in the neuronal profiles per unit thalamic area from P10 to P60 in both Wistar and GAERS. The decrease was greater in the GAERS compared to the Wistar animals. However, in the LGN no reduction was observed either in the Wistar or in the GAERS. Comparing the density of glutamate+ve neurons in the VB thalamic nucleus of P10 of Wistar animals with of P10 GAERS showed statistically significant greater densities of these neurons in GAERS than in the Wistar rats. However no significant difference was present at P60 between the Wistar and GAERS animals. The disproportional decrease in GAERS may be related to the onset of absence seizures or may be related to neurogenesis of absence epilepsy.

  6. Basal and Activated Calcium Sensitization Mediated by RhoA/Rho Kinase Pathway in Rats with Genetic and Salt Hypertension

    PubMed Central

    Bencze, Michal; Vaněčková, Ivana; Kuneš, Jaroslav; Zicha, Josef

    2017-01-01

    Calcium sensitization mediated by RhoA/Rho kinase pathway can be evaluated either in the absence (basal calcium sensitization) or in the presence of endogenous vasoconstrictor systems (activated calcium sensitization). Our aim was to compare basal and activated calcium sensitization in three forms of experimental hypertension with increased sympathetic tone and enhanced calcium entry—spontaneously hypertensive rats (SHR), heterozygous Ren-2 transgenic rats (TGR), and salt hypertensive Dahl rats. Activated calcium sensitization was determined as blood pressure reduction induced by acute administration of Rho kinase inhibitor fasudil in conscious rats with intact sympathetic nervous system (SNS) and renin-angiotensin system (RAS). Basal calcium sensitization was studied as fasudil-dependent difference in blood pressure response to calcium channel opener BAY K8644 in rats subjected to RAS and SNS blockade. Calcium sensitization was also estimated from reduced development of isolated artery contraction by Rho kinase inhibitor Y-27632. Activated calcium sensitization was enhanced in all three hypertensive models (due to the hyperactivity of vasoconstrictor systems). In contrast, basal calcium sensitization was reduced in SHR and TGR relative to their controls, whereas it was augmented in salt-sensitive Dahl rats relative to their salt-resistant controls. Similar differences in calcium sensitization were seen in femoral arteries of SHR and Dahl rats. PMID:28197417

  7. Basal and Activated Calcium Sensitization Mediated by RhoA/Rho Kinase Pathway in Rats with Genetic and Salt Hypertension.

    PubMed

    Behuliak, Michal; Bencze, Michal; Vaněčková, Ivana; Kuneš, Jaroslav; Zicha, Josef

    2017-01-01

    Calcium sensitization mediated by RhoA/Rho kinase pathway can be evaluated either in the absence (basal calcium sensitization) or in the presence of endogenous vasoconstrictor systems (activated calcium sensitization). Our aim was to compare basal and activated calcium sensitization in three forms of experimental hypertension with increased sympathetic tone and enhanced calcium entry-spontaneously hypertensive rats (SHR), heterozygous Ren-2 transgenic rats (TGR), and salt hypertensive Dahl rats. Activated calcium sensitization was determined as blood pressure reduction induced by acute administration of Rho kinase inhibitor fasudil in conscious rats with intact sympathetic nervous system (SNS) and renin-angiotensin system (RAS). Basal calcium sensitization was studied as fasudil-dependent difference in blood pressure response to calcium channel opener BAY K8644 in rats subjected to RAS and SNS blockade. Calcium sensitization was also estimated from reduced development of isolated artery contraction by Rho kinase inhibitor Y-27632. Activated calcium sensitization was enhanced in all three hypertensive models (due to the hyperactivity of vasoconstrictor systems). In contrast, basal calcium sensitization was reduced in SHR and TGR relative to their controls, whereas it was augmented in salt-sensitive Dahl rats relative to their salt-resistant controls. Similar differences in calcium sensitization were seen in femoral arteries of SHR and Dahl rats.

  8. Degradation of endogenous bacterial cell wall polymers by the muralytic enzyme mutanolysin prevents hepatobiliary injury in genetically susceptible rats with experimental intestinal bacterial overgrowth.

    PubMed Central

    Lichtman, S N; Okoruwa, E E; Keku, J; Schwab, J H; Sartor, R B

    1992-01-01

    Jejunal self-filling blind loops with subsequent small bowel bacterial overgrowth (SBBO) induce hepatobiliary injury in genetically susceptible Lewis rats. Lesions consist of portal tract inflammation, bile duct proliferation, and destruction. To determine the pathogenesis of SBBO-induced hepatobiliary injury, we treated Lewis rats with SBBO by using several agents with different mechanisms of activity. Buffer treatment, ursodeoxycholic acid, prednisone, methotrexate, and cyclosporin A failed to prevent SBBO-induced injury as demonstrated by increased plasma aspartate aminotransferase (AST) and elevated histology scores. However, hepatic injury was prevented by mutanolysin, a muralytic enzyme whose only known activity is to split the beta 1-4 N-acetylmuramyl-N-acetylglucosamine linkage of peptidoglycan-polysaccharide (PG-PS), a bacterial cell wall polymer with potent inflammatory and immunoregulatory properties. Mutanolysin therapy started on the day blind loops were surgically created and continued for 8 wk significantly diminished AST (101 +/- 37 U/liter) and liver histology scores (2.2 +/- 2.7) compared to buffer-treated rats (228 +/- 146 U/liter, P < 0.05, 8.2 +/- 1.9, P < 0.001 respectively). Mutanolysin treatment started during the early phase of hepatic injury, 16-21 d after surgery, decreased AST in 7 of 11 rats from 142 +/- 80 to 103 +/- 24 U/liter contrasted to increased AST in 9 of 11 buffer-treated rats from 108 +/- 52 to 247 +/- 142 U/liter, P < 0.05. Mutanolysin did not change total bacterial numbers within the loop, eliminate Bacteroides sp., have in vitro antibiotic effects, or diminish mucosal PG-PS transport. However, mutanolysin treatment prevented elevation of plasma anti-PG antibodies and tumor necrosis factor-alpha (TNF alpha) levels which occurred in buffer treated rats with SBBO and decreased TNF alpha production in isolated Kupffer cells stimulated in vitro with PG-PS. Based on the preventive and therapeutic activity of this highly specific

  9. A 90-day safety study of genetically modified rice expressing rhIGF-1 protein in C57BL/6J rats.

    PubMed

    Tang, Maoxue; Xie, Tingting; Cheng, Wenke; Qian, Lili; Yang, Shulin; Yang, Daichang; Cui, Wentao; Li, Kui

    2012-06-01

    Genetically modified plants expressing disease resistance traits offer new treatment strategies for human diseases, but at the same time present a challenge in terms of food safety assessment. The present 90-day feeding study was designed to assess the safety of transgenic rice expressing the recombinant human insulin-like growth factor-1 (rhIGF-1) compared to its parental wild rice. Male and female C57BL/6J rats were given a nutritionally balanced purified diet with 20% transgenic rhIGF-1 rice or 20% parental rice for 90 days. This corresponds to a mean daily rhIGF-1 protein intake of approximately 217.6 mg/kg body weight based on the average feed consumption. In the animal study a range of biological, biochemical, clinical, microbiological and pathological parameters were examined and several significant differences were observed between groups, but none of the effects were considered to be adverse. In conclusion, no adverse or toxic effects on C57BL/6J rats were observed in the design used in this 90-day study. These results will provide valuable information for the safety assessment of genetically modified food crops.

  10. Identification of Genetic Loci Affecting the Severity of Symptoms of Hirschsprung Disease in Rats Carrying Ednrbsl Mutations by Quantitative Trait Locus Analysis

    PubMed Central

    Torigoe, Daisuke; Lei, Chuzhao; Lan, Xianyong; Chen, Hong; Sasaki, Nobuya; Wang, Jinxi; Agui, Takashi

    2015-01-01

    Hirschsprung’s disease (HSCR) is a congenital disease in neonates characterized by the absence of the enteric ganglia in a variable length of the distal colon. This disease results from multiple genetic interactions that modulate the ability of enteric neural crest cells to populate developing gut. We previously reported that three rat strains with different backgrounds (susceptible AGH-Ednrbsl/sl, resistant F344-Ednrbsl/sl, and LEH-Ednrbsl/sl) but the same null mutation of Ednrb show varying severity degrees of aganglionosis. This finding suggests that strain-specific genetic factors affect the severity of HSCR. Consistent with this finding, a quantitative trait locus (QTL) for the severity of HSCR on chromosome (Chr) 2 was identified using an F2 intercross between AGH and F344 strains. In the present study, we performed QTL analysis using an F2 intercross between the susceptible AGH and resistant LEH strains to identify the modifier/resistant loci for HSCR in Ednrb-deficient rats. A significant locus affecting the severity of HSCR was also detected within the Chr 2 region. These findings strongly suggest that a modifier gene of aganglionosis exists on Chr 2. In addition, two potentially causative SNPs (or mutations) were detected upstream of a known HSCR susceptibility gene, Gdnf. These SNPs were possibly responsible for the varied length of gut affected by aganglionosis. PMID:25790447

  11. Loss of calcitonin receptors: A genetically transmitted defect in rats with high incidence of C-cell tumors

    SciTech Connect

    Bouizar, Z.; Minvielle, S.; Treilhou-Lahille, F.; Rostene, W.H.; Pidoux, E.; Feingold, N.; Milhaud, G.; Moukhtar, M.S. )

    1989-09-15

    C-cell tumors (medullary thyroid carcinoma) occur in humans and several other mammalian species. This tumor develops spontaneously with a high incidence (50%) in old Wag/Rij (Wistar-derived strain) rats. We have recently shown that calcitonin binding sites, which are present in the Wistar rats, are lost from renal medulla of the Wag/Rij rats before they reach the age of 1 month. In the present work, we investigated the distribution of calcitonin binding sites in the kidneys of first and second generation hybrids of Wistar x Wag/Rij rats. The absence of calcitonin binding sites from the renal medullas of 25% of F2 hybrids indicates that the deficiency is inherited in a Mendelian fashion and opens the way to establishing inbred strains lacking renal medullary calcitonin binding sites.

  12. Subchronic feeding study of stacked trait genetically-modified soybean (3Ø5423 × 40-3-2) in Sprague-Dawley rats.

    PubMed

    Qi, Xiaozhe; He, Xiaoyun; Luo, Yunbo; Li, Shuangying; Zou, Shiying; Cao, Sishuo; Tang, Maozhi; Delaney, Bryan; Xu, Wentao; Huang, Kunlun

    2012-09-01

    The genetically-modified (GM) soybean 3Ø5423 × 40-3-2 expresses siRNA for the fatty acid desaturase-2 enzyme which results in higher concentrations of oleic acid (18:1) relative to linoleic acid (18:2) compared with non-GM soybeans. It also expresses the CP4 EPSPS protein for tolerance to glyphosate. In this study, three different dietary concentrations (7.5%, 15% and 30% wt/wt) of 3Ø5423 × 40-3-2 or non-GM soybeans were fed to Sprague-Dawley rats for 90 days during which in-life nutritional and growth performance variables were evaluated followed by analysis of standard clinical chemistry, hematology and organ variables. Compared with rats fed the non-GM control diet, some statistically significant differences were observed in rats fed the 3Ø5423 × 40-3-2 diet. However the differences were not considered treatment-related and commonly fell within the normal ranges of the control group consuming the commercial diet. These results demonstrated that the GM soybean 3Ø5423 × 40-3-2 is as safe as non-GM soybeans.

  13. Genetic isolation of a region of chromosome 8 that exerts major effects on blood pressure and cardiac mass in the spontaneously hypertensive rat.

    PubMed Central

    Kren, V; Pravenec, M; Lu, S; Krenova, D; Wang, J M; Wang, N; Merriouns, T; Wong, A; St Lezin, E; Lau, D; Szpirer, C; Szpirer, J; Kurtz, T W

    1997-01-01

    The spontaneously hypertensive rat (SHR) is the most widely studied animal model of essential hypertension. Despite > 30 yr of research, the primary genetic lesions responsible for hypertension in the SHR remain undefined. In this report, we describe the construction and hemodynamic characterization of a congenic strain of SHR (SHR-Lx) that carries a defined segment of chromosome 8 from a normotensive strain of Brown-Norway rats (BN-Lx strain). Transfer of this segment of chromosome 8 from the BN-Lx strain onto the SHR background resulted in substantial reductions in systolic and diastolic blood pressure and cardiac mass. Linkage and comparative mapping studies indicate that the transferred chromosome segment contains a number of candidate genes for hypertension, including genes encoding a brain dopamine receptor and a renal epithelial potassium channel. These findings demonstrate that BP regulatory gene(s) exist within the differential chromosome segment trapped in the SHR-Lx congenic strain and that this region of chromosome 8 plays a major role in the hypertension of SHR vs. BN-Lx rats. PMID:9045857

  14. Local and systemic responses following intravitreous injection of AAV2-encoded modified Volvox channelrhodopsin-1 in a genetically blind rat model.

    PubMed

    Sugano, E; Tabata, K; Takahashi, M; Nishiyama, F; Shimizu, H; Sato, M; Tamai, M; Tomita, H

    2016-02-01

    We previously designed a modified channelrhodopsin-1 (mVChR1) protein chimera with a broader action than that of Chlamydomonas channelrhodopsin-2 and reported that its transduction into retinal ganglion cells can restore visual function in genetically blind, dystrophic Royal College of Surgeons (RCS) rats, with photostimuli ranging from 486 to 640 nm. In the current study, we sought to investigate the safety and influence of mVChR1 transgene expression. Adeno-associated virus type 2 encoding mVChR1 was administered by intravitreous injection into dystrophic RCS rats. Reverse-transcription PCR was used to monitor virus and transgene dissemination and the results demonstrated that their expression was restricted specifically within the eye tissues, and not in non-target organs. Moreover, examination of the blood, plasma and serum revealed that no excess immunoreactivity was present, as determined using standard clinical hematological parameters. Serum antibodies targeting the recombinant adeno-associated virus (rAAV) capsid increased after the injection; however, no increase in mVChR1 antibody was detected during the observation period. In addition, retinal histological examination showed no signs of inflammation in rAAV-injected rats. In conclusion, our results demonstrate that mVChR1 can be exogenously expressed without harmful immunological reactions in vivo. These findings will aid in studies of AAV gene transfer to restore vision in late-stage retinitis pigmentosa.

  15. Evaluation of GAD67 immunoreactivity in the region of substantia nigra pars reticulata in resistance to development of convulsive seizure in genetic absence epilepsy rats

    PubMed Central

    Gulcebi, Medine; Akman, Ozlem; Carcak, Nihan; Karamahmutoglu, Tugba; Onat, Filiz

    2016-01-01

    OBJECTIVE: Nonconvulsive absence epilepsy and convulsive epilepsy seizures are rarely seen in the same patient. It has been demonstrated that there is a resistance to development of convulsive seizures in genetic absence epilepsy models. The present study investigated glutamic acid decarboxylase (GAD) immunoreactivity in the brain region related to the interaction of these two seizure types, namely substantia nigra pars reticulata (SNR) subregions, SNRanterior and SNRposterior. METHODS: Nonepileptic adult male Wistar rats and Genetic Absence Epilepsy Rats from Strasbourg (GAERS) were used. Experimental groups of Wistar and GAERS were electrically stimulated for kindling model to induce convulsive epileptic seizures. An electrical stimulation cannula was stereotaxically implanted to the basolateral amygdala and recording electrodes were placed on the cortex. Sagittal sections of SNR were used to evaluate immunohistochemical reaction. Sections were incubated with anti-GAD67 antibody. Densitometric analysis of GAD67 immunoreactive neurons was performed using photographs of stained sections. One-way analysis of variance and post hoc Bonferroni test were used for statistical analysis of the data. RESULTS: There was no difference in GAD67 immunoreactivity of SNR subregions of control Wistar and control GAERS. An increase in GAD67 immunoreactivity was detected in SNRposterior subregion of stimulated Wistar rats, whereas there was a decrease in GAD67 immunoreactivity in SNRposterior of stimulated GAERS. The difference in GAD67 immunoreactivity between these two groups was statistically significant. CONCLUSION: Level of synthetized gamma-aminobutyric acid in SNRposterior subregion plays an important role in the interaction of nonconvulsive absence epilepsy seizures and convulsive epilepsy seizures. PMID:28275746

  16. The feeding value of soybeans fed to rats, chickens, catfish and dairy cattle is not altered by genetic incorporation of glyphosate tolerance.

    PubMed

    Hammond, B G; Vicini, J L; Hartnell, G F; Naylor, M W; Knight, C D; Robinson, E H; Fuchs, R L; Padgette, S R

    1996-03-01

    Animal feeding studies were conducted with rats, broiler chickens, catfish and dairy cows as part of a safety assessment program for a soybean variety genetically modified to tolerate in-season application of glyphosate. These studies were designed to compare the feeding value (wholesomeness) of two lines of glyphosate-tolerant soybeans (GTS) to the feeding value of the parental cultivar from which they were derived. Processed GTS meal was incorporated into the diets at the same concentrations as used commercially; diary cows were fed 10 g/100 g cracked soybeans in the diet, a level that is on the high end of what is normally fed commercially. In a separate study, laboratory rats were fed 5 and 10 g unprocessed soybean meal 100 g diet. The study durations were 4 wk (rats and dairy cows), 6 wk (broilers) and 10 wk (catfish). Growth, feed conversion (rats, catfish, broilers), fillet composition (catfish), and breast muscle and fat pad weights (broilers) were compared for animals fed the parental and GTS lines. Milk production, milk composition, rumen fermentation and nitrogen digestibility were also compared for dairy cows. In all studies, measured variables were similar for animals fed both GTS lines and the parental line, indicating that the feeding value of the two GTS lines is comparable to that of the parental line. These studies support detailed compositional analysis of the GTS seeds, which showed no meaningful differences between the parental and GTS lines in the concentrations of important nutrients and antinutrients. They also confirmed the results of other studies that demonstrated the safety of the introduced protein, a bacterial 5-enolpyruvyl-shikimate-3-phosphate synthase from Agrobacterium sp. strain CP4.

  17. Dietary effects of Raphanus sativus cv Sango on lipid and oxysterols accumulation in rat brain: A lipidomic study on a non-genetic obesity model.

    PubMed

    Cardenia, Vladimiro; Vivarelli, Fabio; Cirillo, Silvia; Paolini, Moreno; Rodriguez-Estrada, Maria Teresa; Canistro, Donatella

    2017-10-01

    The present study aimed to evaluate the impact of Raphanus sativus cv Sango sprout juice (SSJ) administration (75mg/kg b.w. SSJ/day) on the brain lipidomic profile (fatty acid, sterols, cholesterol oxidation) of rats (non-genetic model) subjected to a high-fat (34% crude fat) dietary regimen. The SSJ did not affect the lipid infiltration (7.7-9.3%) and the fatty acid composition of the rat brain, which was mainly composed by unsaturated fatty acids (∼58%); however, the high-fat diet regimen significantly halved linoleic acid (LA). The high-fat diet also decreased (21.13mg/g) the level of brain cholesterol with respect to the regular diet (4.5% crude fat) (23.83mg/g); however, when the diet was shifted from high-fat to a regular regimen with or without SSJ supplementation, the levels of cholesterol significantly (p <0.05) increased up to 30.46mg/g of brain. The main oxysterols were 24(S)-hydroxycholesterol (24(S)-HC) and β-epoxycholesterol (β-EC). The high-fat diet led to the highest cholesterol oxidation (63.1μg/g), increasing 27-hydroxycholesterol (27-HC) infiltration (0.24μg/g rat brain) through the blood-brain barrier (BBB) compared to the regular diet (0.13μg/g rat brain). On the other hand, when the diet was switched from high-fat to a regular regimen with SSJ supplementation, a significant reduction of 27-HC in the rat brain was found. Although 24-HC did not significantly change (p=0.054), an increasing trend was observed when high-fat diet was supplied. The principal component analysis (PCA) revealed that SSJ was more active in counteracting cholesterol oxidation when supplied with the high-fat diet, due to inverse correlation with 24(S)-HC and 27-HC; however, further studies are needed to better understand which is the relationship between LA and cholesterol homeostasis in rat brain. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Role of a Genetic Polymorphism in the Corticotropin-Releasing Factor Receptor 1 Gene in Alcohol Drinking and Seeking Behaviors of Marchigian Sardinian Alcohol-Preferring Rats

    PubMed Central

    Ayanwuyi, Lydia O.; Carvajal, Francisca; Lerma-Cabrera, Jose M.; Domi, Esi; Björk, Karl; Ubaldi, Massimo; Heilig, Markus; Roberto, Marisa; Ciccocioppo, Roberto; Cippitelli, Andrea

    2013-01-01

    Marchigian Sardinian alcohol-preferring (msP) rats exhibit innate preference for alcohol, are highly sensitive to stress and stress-induced alcohol seeking. Genetic analysis showed that over-expression of the corticotropin-releasing factor (CRF) system of msP rats is correlated with the presence of two single nucleotide polymorphisms (SNPs) occurring in the promoter region (position −1836 and −2097) of the CRF1 receptor (CRF1-R) gene. Here we examined whether these point mutations were associated to the innate alcohol preference, stress-induced drinking, and seeking. We have recently re-derived the msP rats to obtain two distinct lines carrying the wild type (GG) and the point mutations (AA), respectively. The phenotypic characteristics of these two lines were compared with those of unselected Wistar rats. Both AA and GG rats showed similar patterns of voluntary alcohol intake and preference. Similarly, the pharmacological stressor yohimbine (0.0, 0.625, 1.25, and 2.5 mg/kg) elicited increased operant alcohol self-administration under fixed and progressive ratio reinforcement schedules in all three lines. Following extinction, yohimbine (0.0, 0.625, 1.25, and 2.5 mg/kg) significantly reinstated alcohol seeking in the three groups. However, at the highest dose this effect was no longer evident in AA rats. Treatment with the CRF1-R antagonist antalarmin (0, 5, 10, and 20 mg/kg) significantly reduced alcohol-reinforced lever pressing in the AA line (10 and 20 mg/kg) while a weaker or no effect was observed in the Wistar and the GG group, respectively. Finally, antalarmin significantly reduced yohimbine-induced increase in alcohol drinking in all three groups. In conclusion, these specific SNPs in the CRF1-R gene do not seem to play a primary role in the expression of the msP excessive drinking phenotype or stress-induced drinking but may be associated with a decreased threshold for stress-induced alcohol seeking and an increased sensitivity to the effects

  19. Effects of genetically modified T2A-1 rice on the GI health of rats after 90-day supplement

    PubMed Central

    Yuan, Yanfang; Xu, Wentao; He, Xiaoyun; Liu, Haiyan; Cao, Sishuo; Qi, Xiaozhe; Huang, Kunlun; Luo, Yunbo

    2013-01-01

    Bacillus thuringiensis insecticidal toxin (Bt) rice will be commercialized as a main food source. Traditional safety assessments on genetically modified products pay little attention on gastrointestinal (GI) health. More data about GI health of Bt rice must be provided to dispel public' doubts about the potential effects on human health. We constructed an improved safety assessment animal model using a basic subchronic toxicity experiment, measuring a range of parameters including microflora composition, intestinal permeability, epithelial structure, fecal enzymes, bacterial activity, and intestinal immunity. Significant differences were found between rice-fed groups and AIN93G-fed control groups in several parameters, whereas no differences were observed between genetically modified and non-genetically modified groups. No adverse effects were found on GI health resulting from genetically modified T2A-1 rice. In conclusion, this study may offer a systematic safety assessment model for GM material with respect to the effects on GI health. PMID:23752350

  20. Effects of genetically modified T2A-1 rice on the GI health of rats after 90-day supplement.

    PubMed

    Yuan, Yanfang; Xu, Wentao; He, Xiaoyun; Liu, Haiyan; Cao, Sishuo; Qi, Xiaozhe; Huang, Kunlun; Luo, Yunbo

    2013-01-01

    Bacillus thuringiensis insecticidal toxin (Bt) rice will be commercialized as a main food source. Traditional safety assessments on genetically modified products pay little attention on gastrointestinal (GI) health. More data about GI health of Bt rice must be provided to dispel public' doubts about the potential effects on human health. We constructed an improved safety assessment animal model using a basic subchronic toxicity experiment, measuring a range of parameters including microflora composition, intestinal permeability, epithelial structure, fecal enzymes, bacterial activity, and intestinal immunity. Significant differences were found between rice-fed groups and AIN93G-fed control groups in several parameters, whereas no differences were observed between genetically modified and non-genetically modified groups. No adverse effects were found on GI health resulting from genetically modified T2A-1 rice. In conclusion, this study may offer a systematic safety assessment model for GM material with respect to the effects on GI health.

  1. Effects of genetic strain on stress-induced weight and body fat loss in rats: Application to air pollution research

    EPA Science Inventory

    Exposure to some air pollutants is suspected of contributing to obesity. Hazelton chambers are commonly used in air pollution studies but we found unexpected reductions in body weight and body fat of rats housed in Hazelton chambers under control conditions. We suspect that stres...

  2. Genetic control of immune responses to Moloney sarcomas in rats: role of non-RT-1 background genes.

    PubMed

    Jones, J M

    1983-08-15

    Bone marrow chimeras, athymic nude rats and a congeneic strain were utilized to verify and further examine non-RT-1 linked background genes that influence immune responses of BN and LEW rats to Moloney sarcomas. In transplants that did not involve RT-1 incompatibility, infusion of high-responder bone marrow into a lethally irradiated low-responder recipient, or low-responder bone marrow into a high-responder recipient, would restore a high antibody response to the gp70 antigen of MuLV. Such transplants did not restore a high response to the p30 antigen. Athymic nude rats did not exhibit a significant response to either p30 or gp70 while euthymic littermates exhibited a significant response to both antigens. Growth of Moloney sarcomas as well as antibody and cellular responses to antigens expressed by such tumors were measured in LEW-IN rats which carry the RT-1 of BN and the background of LEW. For each of these parameters, LEW-IN resembled LEW more closely than BN.

  3. Effects of genetic strain on stress-induced weight and body fat loss in rats: Application to air pollution research

    EPA Science Inventory

    Exposure to some air pollutants is suspected of contributing to obesity. Hazelton chambers are commonly used in air pollution studies but we found unexpected reductions in body weight and body fat of rats housed in Hazelton chambers under control conditions. We suspect that stres...

  4. Expression of new loci associated with obesity in diet-induced obese rats: from genetics to physiology.

    PubMed

    Gutierrez-Aguilar, Ruth; Kim, Dong-Hoon; Woods, Stephen C; Seeley, Randy J

    2012-02-01

    Genome-wide association studies (GWAS) are a powerful tool for revealing genes associated with common human obesity. New loci associated with obesity have recently been reported, but their function and metabolic implications remain to be elucidated. In order to begin identifying the role of some of these obesity-related loci, the closest genes to the polymorphism of each locus were selected and their expression was compared in the hypothalamus, adipose tissue, liver, soleus muscle, and extensor digitorum longus muscle (EDL) of Long-Evans rats maintained on chow or a high-fat diet (HFD) for 6 weeks. From a total of 19 genes analyzed, seven genes (ETV5, FTO, GNPDA2, KCTD15, TMEM18, MC4R, and SH2B1) were down-regulated in the hypothalamus of HFD compared to chow-fed rats. In adipose tissue of rats fed on HFD, the mRNA levels of BCDIN3, KCTD15, and SULT1A1 were down-regulated, whereas those of MTCH2, PTER, and TUFM were up-regulated. In the liver, three genes were up-regulated (PTER, SULT1A1, and TUFM) in HFD relative to chow-fed rats, and TMEM18 was down-regulated. Finally, in soleus muscle of HFD-fed rats, BCDIN3, BDNF, and TMEM18 were down-regulated, and in the EDL muscle SH2B1 and TUFM were up-regulated. mRNA levels in the hypothalamus were compared between fed and fasted states, and only KCTD15 was down-regulated during fasting when fed a chow diet. In conclusion, novel genes found to be associated with obesity are regulated by a HFD and the mRNA levels of KCTD15 is dependent on the nutritional status. These results suggest a potential role of these genes in the regulation of energy balance.

  5. Variability of control data and relevance of observed group differences in five oral toxicity studies with genetically modified maize MON810 in rats.

    PubMed

    Schmidt, Kerstin; Schmidtke, Jörg; Schmidt, Paul; Kohl, Christian; Wilhelm, Ralf; Schiemann, Joachim; van der Voet, Hilko; Steinberg, Pablo

    2017-04-01

    The data of four 90-day feeding trials and a 1-year feeding trial with the genetically modified (GM) maize MON810 in Wistar Han RCC rats performed in the frame of EU-funded project GRACE were analysed. Firstly, the data obtained from the groups having been fed the non-GM maize diets were combined to establish a historical control data set for Wistar Han RCC rats at the animal housing facility (Slovak Medical University, Bratislava, Slovakia). The variability of all parameters is described, and the reference values and ranges have been derived. Secondly, the consistency of statistically significant differences found in the five studies was analysed. In order to do so, the body weight development, organ weight, haematology and clinical biochemistry data were compared between the studies. Based on the historical control data, equivalence ranges for these parameters were defined, and the values measured in the GM maize-fed groups were compared with these equivalence ranges. Thirdly, the (statistical) power of these feeding studies with whole food/feed was assessed and detectable toxicologically relevant group differences were derived. Linear mixed models (LMM) were applied, and standardized effect sizes (SES) were calculated in order to compare different parameters as well as to provide an overall picture of group and study differences at a glance. The comparison of the five feeding trials showed a clear study effect in the control data. It also showed inconsistency both in the frequency of statistically significant differences and in the difference values between control and test groups.

  6. Effect of Dose and Administration Period of Seed Cake of Genetically Modified and Non-Modified Flax on Selected Antioxidative Activities in Rats.

    PubMed

    Matusiewicz, Magdalena; Kosieradzka, Iwona; Zuk, Magdalena; Szopa, Jan

    2015-06-23

    Flaxseed cake containing antioxidants is a valuable dietary component. Its nutritional effect may be diminished by the presence of anti-nutrients. The work was aimed at determining the effect of different contents of flaxseed cake in diets and their administration period on the development of rats and selected parameters of their health status. Diets with 15% and 30% addition of genetically modified (GM) flax seed cake with enhanced synthesis of polyphenols, as well as Linola non-GM flax were administered in short-term (33 days) and long-term (90 days) experiments. The 30% addition of flaxseed cake reduced digestibility of dietary nutrients, GM flaxseed cake lowered body weight gains. The relative weight of selected organs, hematological blood markers and serum activities of aspartate and alanine aminotransferases (AST, ALT) were not affected. Flaxseed cake consumption reduced serum concentration of albumins and increased globulins. Administration of 30% flaxseed cake improved plasma total antioxidant status and 30% GM flaxseed cake lowered liver thiobarbituric acid reactive substances. The activities of superoxide dismutase in erythrocytes, glutathione peroxidase in plasma and the liver concentration of 8-oxo-2'-deoxyguanosine were not changed. Most morphometric parameters of the small intestine did not differ between feeding groups. The administration of diets with 30% addition of flaxseed cake for 90 days improved the antioxidant status in rats.

  7. A 90-day subchronic study of rats fed lean pork from genetically modified pigs with muscle-specific expression of recombinant follistatin.

    PubMed

    Zou, Shiying; Tang, Min; He, Xiaoyun; Cao, Yuan; Zhao, Jie; Xu, Wentao; Liang, Zhihong; Huang, Kunlun

    2015-11-01

    Because cardiovascular disease incidence has rapidly increased in recent years, people are choosing relatively healthier diets with low animal fat. A transgenic pig with low fat and a high percentage of lean meat was created in 2011; this pig overexpresses the follistatin (FST) gene. To evaluate the safety of lean pork derived from genetically modified (GM) pigs, a subchronic oral toxicity study was conducted using Sprague-Dawley rats. GM pork and non-GM pork were incorporated into the diet at levels of 3.75%, 7.5%, and 15% (w/w), and the main nutrients of the various diets were subsequently balanced. The safety of GM pork was assessed by comparison of the toxicology response variables in Sprague-Dawley rats consuming diets containing GM pork with those consuming non-GM pork. No treatment-related adverse or toxic effects were observed based on an examination of the daily clinical signs, body weight, food consumption, hematology, serum biochemistry, and organ weight or based on gross and histopathological examination. The results demonstrate that GM pork is as safe for consumption as conventional pork. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Prediction of Endocrine System Affectation in Fisher 344 Rats by Food Intake Exposed with Malathion, Applying Naïve Bayes Classifier and Genetic Algorithms.

    PubMed

    Mora, Juan David Sandino; Hurtado, Darío Amaya; Sandoval, Olga Lucía Ramos

    2016-01-01

    Reported cases of uncontrolled use of pesticides and its produced effects by direct or indirect exposition, represent a high risk for human health. Therefore, in this paper, it is shown the results of the development and execution of an algorithm that predicts the possible effects in endocrine system in Fisher 344 (F344) rats, occasioned by ingestion of malathion. It was referred to ToxRefDB database in which different case studies in F344 rats exposed to malathion were collected. The experimental data were processed using Naïve Bayes (NB) machine learning classifier, which was subsequently optimized using genetic algorithms (GAs). The model was executed in an application with a graphical user interface programmed in C#. There was a tendency to suffer bigger alterations, increasing levels in the parathyroid gland in dosages between 4 and 5 mg/kg/day, in contrast to the thyroid gland for doses between 739 and 868 mg/kg/day. It was showed a greater resistance for females to contract effects on the endocrine system by the ingestion of malathion. Females were more susceptible to suffer alterations in the pituitary gland with exposure times between 3 and 6 months. The prediction model based on NB classifiers allowed to analyze all the possible combinations of the studied variables and improving its accuracy using GAs. Excepting the pituitary gland, females demonstrated better resistance to contract effects by increasing levels on the rest of endocrine system glands.

  9. Prediction of Endocrine System Affectation in Fisher 344 Rats by Food Intake Exposed with Malathion, Applying Naïve Bayes Classifier and Genetic Algorithms

    PubMed Central

    Mora, Juan David Sandino; Hurtado, Darío Amaya; Sandoval, Olga Lucía Ramos

    2016-01-01

    Background: Reported cases of uncontrolled use of pesticides and its produced effects by direct or indirect exposition, represent a high risk for human health. Therefore, in this paper, it is shown the results of the development and execution of an algorithm that predicts the possible effects in endocrine system in Fisher 344 (F344) rats, occasioned by ingestion of malathion. Methods: It was referred to ToxRefDB database in which different case studies in F344 rats exposed to malathion were collected. The experimental data were processed using Naïve Bayes (NB) machine learning classifier, which was subsequently optimized using genetic algorithms (GAs). The model was executed in an application with a graphical user interface programmed in C#. Results: There was a tendency to suffer bigger alterations, increasing levels in the parathyroid gland in dosages between 4 and 5 mg/kg/day, in contrast to the thyroid gland for doses between 739 and 868 mg/kg/day. It was showed a greater resistance for females to contract effects on the endocrine system by the ingestion of malathion. Females were more susceptible to suffer alterations in the pituitary gland with exposure times between 3 and 6 months. Conclusions: The prediction model based on NB classifiers allowed to analyze all the possible combinations of the studied variables and improving its accuracy using GAs. Excepting the pituitary gland, females demonstrated better resistance to contract effects by increasing levels on the rest of endocrine system glands. PMID:27833725

  10. Effect of Dose and Administration Period of Seed Cake of Genetically Modified and Non-Modified Flax on Selected Antioxidative Activities in Rats

    PubMed Central

    Matusiewicz, Magdalena; Kosieradzka, Iwona; Zuk, Magdalena; Szopa, Jan

    2015-01-01

    Flaxseed cake containing antioxidants is a valuable dietary component. Its nutritional effect may be diminished by the presence of anti-nutrients. The work was aimed at determining the effect of different contents of flaxseed cake in diets and their administration period on the development of rats and selected parameters of their health status. Diets with 15% and 30% addition of genetically modified (GM) flax seed cake with enhanced synthesis of polyphenols, as well as Linola non-GM flax were administered in short-term (33 days) and long-term (90 days) experiments. The 30% addition of flaxseed cake reduced digestibility of dietary nutrients, GM flaxseed cake lowered body weight gains. The relative weight of selected organs, hematological blood markers and serum activities of aspartate and alanine aminotransferases (AST, ALT) were not affected. Flaxseed cake consumption reduced serum concentration of albumins and increased globulins. Administration of 30% flaxseed cake improved plasma total antioxidant status and 30% GM flaxseed cake lowered liver thiobarbituric acid reactive substances. The activities of superoxide dismutase in erythrocytes, glutathione peroxidase in plasma and the liver concentration of 8-oxo-2′-deoxyguanosine were not changed. Most morphometric parameters of the small intestine did not differ between feeding groups. The administration of diets with 30% addition of flaxseed cake for 90 days improved the antioxidant status in rats. PMID:26110393

  11. [The impact of components of conventional and genetically modified soybeans on parameters of the immune and reproductive systems in female rats].

    PubMed

    Dolaĭchuk, O P; Fedoruk, R S; Koval'chuk, I I

    2013-01-01

    The article presents results of research of the content of glycoproteins and their specific carbohydrate components, total protein, hemoglobin, erythrocyte, leucocytes molecules of average mass and circulating immune complexes in the blood of female rats under conditions feeding of conventional and transgenic soybeans. Also the reproductive function and mass coefficient of fetus of the studied animals was analyzed. The studies were conducted in three groups of female rats aged 3 months. Animals of I group (control) were kept on a balanced diet during the study period. Animals of groups II and III (research) received a diet according to the scheme of the control group with the addition of 30% from the nutritional value diet native or transgenic soybean, respectively. We found that soy feeding had no significant effect on hematological data in the second and third experimental groups versus control. However, addition to the diet of soybeans, including genetically modified, has a significant impact on the content of glycoproteins and their specific carbohydrate components, female's fertility and less pronounced impact on the data of functional status of their immune system. A generalized analysis of the results of research leads to the conclusion that there is no definite negative or positive impact of GM soy components on their physiological state compared with animals fed native soybeans.

  12. Evaluation of the safety and nutritional equivalence of a genetically modified cottonseed meal in a 90-day dietary toxicity study in rats.

    PubMed

    Dryzga, M D; Yano, B L; Andrus, A K; Mattsson, J L

    2007-10-01

    Meal prepared from Cry1F/Cry1Ac transgenic/genetically modified cottonseed (WIDESTRIKE Insect Protection, hereafter referred to as WIDESTRIKE) was compared to cottonseed meal prepared from four conventionally bred lines of cotton (three commercial non-transgenic line controls (PHY72, PHY78 and 98M-2983), and a near isoline non-transgenic control (PSC355) in a 90-day dietary study to evaluate safety and nutritional equivalence. Diets were formulated with 10% WIDESTRIKE cottonseed meal equivalent to 7,235 mg/kg/day for males and 7,935 mg/kg/day for females. Animals were evaluated by cage-side and hand-held detailed clinical observations, body weight, and feed consumption. Functional tests, motor activity and ophthalmic examinations were conducted pre-exposure and prior to study termination. Standard hematology, clinical chemistry, prothrombin time and urinalysis parameters were evaluated. All rats had a complete necropsy and selected organs were weighed. Histopathologic examinations were performed on all rats fed the diets containing the near isoline non-transgenic control or WIDESTRIKE. Following 90 days of feeding, no adverse effects were observed during the conduct of clinical observations or in any of the parameters measured in this study. This study demonstrated that rodent diets prepared with 10% cottonseed meal from WIDESTRIKE cottonseeds do not produce any untoward effects and are nutritionally equivalent to cottonseed meals prepared from other, non-transgenic cottonseeds.

  13. Immune responses to adeno-associated virus type 2 encoding channelrhodopsin-2 in a genetically blind rat model for gene therapy.

    PubMed

    Sugano, E; Isago, H; Wang, Z; Murayama, N; Tamai, M; Tomita, H

    2011-03-01

    We had previously reported that transduction of the channelrhodopsin-2 (ChR2) gene into retinal ganglion cells restores visual function in genetically blind, dystrophic Royal College of Surgeons (RCS) rats. In this study, we attempted to reveal the safety and influence of exogenous ChR2 gene expression. Adeno-associated virus (AAV) type 2 encoding ChR2 fused to Venus (rAAV-ChR2V) was administered by intra-vitreous injection to dystrophic RCS rats. However, rAAV-ChR2 gene expression was detected in non-target organs (intestine, lung and heart) in some cases. ChR2 function, monitored by recording visually evoked potentials, was stable across the observation period (64 weeks). No change in retinal histology and no inflammatory marker of leucocyte adhesion in the retinal vasculature were observed. Although antibodies to rAAV (0.01-12.21 μg ml(-1)) and ChR2 (0-4.77 μg ml(-1)) were detected, their levels were too low for rejection. T-lymphocyte analysis revealed recognition by T cells and a transient inflammation-like immune reaction only until 1 month after the rAAV-ChR2V injection. In conclusion, ChR2, which originates from Chlamydomonas reinhardtii, can be expressed without immunologically harmful reactions in vivo. These findings will help studies of ChR2 gene transfer to restore vision in progressed retinitis pigmentosa.

  14. Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease.

    PubMed

    Simile, Maria M; Latte, Gavinella; Demartis, Maria I; Brozzetti, Stefania; Calvisi, Diego F; Porcu, Alberto; Feo, Claudio F; Seddaiu, Maria A; Daino, Lucia; Berasain, Carmen; Tomasi, Maria L; Avila, Matias A; Feo, Francesco; Pascale, Rosa M

    2016-08-02

    Previous studies showed that YAP1 is over-expressed in hepatocellular carcinoma (HCC). Here we observed higher expression of Yap1/Ctgf axis in dysplastic nodules and HCC chemically-induced in F344 rats, genetically susceptible to hepatocarcinogenesis, than in lesions induced in resistant BN rats. In BN rats, highest increase in Yap1-tyr357, p73 phosphorylation and Caspase 3 cleavage occurred. In human HCCs with poorer prognosis (< 3 years survival after partial liver resection, HCCP), levels of YAP1, CTGF, 14-3-3, and TEAD proteins, and YAP1-14-3-3 and YAP1-TEAD complexes were higher than in HCCs with better outcome (> 3 years survival; HCCB). In the latter, higher levels of phosphorylated YAP1-ser127, YAP1-tyr357 and p73, YAP1 ubiquitination, and Caspase 3 cleavage occurred. Expression of stemness markers NANOG, OCT-3/4, and CD133 were highest in HCCP and correlated with YAP1 and YAP1-TEAD levels. In HepG2, Huh7, and Hep3B cells, forced YAP1 over-expression led to stem cell markers expression and increased cell viability, whereas inhibition of YAP1 expression by specific siRNA, or transfection of mutant YAP1 which does not bind to TEAD, induced opposite alterations. These changes were associated, in Huh7 cells transfected with YAP1 or YAP1 siRNA, with stimulation or inhibition of cell migration and invasivity, respectively. Furthermore, transcriptome analysis showed that YAP1 transfection in Huh7 cells induces over-expression of genes involved in tumor stemness. In conclusion, Yap1 post-translational modifications favoring its ubiquitination and apoptosis characterize HCC with better prognosis, whereas conditions favoring the formation of YAP1-TEAD complexes are associated with aggressiveness and acquisition of stemness features by HCC cells.

  15. Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model

    PubMed Central

    Flagel, Shelly B.; Chaudhury, Sraboni; Waselus, Maria; Kelly, Rebeca; Sewani, Salima; Clinton, Sarah M.; Thompson, Robert C.; Watson, Stanley J.; Akil, Huda

    2016-01-01

    This study provides a demonstration in the rat of a clear genetic difference in the propensity for addiction-related behaviors following prolonged cocaine self-administration. It relies on the use of selectively bred high-responder (bHR) and low-responder (bLR) rat lines that differ in several characteristics associated with “temperament,” including novelty-induced locomotion and impulsivity. We show that bHR rats exhibit behaviors reminiscent of human addiction, including persistent cocaine-seeking and increased reinstatement of cocaine seeking. To uncover potential underlying mechanisms of this differential vulnerability, we focused on the core of the nucleus accumbens and examined expression and epigenetic regulation of two transcripts previously implicated in bHR/bLR differences: fibroblast growth factor (FGF2) and the dopamine D2 receptor (D2). Relative to bHRs, bLRs had lower FGF2 mRNA levels and increased association of a repressive mark on histones (H3K9me3) at the FGF2 promoter. These differences were apparent under basal conditions and persisted even following prolonged cocaine self-administration. In contrast, bHRs had lower D2 mRNA under basal conditions, with greater association of H3K9me3 at the D2 promoter and these differences were no longer apparent following prolonged cocaine self-administration. Correlational analyses indicate that the association of H3K9me3 at D2 may be a critical substrate underlying the propensity to relapse. These findings suggest that low D2 mRNA levels in the nucleus accumbens core, likely mediated via epigenetic modifications, may render individuals more susceptible to cocaine addiction. In contrast, low FGF2 levels, which appear immutable even following prolonged cocaine exposure, may serve as a protective factor. PMID:27114539

  16. Detection of Trypanosoma lewisi from wild rats in Southern China and its genetic diversity based on the ITS1 and ITS2 sequences.

    PubMed

    Tang, Hai-Jun; Lan, You-Gen; Wen, Yan-Zi; Zhang, Xi-Chen; Desquesnes, Marc; Yang, Ting-Bao; Hide, Geoff; Lun, Zhao-Rong

    2012-07-01

    Trypanosoma lewisi has widely been considered as a non-pathogenic rat trypanosome. However, more and more cases of humans infected with T. lewisi have been reported around the world, indicating that it can infect humans in some undetermined circumstances. Quick and sensitive diagnosis of infection by T. lewisi is important for both treatment of patients and epidemiological studies of this parasite. In this paper, three methods i.e. wet blood smear (diagnosis by microscopy), PCR and LAMP were used to detect T. lewisi from 238 wild rats (Rattus norvegicus) collected from the field in Huadu, Guangdong province, China. Infection rates of these samples detected by the 3 methods was 6.7% (16/238), 12.6% (30/238), and 18.9% (45/238), respectively. LAMP could detect all samples shown positive by microscopical observation of wet smear and by single PCR indicating good potential for application in the detection of T. lewisi. So far as we know, this is the first report of the LAMP method being used to detect T. lewisi in wild rats. The specific T. lewisi LAMP primers were able to amplify the target fragment from the genomic DNA of 19 T. lewisi strains isolated from Huadu, Guangdong province (n=16), Changchun, Jilin province of China (n=1) and from Thailand (n=2). Based on the analyses of ITS1 (internal transcribed spacer 1) and ITS2 sequences, these 19 strains show a very close genetic relationship with over 96-97% similarity to the other corresponding sequences of T. lewisi published in Genbank. Phylogenetic trees of the species in the subgenus Herpetosoma were constructed, based on the ITS1 and ITS2 sequences, and these results also indicate that they are closely related and in the same clade.

  17. Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease

    PubMed Central

    Demartis, Maria I.; Brozzetti, Stefania; Calvisi, Diego F.; Porcu, Alberto; Feo, Claudio F.; Seddaiu, Maria A.; Daino, Lucia; Berasain, Carmen; Tomasi, Maria L.; Avila, Matias A.; Feo, Francesco; Pascale, Rosa M.

    2016-01-01

    Previous studies showed that YAP1 is over-expressed in hepatocellular carcinoma (HCC). Here we observed higher expression of Yap1/Ctgf axis in dysplastic nodules and HCC chemically-induced in F344 rats, genetically susceptible to hepatocarcinogenesis, than in lesions induced in resistant BN rats. In BN rats, highest increase in Yap1-tyr357, p73 phosphorylation and Caspase 3 cleavage occurred. In human HCCs with poorer prognosis (< 3 years survival after partial liver resection, HCCP), levels of YAP1, CTGF, 14–3–3, and TEAD proteins, and YAP1-14-3-3 and YAP1-TEAD complexes were higher than in HCCs with better outcome (> 3 years survival; HCCB). In the latter, higher levels of phosphorylated YAP1-ser127, YAP1-tyr357 and p73, YAP1 ubiquitination, and Caspase 3 cleavage occurred. Expression of stemness markers NANOG, OCT-3/4, and CD133 were highest in HCCP and correlated with YAP1 and YAP1-TEAD levels. In HepG2, Huh7, and Hep3B cells, forced YAP1 over-expression led to stem cell markers expression and increased cell viability, whereas inhibition of YAP1 expression by specific siRNA, or transfection of mutant YAP1 which does not bind to TEAD, induced opposite alterations. These changes were associated, in Huh7 cells transfected with YAP1 or YAP1 siRNA, with stimulation or inhibition of cell migration and invasivity, respectively. Furthermore, transcriptome analysis showed that YAP1 transfection in Huh7 cells induces over-expression of genes involved in tumor stemness. In conclusion, Yap1 post-translational modifications favoring its ubiquitination and apoptosis characterize HCC with better prognosis, whereas conditions favoring the formation of YAP1-TEAD complexes are associated with aggressiveness and acquisition of stemness features by HCC cells. PMID:27359056

  18. Chronic effects of soft drink consumption on the health state of Wistar rats: A biochemical, genetic and histopathological study

    PubMed Central

    ALKHEDAIDE, ADEL; SOLIMAN, MOHAMED MOHAMED; SALAH-ELDIN, ALAA-ELDIN; ISMAIL, TAMER AHMED; ALSHEHIRI, ZAFER SAAD; ATTIA, HOSSAM FOUAD

    2016-01-01

    The present study was performed to examine the effects of chronic soft drink consumption (SDC) on oxidative stress, biochemical alterations, gene biomarkers and histopathology of bone, liver and kidney. Free drinking water of adult male Wistar rats was substituted with three different soft drinks: Coca-Cola, Pepsi and 7-Up, for three consecutive months. The serum and organs were collected for examining the biochemical parameters associated with bone, liver and kidney functions. Semi-quantitative reverse transcription polymerase chain reaction was used to observe the changes in the expression of genes in the liver and kidney, which are associated with oxidative stress resistance. Histopathological investigations were performed to determine the changes in bone, liver and kidney tissues using hematoxylin and eosin stains. SDC affected liver, kidney and bone function biomarkers. Soft drinks increased oxidative stress, which is represented by an increase in malondialdehyde and a decrease in antioxidant levels. SDC affected serum mineral levels, particularly calcium and phosphorus. Soft drinks downregulated the expression levels of glutathione-S-transferase and super oxide dismutase in the liver compared with that of control rats. Rats administered Coca-Cola exhibited a hepatic decrease in the mRNA expression of α2-macroglobulin compared with rats administered Pepsi and 7-Up. On the other hand, SDC increased the mRNA expression of α1-acid glycoprotein. The present renal studies revealed that Coca-Cola increased the mRNA expression levels of desmin, angiotensinogen and angiotensinogen receptor compared with the other groups, together with mild congestion in renal histopathology. Deleterious histopathological changes were reported predominantly in the bone and liver of the Coca-Cola and Pepsi groups. In conclusion, a very strict caution must be considered with SDC due to the increase in oxidative stress biomarkers and disruption in the expression of certain genes

  19. Effect of genetic strain and gender on age-related changes in body composition of the laboratory rat.

    PubMed

    Gordon, C J; Jarema, K; Johnstone, A F M; Phillips, P M

    2016-01-01

    Body fat serves as a storage compartment for lipophilic pollutants and affects the pharmacokinetics of many toxic chemicals. Understanding how body fat varies with gender, strain, and age may be essential for development of experimental models to study mechanisms of toxicity. Nuclear magnetic resonance (NMR)-based analysis serves as a noninvasive means of assessing proportions of fat, lean, and fluid in rodents over their lifetime. The aim of this study was to track changes in body composition of male and female Long-Evans (LE), Sprague-Dawley (SD), Fischer (F334), and Brown Norway (BN) rats from postweaning over a >2-yr period. Percent fat of preweaned LE and SD rats was markedly higher compared to the other strains. LE and SD strains displayed marked increases in body fat from weaning to 8 mo of age. Postweaned F344 male and females showed relatively low levels of percent fat; however, at 2 yr of age percent fat of females was equal to that of SD and LE in females. BN rats showed the highest levels of lean tissue and lowest levels of fat. Percent fat of the BN strain rose at the slowest rate as they aged. Percent fluid was consistently higher in males for all strains. Females tended to have higher percent fat than males in LE, SD, and F344 strains. Assessing changes in body fat as well as lean and fluid of various strains of male and female rats over their lifetime may prove useful in many research endeavors, including pharmacokinetics of lipophilic toxicants, mechanisms underlying obesity, and metabolic disorders.

  20. Rimonabant reduces the essential value of food in the genetically obese Zucker rat: an exponential demand analysis.

    PubMed

    Rasmussen, Erin B; Reilly, William; Buckley, Jessica; Boomhower, Steven R

    2012-02-01

    Research on free-food intake suggests that cannabinoids are implicated in the regulation of feeding. Few studies, however, have characterized how environmental factors that affect food procurement interact with cannabinoid drugs that reduce food intake. Demand analysis provides a framework to understand how cannabinoid blockers, such as rimonabant, interact with effort in reducing demand for food. The present study examined the effects rimonabant had on demand for sucrose in obese Zucker rats when effort to obtain food varied and characterized the data using the exponential ("essential value") model of demand. Twenty-nine male (15 lean, 14 obese) Zucker rats lever-pressed under eight fixed ratio (FR) schedules of sucrose reinforcement, in which the number of lever-presses to gain access to a single sucrose pellet varied between 1 and 300. After behavior stabilized under each FR schedule, acute doses of rimonabant (1-10mg/kg) were administered prior to some sessions. The number of food reinforcers and responses in each condition was averaged and the exponential and linear demand equations were fit to the data. These demand equations quantify the value of a reinforcer by its sensitivity to price (FR) increases. Under vehicle conditions, obese Zucker rats consumed more sucrose pellets than leans at smaller fixed ratios; however, they were equally sensitive to price increases with both models of demand. Rimonabant dose-dependently reduced reinforcers and responses for lean and obese rats across all FR schedules. Data from the exponential analysis suggest that rimonabant dose-dependently increased elasticity, i.e., reduced the essential value of sucrose, a finding that is consistent with graphical depictions of normalized demand curves.

  1. Combined effects of low-dose spironolactone and captopril therapy in a rat model of genetic hypertrophic cardiomyopathy.

    PubMed

    de Resende, Micheline Monteiro; Kriegel, Alison Jessica; Greene, Andrew Seth

    2006-12-01

    For several years, the severe side effects associated with the use of high doses of the aldosterone antagonist, spironolactone, limited its clinical use. Studies have recently shown efficacy and minimal side effects of low-dose spironolactone combined with standard therapy in the treatment of heart failure and hypertensive patients. The authors evaluated the effects of low-dose spironolactone alone or in combination with angiotensin-converting enzyme (ACE) inhibitors on the progression of left ventricular dysfunction and remodeling in a congenic rat model of hypertrophic cardiomyopathy. The congenic SS-16/Mcwi rats developed severe cardiac hypertrophy despite being normotensive even on high-salt diet. SS-16/Mcwi and SS/Mcwi rats were fed a low-salt (0.4% NaCl) diet and were treated with vehicle (CON), spironolactone (20 mg/kg/d subcutaneously), captopril (100 mg/kg/d drinking water), or both spironolactone and captopril for 4 weeks. Blood pressure, plasma peptides, cardiac fibrosis, and echocardiography measurements were evaluated. Spironolactone at a low dose had no effect on blood pressure, cardiac hypertrophy, and fibrosis in either strain. However, in combination with captopril, spironolactone decreased the cardiac hypertrophy more than captopril treatment alone. In the SS-16/Mcwi rats, the combined therapy significantly preserved the cardiac index when compared with control. These data indicate that the addition of low-dose spironolactone to captopril treatment was more effective in preventing the progression of heart hypertrophy and ventricular dysfunction in the SS-16/Mcwi than captopril alone. This study suggests that combined spironolactone and captopril therapy may be useful in the treatment of hypertrophic cardiomyopathy.

  2. Chronic effects of soft drink consumption on the health state of Wistar rats: A biochemical, genetic and histopathological study.

    PubMed

    Alkhedaide, Adel; Soliman, Mohamed Mohamed; Salah-Eldin, Alaa-Eldin; Ismail, Tamer Ahmed; Alshehiri, Zafer Saad; Attia, Hossam Fouad

    2016-06-01

    The present study was performed to examine the effects of chronic soft drink consumption (SDC) on oxidative stress, biochemical alterations, gene biomarkers and histopathology of bone, liver and kidney. Free drinking water of adult male Wistar rats was substituted with three different soft drinks: Coca‑Cola, Pepsi and 7‑Up, for three consecutive months. The serum and organs were collected for examining the biochemical parameters associated with bone, liver and kidney functions. Semi‑quantitative reverse transcription polymerase chain reaction was used to observe the changes in the expression of genes in the liver and kidney, which are associated with oxidative stress resistance. Histopathological investigations were performed to determine the changes in bone, liver and kidney tissues using hematoxylin and eosin stains. SDC affected liver, kidney and bone function biomarkers. Soft drinks increased oxidative stress, which is represented by an increase in malondialdehyde and a decrease in antioxidant levels. SDC affected serum mineral levels, particularly calcium and phosphorus. Soft drinks downregulated the expression levels of glutathione‑S‑transferase and super oxide dismutase in the liver compared with that of control rats. Rats administered Coca‑Cola exhibited a hepatic decrease in the mRNA expression of α2‑macroglobulin compared with rats administered Pepsi and 7‑Up. On the other hand, SDC increased the mRNA expression of α1‑acid glycoprotein. The present renal studies revealed that Coca‑Cola increased the mRNA expression levels of desmin, angiotensinogen and angiotensinogen receptor compared with the other groups, together with mild congestion in renal histopathology. Deleterious histopathological changes were reported predominantly in the bone and liver of the Coca‑Cola and Pepsi groups. In conclusion, a very strict caution must be considered with SDC due to the increase in oxidative stress biomarkers and disruption in the expression

  3. Quality and safety evaluation of genetically modified potatoes spunta with Cry V gene: compositional analysis, determination of some toxins, antinutrients compounds and feeding study in rats.

    PubMed

    El Sanhoty, Rafaat; El-Rahman, Ahamed Ali Abd; Bögl, Klaus Werner

    2004-02-01

    The aim of this study was to evaluate the composition, nutritional and toxicology safety of GM potato Spunta lines compared to that of conventional potato Spunta. Compositional analyses were conducted to measure the proximate chemical composition with references to 14 components, total solid, protein, lipid, crude fibre, ash, carbohydrate, starch, reducing sugar, nonreducing sugar, sodium, calcium, potassium, phosphorus, and ascorbic acid. Some toxins and anti-nutrients compounds were determined. Feeding study of GM potatoes line (G2 and G3) in rats were done for 30 days. Four groups of albino rats were used for studying the effect and the safety assessment of GM potatoes Spunta G2 and G3. Group (I) was fed on control basal diet, group (II) was fed on control diet plus 30% freeze-dried nongenetically modified potato Spunta, group (III) was fed on control diet plus 30% freeze-dried genetically modified potato Spunta, and group (IV) was fed on control diet plus 30% freeze-dried genetically modified potato Spunta GMO G3. There were no significant differences between GM potatoes G2, G3, and Spunta control potato line in the proximate chemical composition. The levels of glycoalkaloids in transgenic potato tubers and nontransgenic were determined and there were also no significant differences between the GM potatoes and conventional potato line, the levels were in agreement with a safety level recommended by FAO/WHO (200 mg/ kg) for acute toxicity. Protease inhibitor activity and total phenol were estimated and no significant differences between the GM potatoes line and conventional potato Spunta line were found. During the period tested, rats in each group (I, II, III, IV) grew well without marked differences in appearance. No statistical difference were found in food intake, daily body weight gain and feed efficiency. But there is a slightly significant difference in finally body weight between the control group and experimental groups. No significant difference were

  4. Ninety-day oral toxicity studies on two genetically modified maize MON810 varieties in Wistar Han RCC rats (EU 7th Framework Programme project GRACE).

    PubMed

    Zeljenková, Dagmar; Ambrušová, Katarína; Bartušová, Mária; Kebis, Anton; Kovrižnych, Jevgenij; Krivošíková, Zora; Kuricová, Miroslava; Líšková, Aurélia; Rollerová, Eva; Spustová, Viera; Szabová, Elena; Tulinská, Jana; Wimmerová, Soňa; Levkut, Mikuláš; Révajová, Viera; Ševčíková, Zuzana; Schmidt, Kerstin; Schmidtke, Jörg; La Paz, Jose Luis; Corujo, Maria; Pla, Maria; Kleter, Gijs A; Kok, Esther J; Sharbati, Jutta; Hanisch, Carlos; Einspanier, Ralf; Adel-Patient, Karine; Wal, Jean-Michel; Spök, Armin; Pöting, Annette; Kohl, Christian; Wilhelm, Ralf; Schiemann, Joachim; Steinberg, Pablo

    2014-12-01

    The GMO Risk Assessment and Communication of Evidence (GRACE; www.grace-fp7.eu ) project is funded by the European Commission within the 7th Framework Programme. A key objective of GRACE is to conduct 90-day animal feeding trials, animal studies with an extended time frame as well as analytical, in vitro and in silico studies on genetically modified (GM) maize in order to comparatively evaluate their use in GM plant risk assessment. In the present study, the results of two 90-day feeding trials with two different GM maize MON810 varieties, their near-isogenic non-GM varieties and four additional conventional maize varieties are presented. The feeding trials were performed by taking into account the guidance for such studies published by the EFSA Scientific Committee in 2011 and the OECD Test Guideline 408. The results obtained show that the MON810 maize at a level of up to 33 % in the diet did not induce adverse effects in male and female Wistar Han RCC rats after subchronic exposure, independently of the two different genetic backgrounds of the event.

  5. Integration of genotoxicity and population genetic analyses in kangaroo rats (Dipodomys merriami) exposed to radionuclide contamination at the Nevada Test Site, USA

    USGS Publications Warehouse

    Theodorakis, Christopher W.; Bickham, John W.; Lamb, Trip; Medica, Philip A.; Lyne, T. Barrett

    2001-01-01

    We examined effects of radionuclide exposure at two atomic blast sites on kangaroo rats (Dipodomys merriami) at the Nevada Test Site, Nevada, USA, using genotoxicity and population genetic analyses. We assessed chromosome damage by micronucleus and flow cytometric assays and genetic variation by randomly amplified polymorphic DNA (RAPD) and mitochondrial DNA (mtDNA) analyses. The RAPD analysis showed no population structure, but mtDNA exhibited differentiation among and within populations. Genotoxicity effects were not observed when all individuals were analyzed. However, individuals with mtDNA haplotypes unique to the contaminated sites had greater chromosomal damage than contaminated-site individuals with haplotypes shared with reference sites. When interpopulation comparisons used individuals with unique haplotypes, one contaminated site had greater levels of chromosome damage than one or both of the reference sites. We hypothesize that shared-haplotype individuals are potential migrants and that unique-haplotype individuals are potential long-term residents. A parsimony approach was used to estimate the minimum number of migration events necessary to explain the haplotype distributions on a phylogenetic tree. The observed predominance of migration events into the contaminated sites supported our migration hypothesis. We conclude the atomic blast sites are ecological sinks and that immigration masks the genotoxic effects of radiation on the resident populations.

  6. Graft of the gelatin sponge scaffold containing genetically-modified neural stem cells promotes cell differentiation, axon regeneration, and functional recovery in rat with spinal cord transection.

    PubMed

    Du, Bao-Ling; Zeng, Xiang; Ma, Yuan-Huan; Lai, Bi-Qin; Wang, Jun-Mei; Ling, Eng-Ang; Wu, Jin-Lang; Zeng, Yuan-Shan

    2015-04-01

    Biological materials combined with genetically-modified neural stem cells (NSCs) are candidate therapy targeting spinal cord injury (SCI). Based on our previous studies, here we performed gelatin sponge (GS) scaffold seeded with neurotrophin-3 (NT-3) and its receptor TrkC gene modifying NSCs for repairing SCI. Eight weeks later, compared with other groups, neurofilament-200 and 5-hydroxytryptamine positive nerve fibers were more in the injury site of the N+T-NSCs group. Immunofluorescence staining showed the grafted NSCs could differentiate into microtubule associated protein (Map2), postsynaptic density (PSD95), and mouse oligodendrocyte special protein (MOSP) positive cells. The percentage of the Map2, PSD95, and MOSP positive cells in the N+T-NSCs group was higher than the other groups. Immuno-electron microscopy showed the grafted NSCs making contact with each other in the injury site. Behavioral analysis indicated the recovery of hindlimbs locomotion was better in the groups receiving cell transplant, the best recovery was found in the N+T-NSCs group. Electrophysiology revealed the amplitude of cortical motor evoked potentials was increased significantly in the N+T-NSCs group, but the latency remained long. These findings suggest the GS scaffold containing genetically-modified NSCs may bridge the injury site, promote axon regeneration and partial functional recovery in SCI rats. © 2014 Wiley Periodicals, Inc.

  7. Integration of genotoxicity and population genetic analyses in kangaroo rats (Dipodomys merriami) exposed to radionuclide contamination at the Nevada Test Site, USA.

    PubMed

    Theodorakis, C W; Bickham, J W; Lamb, T; Medica, P A; Lyne, T B

    2001-02-01

    We examined effects of radionuclide exposure at two atomic blast sites on kangaroo rats (Dipodomys merriami) at the Nevada Test Site, Nevada, USA, using genotoxicity and population genetic analyses. We assessed chromosome damage by micronucleus and flow cytometric assays and genetic variation by randomly amplified polymorphic DNA (RAPD) and mitochondrial DNA (mtDNA) analyses. The RAPD analysis showed no population structure, but mtDNA exhibited differentiation among and within populations. Genotoxicity effects were not observed when all individuals were analyzed. However, individuals with mtDNA haplotypes unique to the contaminated sites had greater chromosomal damage than contaminated-site individuals with haplotypes shared with reference sites. When interpopulation comparisons used individuals with unique haplotypes, one contaminated site had greater levels of chromosome damage than one or both of the reference sites. We hypothesize that shared-haplotype individuals are potential migrants and that unique-haplotye individuals are potential long-term residents. A parsimony approach was used to estimate the minimum number of migration events necessary to explain the haplotype distributions on a phylogenetic tree. The observed predominance of migration events into the contaminated sites supported our migration hypothesis. We conclude the atomic blast sites are ecological sinks and that immigration masks the genotoxic effects of radiation on the resident populations.

  8. Effects of environmental and physiological covariates on sex differences in unconditioned and conditioned anxiety and fear in a large sample of genetically heterogeneous (N/Nih-HS) rats

    PubMed Central

    2011-01-01

    Physiological and environmental variables, or covariates, can account for an important portion of the variability observed in behavioural/physiological results from different laboratories even when using the same type of animals and phenotyping procedures. We present the results of a behavioural study with a sample of 1456 genetically heterogeneous N/Nih-HS rats, including males and females, which are part of a larger genome-wide fine-mapping QTL (Quantitative Trait Loci) study. N/Nih-HS rats have been derived from 8 inbred strains and provide very small distance between genetic recombinations, which makes them a unique tool for fine-mapping QTL studies. The behavioural test battery comprised the elevated zero-maze test for anxiety, novel-cage (open-field like) activity, two-way active avoidance acquisition (related to conditioned anxiety) and context-conditioned freezing (i.e. classically conditioned fear). Using factorial analyses of variance (ANOVAs) we aimed to analyse sex differences in anxiety and fear in this N/Nih-HS rat sample, as well as to assess the effects of (and interactions with) other independent factors, such as batch, season, coat colour and experimenter. Body weight was taken as a quantitative covariate and analysed by covariance analysis (ANCOVA). Obliquely-rotated factor analyses were also performed separately for each sex, in order to evaluate associations among the most relevant variables from each behavioural test and the common dimensions (i.e. factors) underlying the different behavioural responses. ANOVA analyses showed a consistent pattern of sex effects, with females showing less signs of anxiety and fear than males across all tests. There were also significant main effects of batch, season, colour and experimenter on almost all behavioural variables, as well as "sex × batch", "sex × season" and "sex × experimenter" interactions. Body weight showed significant effects in the ANCOVAs of most behavioural measures, but sex effects were

  9. Differential gene expression in pancreatic tissues of streptozocin-induced diabetic rats and genetically-diabetic mice in response to hypoglycemic dipeptide cyclo (His-Pro) treatment.

    PubMed

    Choi, Song Ah; Suh, Hyung Joo; Yun, Jong Won; Choi, Jang Won

    2012-09-01

    Diabetic studies are mostly interested in gene expression in the pancreas, the site of insulin secretion that regulates blood glucose levels. However, a single gene approach has been ruled out for many years in discovering new genes or the molecular networks involved in the induction process of diabetes. To understand the molecular mechanisms by which cyclo (His-Pro) (CHP) affects amelioration of diabetes mellitus, we performed gene expression profiling in the pancreatic tissues of two diabetic animal models, streptozocin (STZ)-induced diabetic rats (T1DM) and genetically-diabetic (C57BL/6J ob/ob) mice (T2DM). To understand the healing process of these diabetic rodents, we examined the effects of CHP on various gene expression in pancreatic tissues of both animal models. Our microarray analysis revealed that a total of 1,175 genes were down-regulated and 629 genes were up-regulated in response to STZ treatment, and the altered expression levels of numerous genes were restored to normal state upon CHP treatment. In particular, 476 genes showed significantly altered gene expression upon CHP treatment. In a functional classification, 7,198 genes were counted as differentially expressed in pancreatic tissues of STZ- and CHP-treated rats compared with control, whereas 1,534 genes were restored to normal states by CHP treatment. Microarray data demonstrated for the first time that overexpression of the genes encoding IL-1 receptor, lipid metabolic enzymes (e.g. Mte1, Ptdss1, and Sult2a1), myo-inositol oxygenase, glucagon, and somatostatin as well as down-regulation of olfactory receptor 984 and mitochondrial ribosomal protein, which are highly linked to T1DM etiology. In genetically-diabetic mice, 4,384 genes were altered in gene expression by more than 2-fold compared to the control mice, when counted differentially expressed. In genetically-diabetic mice, 4,384 genes altered in expression by higher than 2-fold were counted as differentially expressed genes in

  10. Combination of selenium and green tea improves the efficacy of chemoprevention in a rat colorectal cancer model by modulating genetic and epigenetic biomarkers.

    PubMed

    Hu, Ying; McIntosh, Graeme H; Le Leu, Richard K; Nyskohus, Laura S; Woodman, Richard J; Young, Graeme P

    2013-01-01

    Dietary supplementation of selenium and green tea holds promise in cancer prevention. In this study, we evaluated the efficacies of selenium and green tea administered individually and in combination against colorectal cancer in an azoxymethane (AOM)-induced rat colonic carcinogenesis model and determined the underlying mechanisms of the protection. Four-week old Sprague-Dawley male rats were fed with diets containing 0.5% green tea extract, 1 ppm selenium as selenium-enriched milk protein, or combination of 1 ppm selenium and 0.5% green tea extract. Animals received 2 AOM (15 mg/kg) treatments to induce colonic oncogenesis. Rats were killed 8 or 30 wk later after the last AOM to examine the effect of dietary intervention on aberrant crypt foci (ACF) formation or tumor development. On sacrifice, colons were examined for ACF and tumors, the mRNA levels of SFRP5 and Cyclin D1, and the proteins levels of ß-catenin, COX-2, Ki-67, DNMT1 and acetyl histone H3. The combination of selenium and green tea resulted in a significant additive inhibition of large ACF formation, this effect was greater than either selenium or green tea alone, P<0.01; the combination also had a significant additive inhibition effect on all tumor endpoints, the effect of the combination diet on tumor incidence, multiplicity and size was greater than selenium or green tea alone, P<0.01. Rats fed the combination diet showed marked reduction of DNMT1 expression and induction of histone H3 acetylation, which were accompanied by restoration of SFRP5 mRNA in normal-appearing colonic crypts. The combination diet also significantly reduced ß-catenin nuclear translocation, Cyclin D1 expression and cell proliferation. These data show, for the first time, that combination of selenium and green tea is more effective in suppressing colorectal oncogenesis than either agent alone. The preventive effect is associated with regulation of genetic and epigenetic biomarkers implicated in colonic carcinogenesis.

  11. Combination of Selenium and Green Tea Improves the Efficacy of Chemoprevention in a Rat Colorectal Cancer Model by Modulating Genetic and Epigenetic Biomarkers

    PubMed Central

    Hu, Ying; McIntosh, Graeme H.; Le Leu, Richard K.; Nyskohus, Laura S.; Woodman, Richard J.; Young, Graeme P.

    2013-01-01

    Dietary supplementation of selenium and green tea holds promise in cancer prevention. In this study, we evaluated the efficacies of selenium and green tea administered individually and in combination against colorectal cancer in an azoxymethane (AOM)-induced rat colonic carcinogenesis model and determined the underlying mechanisms of the protection. Four-week old Sprague-Dawley male rats were fed with diets containing 0.5% green tea extract, 1ppm selenium as selenium-enriched milk protein, or combination of 1ppm selenium and 0.5% green tea extract. Animals received 2 AOM (15 mg/kg) treatments to induce colonic oncogenesis. Rats were killed 8 or 30 wk later after the last AOM to examine the effect of dietary intervention on aberrant crypt foci (ACF) formation or tumor development. On sacrifice, colons were examined for ACF and tumors, the mRNA levels of SFRP5 and Cyclin D1, and the proteins levels of ß-catenin, COX-2, Ki-67, DNMT1 and acetyl histone H3. The combination of selenium and green tea resulted in a significant additive inhibition of large ACF formation, this effect was greater than either selenium or green tea alone, P<0.01; the combination also had a significant additive inhibition effect on all tumor endpoints, the effect of the combination diet on tumor incidence, multiplicity and size was greater than selenium or green tea alone, P<0.01. Rats fed the combination diet showed marked reduction of DNMT1 expression and induction of histone H3 acetylation, which were accompanied by restoration of SFRP5 mRNA in normal-appearing colonic crypts. The combination diet also significantly reduced ß-catenin nuclear translocation, Cyclin D1 expression and cell proliferation. These data show, for the first time, that combination of selenium and green tea is more effective in suppressing colorectal oncogenesis than either agent alone. The preventive effect is associated with regulation of genetic and epigenetic biomarkers implicated in colonic carcinogenesis. PMID

  12. 5-HT1A receptor gene silencers Freud-1 and Freud-2 are differently expressed in the brain of rats with genetically determined high level of fear-induced aggression or its absence.

    PubMed

    Kondaurova, Elena M; Ilchibaeva, Tatiana V; Tsybko, Anton S; Kozhemyakina, Rimma V; Popova, Nina K; Naumenko, Vladimir S

    2016-09-01

    Serotonin 5-HT1A receptor is known to play a crucial role in the mechanisms of genetically defined aggression. In its turn, 5-HT1A receptor functional state is under control of multiple factors. Among others, transcriptional factors Freud-1 and Freud-2 are known to be involved in the repression of 5-HT1A receptor gene expression. However, implication of these factors in the regulation of behavior is unclear. Here, we investigated the expression of 5-HT1A receptor and silencers Freud-1 and Freud-2 in the brain of rats selectively bred for 85 generations for either high level of fear-induced aggression or its absence. It was shown that Freud-1 and Freud-2 levels were different in aggressive and nonaggressive animals. Freud-1 protein level was decreased in the hippocampus, whereas Freud-2 protein level was increased in the frontal cortex of highly aggressive rats. There no differences in 5-HT1A receptor gene expression were found in the brains of highly aggressive and nonaggressive rats. However, 5-HT1A receptor protein level was decreased in the midbrain and increased in the hippocampus of highly aggressive rats. These data showed the involvement of Freud-1 and Freud-2 in the regulation of genetically defined fear-induced aggression. However, these silencers do not affect transcription of the 5-HT1A receptor gene in the investigated rats. Our data indicate the implication of posttranscriptional rather than transcriptional regulation of 5-HT1A receptor functional state in the mechanisms of genetically determined aggressive behavior. On the other hand, the implication of other transcriptional regulators for 5-HT1A receptor gene in the mechanisms of genetically defined aggression could be suggested.

  13. Genetic predisposition to high anxiety- and depression-like behavior coincides with diminished DNA methylation in the adult rat amygdala.

    PubMed

    McCoy, Chelsea R; Jackson, Nateka L; Day, Jeremy; Clinton, Sarah M

    2017-03-01

    Understanding biological mechanisms that shape vulnerability to emotional dysfunction is critical for elucidating the neurobiology of psychiatric illnesses like anxiety and depression. To elucidate molecular and epigenetic alterations in the brain that contribute to individual differences in emotionality, our laboratory utilized a rodent model of temperamental differences. Rats bred for low response to novelty (Low Responders, LRs) are inhibited in novel situations and display high anxiety, helplessness, and diminished sociability compared to High Novelty Responder (HR) rats. Our current transcriptome profiling experiment identified widespread gene expression differences in the amygdala of adult HR/LR rats; we hypothesize that HR/LR gene expression and downstream behavioral differences stem from distinct epigenetic (specifically DNA methylation) patterning in the HR/LR brain. Although we found similar levels of DNA methyltransferase proteins in the adult HR/LR amygdala, next-generation sequencing analysis of the methylome revealed 793 differentially methylated genomic sites between the groups. Most of the differentially methylated sites were hypermethylated in HR versus LR, so we next tested the hypothesis that enhancing DNA methylation in LRs would improve their anxiety/depression-like phenotype. We found that increasing DNA methylation in LRs (via increased dietary methyl donor content) improved their anxiety-like behavior and decreased their typically high levels of Forced Swim Test (FST) immobility; however, dietary methyl donor depletion exacerbated LRs' high FST immobility. These data are generally consistent with findings in depressed patients showing that treatment with DNA methylation-promoting agents improves depressive symptoms, and highlight epigenetic mechanisms that may contribute to individual differences in risk for emotional dysfunction.

  14. Genetic enhancement of visual learning by activation of protein kinase C pathways in small groups of rat cortical neurons.

    PubMed

    Zhang, Guo-Rong; Wang, Xiaodan; Kong, Lingxin; Lu, Xiu-Gui; Lee, Brian; Liu, Meng; Sun, Mei; Franklin, Corinna; Cook, Robert G; Geller, Alfred I

    2005-09-14

    Although learning and memory theories hypothesize that memories are encoded by specific circuits, it has proven difficult to localize learning within a cortical area. Neural network theories predict that activation of a small fraction of the neurons in a circuit can activate that circuit. Consequently, altering the physiology of a small group of neurons might potentiate a specific circuit and enhance learning, thereby localizing learning to that circuit. In this study, we activated protein kinase C (PKC) pathways in small groups of neurons in rat postrhinal (POR) cortex. We microinjected helper virus-free herpes simplex virus vectors that expressed a constitutively active PKC into POR cortex. This PKC was expressed predominantly in glutamatergic and GABAergic neurons in POR cortex. This intervention increased phosphorylation of five PKC substrates that play critical roles in neurotransmitter release (GAP-43 and dynamin) or glutamatergic neurotransmission (specific subunits of AMPA or NMDA receptors and myristoylated alanine-rich C kinase substrate). Additionally, activation of PKC pathways in cultured cortical neurons supported activation-dependent increases in release of glutamate and GABA. This intervention enhanced the learning rate and accuracy of visual object discriminations. In individual rats, the numbers of transfected neurons positively correlated with this learning. During learning, neuronal activity was increased in neurons proximal to the transfected neurons. These results demonstrate that potentiating small groups of glutamatergic and GABAergic neurons in POR cortex enhances visual object learning. More generally, these results suggest that learning can be mediated by specific cortical circuits.

  15. A peroxisome proliferator-activated receptor gamma agonist influenced daily profile of energy expenditure in genetically obese diabetic rats.

    PubMed

    Yoshida, Yuki; Ichikawa, Mineko; Ohta, Minoru; Kanai, Setsuko; Kobayash, Mikako; Ichimaru, Yuhei; Shimazoe, Takao; Watanabe, Shigenori; Funakoshi, Akihiro; Miyasak, Kyoko

    2002-03-01

    Otsuka Long Evans Tokushima Fatty (OLETF) rats were developed as a model of non-insulin-dependent diabetes mellitus (NIDDM) with mild obesity. We reported that the daily profiles of energy expenditure associated with two peaks (one between 05:00 and 08:00 and the other between 20:00 and 22:00) were observed at 8 weeks of age (without NIDDM), while these two peaks disappeared at 24 weeks of age with NIDDM. As a new anti-diabetic drug, a peroxisome proliferator-activated receptor y agonist pioglitazone hydrochloride has been developed, we examined whether pioglitazone normalized daily profiles of energy expenditure at 24 weeks of age. A control diet and pioglitazone (0.1%)-containing diet were fed from 6 weeks of age. The two peaks of daily profiles of energy expenditure, which disappeared in OLETF rats with the control diet at 24 weeks of age, were reproduced by administration of pioglitazone. The respiratory quotient was lower and fat derived energy used for combustion was increased by pioglitazone at both ages. The body weight, daily food intake, plasma levels of fat, insulin, leptin and the wet weight of visceral fat were not influenced, but the levels of blood hemoglobin Alc and plasma tumor necrosis factor a were decreased by pioglitazone. Administration of pioglitazone improved daily profiles of energy expenditure via affecting glucose and fat metabolisms.

  16. Transthoracic echocardiography in rats. Evalution of commonly used indices of left ventricular dimensions, contractile performance, and hypertrophy in a genetic model of hypertrophic heart failure (SHHF-Mcc-facp-Rats) in comparison with Wistar rats during aging.

    PubMed

    Reffelmann, Thorsten; Kloner, Robert A

    2003-09-01

    Two-weekly echocardiographic examinations were conducted in nine SHHF-Mc-fa(cp) rats in comparison with eight age-matched Wistar rats. In the SHHF-rats, characterized by progressive LV-dilation and decreasing contractile function between 77-87 weeks of age, left ventricular (LV) hypertrophy was most sensitively demonstrated by increased LV-mass-index (p < 0.001). LV-areas and area-ejection fraction (EF) (2D-images) discriminated more sensitively in the early stages than M-mode-derived diameters and fractional shortening (FS); midwall shortening was the most sensitive parameter of reduced systolic function. Post-mortem measurements showed an excellent correlation with calculated LV-mass (r = 0.91). Post-mortem LV-volumes correlated significantly with diastolic LV-diameters, LV-areas, and calculated LV-volumes (r = 0.56-0.59). Mean within-subject standard deviations in controls were 0.5-0.6 mm (LV-diameters), 3.1-4.6 mm(2) (LV-areas), approximately 10% of the mean for FS, area-EF and midwall shortening, and approximately 20% for wall thickness and LV-mass. The data might be used to choose the most sensitive parameters, and to estimate sample size for echocardiographic investigations in rats.

  17. The major histocompatibility complex of the rat,RT 1 : II. biochemical evidence for a complex genetic organization.

    PubMed

    Sporer, R; Black, G; Rigiero, C; Manson, L; Götze, D

    1978-12-01

    Recombinational analysis has shown that the rat MHC,RT1 is divided into two regions:RT1.A, which codes for class I (transplantation) antigens, andRT1.B, which controls the humoral immune response and proliferative response to allogeneic cells as well as the expression of class II (Ia) antigens. Serological and sequence studies suggest that there might be more than one antigen-coding locus within theRT1.A region. Results obtained by sequential immunoprecipitation reveal that both regions code for at least two gene products. By implication, theRT1 complex must therefore harbor at least four loci;RT1.A andD coding for class I glycoproteins (45,000 daltons); andRT1.B andE coding for class II (Ia) glycoproteins (35,000 and 28,000 daltons).

  18. Metabotropic glutamate receptor 5 activity in the nucleus accumbens is required for the maintenance of ethanol self-administration in a rat genetic model of high alcohol intake.

    PubMed

    Besheer, Joyce; Grondin, Julie J M; Cannady, Reginald; Sharko, Amanda C; Faccidomo, Sara; Hodge, Clyde W

    2010-05-01

    Systemic modulation of Group I and II metabotropic glutamate receptors (mGluRs) regulate ethanol self-administration in a variety of animal models. Although these receptors are expressed in reward-related brain regions, the anatomical specificity of their functional involvement in ethanol self-administration remains to be characterized. This study sought to evaluate the functional role of Group I (mGluR5) and Group II (mGluR2/3) in mesocorticolimbic brain regions in ethanol self-administration. Alcohol-preferring (P) rats, a genetic model of high alcohol drinking, were trained to self-administer ethanol (15% v/v) versus water in operant conditioning chambers. Effects of brain site-specific infusion of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and the mGluR2/3 agonist were then assessed on the maintenance of self-administration. Microinjection of the mGluR5 antagonist MPEP in the nucleus accumbens reduced ethanol self-administration at a dose that did not alter locomotor activity. By contrast, infusion of the mGluR2/3 agonist LY379268 in the nucleus accumbens reduced self-administration and produced nonspecific reductions in locomotor activity. The mGluR5 involvement showed anatomical specificity as evidenced by lack of effect of MPEP infusion in the dorsomedial caudate or medial prefrontal cortex on ethanol self-administration. To determine reinforcer specificity, P-rats were trained to self-administer sucrose (.4% w/v) versus water, and effects of intra-accumbens MPEP were tested. The MPEP did not alter sucrose self-administration or motor behavior. These results suggest that mGluR5 activity specifically in the nucleus accumbens is required for the maintenance of ethanol self-administration in individuals with genetic risk for high alcohol consumption. Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  19. Himematsutake (Iwade Strain 101) extract (ABM-FD): genetic toxicology and a 3-month dietary toxicity study in rats.

    PubMed

    Sumiya, T; Ikeda, Y; Broadmeadow, A; May, K; Pritchard, L; Horne, C; Burlinson, B

    2008-06-01

    Agaricus blazei Murrill, an edible mushroom, is used as a functional food due to medicinal effects of (1-->6)-beta-D-glucan protein complex which has been shown to have anti tumour activity in mice. A 13week oral subchronic study in rats performed at 500, 1000 or 2000mg/kg/day caused, at the highest dose, reduced erythrocyte numbers and high mean cell volume in males, high creatinine and urea concentrations in both sexes and low spleen weights in females, but no histopathological change. The findings suggested low level chronic toxicity at 2000mg/kg/day and a no observed adverse effect level (NOAEL) of 1000mg/kg/day. Genotoxicity tests on the aqueous extract were negative in the bacterial reverse mutation test, either with or without S9 mix, up to 5000microg/plate and in a rat bone marrow micronucleus test up to 2g/kg bodyweight. The extract was positive at acceptable levels of toxicity in an L5178Y mouse lymphoma assay following 24h exposure in the absence of S9 and this was associated with an increase in the number of small colonies, suggesting possible clastogenic activity or aneuploidy, rather than point mutation. The aqueous extract of A. blazei is therefore of low subchronic toxicity and did not cause any direct effect upon the DNA molecule and the weak positive in the L5178 mouse lymphoma test was likely due to large deletions or the loss of the whole chromosomes rather than to direct damage to the DNA.

  20. Neonatal handling enduringly decreases anxiety and stress responses and reduces hippocampus and amygdala volume in a genetic model of differential anxiety: Behavioral-volumetric associations in the Roman rat strains.

    PubMed

    Río-Álamos, Cristóbal; Oliveras, Ignasi; Piludu, Maria Antonietta; Gerbolés, Cristina; Cañete, Toni; Blázquez, Gloria; Lope-Piedrafita, Silvia; Martínez-Membrives, Esther; Torrubia, Rafael; Tobeña, Adolf; Fernández-Teruel, Alberto

    2017-02-01

    The hippocampus and amygdala have been proposed as key neural structures related to anxiety. A more active hippocampus/amygdala system has been related to greater anxious responses in situations involving conflict/novelty. The Roman Low- (RLA) and High-avoidance (RHA) rat lines/strains constitute a genetic model of differential anxiety. Relative to RHA rats, RLA rats exhibit enhanced anxiety/fearfulness, augmented hippocampal/amygdala c-Fos expression following exposure to novelty/conflict, increased hippocampal neuronal density and higher endocrine responses to stress. Neonatal handling (NH) is an environmental treatment with long-lasting anxiety/stress-reducing effects in rodents. Since hippocampus and amygdala volume are supposed to be related to anxiety/fear, we hypothesized a greater volume of both areas in RLA than in RHA rats, as well as that NH treatment would reduce anxiety and the volume of both structures, in particular in the RLA strain. Adult untreated and NH-treated RHA and RLA rats were tested for anxiety, sensorimotor gating (PPI), stress-induced corticosterone and prolactin responses, two-way active avoidance acquisition and in vivo 7 T 1H-Magnetic resonance image. As expected, untreated RLA rats showed higher anxiety and post-stress hormone responses, as well as greater hippocampus and amygdala volumes than untreated RHA rats. NH decreased anxiety/stress responses, especially in RLA rats, and significantly reduced hippocampus and amygdala volumes in this strain. Dorsal striatum volume was not different between the strains nor it was affected by NH. Finally, there were positive associations (as shown by correlations, factor analysis and multiple regression) between anxiety and PPI and hippocampus/amygdala volumes.

  1. One-year oral toxicity study on a genetically modified maize MON810 variety in Wistar Han RCC rats (EU 7th Framework Programme project GRACE).

    PubMed

    Zeljenková, Dagmar; Aláčová, Radka; Ondrejková, Júlia; Ambrušová, Katarína; Bartušová, Mária; Kebis, Anton; Kovrižnych, Jevgenij; Rollerová, Eva; Szabová, Elena; Wimmerová, Soňa; Černák, Martin; Krivošíková, Zora; Kuricová, Miroslava; Líšková, Aurélia; Spustová, Viera; Tulinská, Jana; Levkut, Mikuláš; Révajová, Viera; Ševčíková, Zuzana; Schmidt, Kerstin; Schmidtke, Jörg; Schmidt, Paul; La Paz, Jose Luis; Corujo, Maria; Pla, Maria; Kleter, Gijs A; Kok, Esther J; Sharbati, Jutta; Bohmer, Marc; Bohmer, Nils; Einspanier, Ralf; Adel-Patient, Karine; Spök, Armin; Pöting, Annette; Kohl, Christian; Wilhelm, Ralf; Schiemann, Joachim; Steinberg, Pablo

    2016-10-01

    The GRACE (GMO Risk Assessment and Communication of Evidence; www.grace-fp7.eu ) project was funded by the European Commission within the 7th Framework Programme. A key objective of GRACE was to conduct 90-day animal feeding trials, animal studies with an extended time frame as well as analytical, in vitro and in silico studies on genetically modified (GM) maize in order to comparatively evaluate their use in GM plant risk assessment. In the present study, the results of a 1-year feeding trial with a GM maize MON810 variety, its near-isogenic non-GM comparator and an additional conventional maize variety are presented. The feeding trials were performed by taking into account the guidance for such studies published by the EFSA Scientific Committee in 2011 and the OECD Test Guideline 452. The results obtained show that the MON810 maize at a level of up to 33 % in the diet did not induce adverse effects in male and female Wistar Han RCC rats after a chronic exposure.

  2. mRNA GPR162 changes are associated with decreased food intake in rat, and its human genetic variants with impairments in glucose homeostasis in two Swedish cohorts.

    PubMed

    Caruso, Vanni; Sreedharan, Smitha; Carlini, Valeria P; Jacobsson, Josefin A; Haitina, Tatjana; Hammer, Joanna; Stephansson, Olga; Crona, Filip; Sommer, Wolfgang H; Risérus, Ulf; Lannfelt, Lars; Marcus, Claude; Heilig, Markus; de Barioglio, Susana R; Fredriksson, Robert; Schiöth, Helgi B

    2016-05-01

    G protein-coupled receptors (GPCRs) are a class of integral membrane proteins mediating intercellular interactions of fundamental physiological importance for survival including regulation of food intake, blood pressure, and hormonal sensing signaling, among other roles. Homeostatic alterations in the physiological status of GPCRs are often associated with underlying causes of disease, and to date, several orphan GPCRs are still uncharacterized. Findings from our previous study demonstrate that the Rhodopsin family protein GPR162 is widely expressed in GABAergic as well as other neurons within the mouse hippocampus, whereas extensive expression is observed in hypothalamus, amygdala, and ventral tegmental area, regions strictly interconnected and involved in the regulation of energy homeostasis and hedonic feeding. In this study, we provide a further anatomical characterization of GPR162 in mouse brain via in situ hybridization as well as detailed mRNA expression in a panel of rat tissues complementing a specie-specific mapping of the receptor. We also provide an attempt to demonstrate a functional implication of GPR162 in food intake-related behavior via antisense knockdown studies. Furthermore, we performed human genetic studies in which for the first time, variants of the GPR162 gene were associated with impairments in glucose homeostasis. Copyright © 2016. Published by Elsevier B.V.

  3. Transplant of polymer-encapsulated cells genetically engineered to release nerve growth factor allows a normal functional development of the visual cortex in dark-reared rats.

    PubMed

    Pizzorusso, T; Porciatti, V; Tseng, J L; Aebischer, P; Maffei, L

    1997-09-01

    Visual experience is necessary for the normal development of the visual system. Dark-reared mammals show abnormal vision when reintroduced into a normal environment. The absence of visual experience during the critical period results in reduced and/or inappropriate neural responses in visual cortical neurons. The change in electrical activity induced by dark rearing is probably reflected by the modulation of specific unknown molecules. Neurotrophins are present in the developing visual cortex and their production depends on visually driven electrical activity. Recent findings support the possibility that an important link between electrical activity in the visual pathway and correct development of visual properties is represented by neurotrophins. We advance the hypothesis that the visual abnormalities present in dark-reared animals could be due to a decreased production of a neurotrophin secondary to the lack of visual stimulation. We report that some properties of visual cortical response such as receptive field size, orientation selectivity, adaptation to repeated stimulation, response latency and visual acuity are virtually normal in dark-reared rats transplanted with polymer-encapsulated baby hamster kidney cells genetically engineered to release nerve growth factor.

  4. Role of the genetic background of rats in infection by HTLV-I and HTLV-II and in the development of associated diseases.

    PubMed

    Kazanji, M; Ibrahim, F; Fiette, L; Bomford, R; De Thé, G

    1997-09-26

    Three aspects of the rat model of HTLV-I/II infection were investigated. (i) The efficacy of HTLV-I-transformed rat cell lines in infecting different strains of rats: WKY and Lewis HTLV-I-transformed cell lines were injected into adult WKY, Lewis and Brown Norway rats, representing syngeneic and allogeneic combinations. The HTLV-I provirus was not detected in peripheral-blood mononuclear cells (PBMC) from these rats 18 weeks after inoculation, showing that HTLV-I-transformed rat cells are not suitable for virus challenge in vaccination experiments. Rats inoculated with Lewis HTLV-I-transformed cells produced an antibody response to HTLV-I, which was higher in allogeneic (WKY and Brown Norway) than in syngeneic rats. (ii) The susceptibility of rats to HTLV-II infection: After human HTLV-II-producing cells (MO) were injected into adult WKY rats, the HTLV-II provirus was detected in PBMC 12 weeks later. Sequencing of a portion of this provirus confirmed its identity with the HTLV-II from MO cells. (iii) The role of MHC haplotype in susceptibility to neurological disease in rats inoculated as newborns with HTLV-I: The hypothesis that the RT-Ik haplotype confers susceptibility was tested by inoculating newborn OKA (RT-Ik), WKY (RT-Il), Lewis (RT-Il) and Fischer 344 (RT-I lvl) rats with human HTLV-I-producing cells (MT-2). Eighteen months later, only the WKY rats showed histological abnormality of the spinal cord, without clinical paralysis. Fischer 344 rats developed cutaneous tumors and OKA rats mammary tumors. The HTLV-I provirus was not detected in these tumors.

  5. Total internal reflectance fluorescence imaging of genetically engineered ryanodine receptor-targeted Ca(2+) probes in rat ventricular myocytes.

    PubMed

    Pahlavan, Sara; Morad, Marin

    2017-09-01

    The details of cardiac Ca(2+) signaling within the dyadic junction remain unclear because of limitations in rapid spatial imaging techniques, and availability of Ca(2+) probes localized to dyadic junctions. To critically monitor ryanodine receptors' (RyR2) Ca(2+) nano-domains, we combined the use of genetically engineered RyR2-targeted pericam probes, (FKBP-YCaMP, Kd=150nM, or FKBP-GCaMP6, Kd=240nM) with rapid total internal reflectance fluorescence (TIRF) microscopy (resolution, ∼80nm). The punctate z-line patterns of FKBP,(2)-targeted probes overlapped those of RyR2 antibodies and sharply contrasted to the images of probes targeted to sarcoplasmic reticulum (SERCA2a/PLB), or cytosolic Fluo-4 images. FKBP-YCaMP signals were too small (∼20%) and too slow (2-3s) to detect Ca(2+) sparks, but the probe was effective in marking where Fluo-4 Ca(2+) sparks developed. FKBP-GCaMP6, on the other hand, produced rapidly decaying Ca(2+) signals that: a) had faster kinetics and activated synchronous with ICa(3) but were of variable size at different z-lines and b) were accompanied by spatially confined spontaneous Ca(2+) sparks, originating from a subset of eager sites. The frequency of spontaneously occurring sparks was lower in FKBP-GCaMP6 infected myocytes as compared to Fluo-4 dialyzed myocytes, but isoproterenol enhanced their frequency more effectively than in Fluo-4 dialyzed cells. Nevertheless, isoproterenol failed to dissociate FKBP-GCaMP6 from the z-lines. The data suggests that FKBP-GCaMP6 binds predominantly to junctional RyR2s and has sufficient on-rate efficiency as to monitor the released Ca(2+) in individual dyadic clefts, and supports the idea that β-adrenergic agonists may modulate the stabilizing effects of native FKBP on RyR2. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Effect of caffeine and adenosine receptor ligands on the expression of spike-and-wave discharges in Genetic Absence Epilepsy Rats from Strasbourg (GAERS).

    PubMed

    Germé, Katuschia; Faure, Jean-Baptiste; Koning, Estelle; Nehlig, Astrid

    2015-02-01

    The influence of caffeine on epileptic seizures remains a matter of debate. Here we tested on Genetic Absence Epilepsy Rats from Strasbourg (GAERS) the consequences of acute and chronic exposure to caffeine on the expression of spike-and-wave discharges (SWDs). Since caffeine is a mixed nonspecific A(1) and A(2A) adenosine receptor antagonist, we measured also the influence of antagonists and agonists of these receptors on SWD expression. GAERS were equipped with four cortical electrodes over the frontoparietal cortex and the cumulated duration and number of SWDs were recorded for 120 min after the injection of increasing doses of caffeine, specific antagonists and agonists of A(1) and A(2A) adenosine receptors. The effects of chronic caffeine were also studied. In GAERS, caffeine dose-dependently reduced the cumulated number and duration of SWDs which almost disappeared after the injection of the two highest doses of caffeine, 5 and 10 mg/kg. Likewise, the A(1) and A(2A) adenosine receptor antagonists led to a dose-dependent reduction of SWD expression while the agonists dose-dependently increased SWD expression. Conversely, the chronic exposure to caffeine via drinking water for 15 days did not influence SWD expression. With the exception of the two highest doses of caffeine that largely enhanced activity, all compounds including low doses of caffeine had no effect on locomotor activity of GAERS. These data show that the acute exposure to low doses of caffeine, or A(1) and A(2A) adenosine receptor antagonists reduces SWD expression in GAERS, independently from any effect on motor activity. The chronic exposure of GAERS to caffeine does not affect the expression of epilepsy.

  7. Elevated sterol regulatory elementary binding protein 1 and GluA2 levels in the hippocampal nuclear fraction of Genetic Absence Epilepsy Rats from Strasbourg.

    PubMed

    Sekar, Sathiya; Omran, Entesar; Gopalakrishnan, Venkat; Howland, John G; Snutch, Terrance P; Taghibiglou, Changiz

    2017-10-01

    Studies in animal models and human tissues show that nuclear translocation of sterol regulatory element binding protein 1 (SREBP1) and glutamate A2 subunit (GluA2) of cell-surface AMPA receptor (AMPAR) trigger neuronal excitotoxicity-induced apoptosis in stroke. However, it is not known whether a similar type of underlying pathophysiology occurs in absence epilepsy. To explore this issue, we examined the levels of mature SREBP1, GluA2, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), p53, and activated to total caspase 3 ratio in nuclear fractions (NF) of hippocampal homogenate from 8 to 10 week old male Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and non-epileptic control (NEC) strains. Mature SREBP1 and GluA2 levels were elevated approximately two-fold in NFs of GAERS hippocampal homogenates compared to NEC animals. Significant increases in GAPDH (∼15-fold) and total caspase 3 (∼10-fold) levels were also found in NFs of GAERS hippocampal homogenates in comparison to the non-epileptic strain. Data from the current study suggest that absence epilepsy in GAERS is associated with nuclear translocation of mature SREBP1, GluA2 subunit of AMPARs, and recruitment of pro-cell death signaling proteins such as GAPDH and caspase 3. These changes may contribute to hippocampal neuronal/glial cell death in GAERS. Therefore, inhibiting the nuclear accumulation of mature SREBP1 and GluA2 translocation may reduce the pathophysiology of absence epilepsy. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Persistence of 1,25D-induced hypercalciuria in alendronate-treated genetic hypercalciuric stone-forming rats fed a low-calcium diet

    PubMed Central

    Asplin, John R.; Culbertson, Christopher D.; Granja, Ignacio; Krieger, Nancy S.; Bushinsky, David A.

    2014-01-01

    Genetic hypercalciuric stone-forming (GHS) rats demonstrate increased intestinal Ca absorption, increased bone resorption, and reduced renal tubular Ca reabsorption leading to hypercalciuria and all form kidney stones. GHS have increased vitamin D receptors (VDR) at these sites of Ca transport. Injection of 1,25(OH)2D3 (1,25D) leads to a greater increase in urine (u)Ca in GHS than in control Sprague-Dawley (SD), possibly due to the additional VDR. In GHS the increased uCa persists on a low-Ca diet (LCD) suggesting enhanced bone resorption. We tested the hypothesis that LCD, coupled to inhibition of bone resorption by alendronate (alen), would eliminate the enhanced 1,25D-induced hypercalciuria in GHS. SD and GHS were fed LCD and half were injected daily with 1,25D. After 8 days all were also given alen until euthanasia at day 16. At 8 days, 1,25D increased uCa in SD and to a greater extent in GHS. At 16 days, alen eliminated the 1,25D-induced increase in uCa in SD. However, in GHS alen decreased, but did not eliminate, the 1,25D-induced hypercalciuria, suggesting maximal alen cannot completely prevent the 1,25D-induced bone resorption in GHS, perhaps due to increased VDR. There was no consistent effect on mRNA expression of renal transcellular or paracellular Ca transporters. Urine CaP and CaOx supersaturation (SS) increased with 1,25D alone in both SD and GHS. Alen eliminated the increase in CaP SS in SD but not in GHS. If these results are confirmed in humans with IH, the use of bisphosphonates, such as alen, may not prevent the decreased bone density observed in these patients. PMID:24573387

  9. Genetic differences in NMDA and D1 receptor levels, and operant responding for food and morphine in Lewis and Fischer 344 rats.

    PubMed

    Martín, Sonsoles; Lyupina, Yulia; Crespo, José Antonio; González, Begoña; García-Lecumberri, Carmen; Ambrosio, Emilio

    2003-05-30

    Previously, we have shown that Lewis (LEW) rats acquire faster than Fischer 344 (F344) rats operant food- and morphine-reinforced tasks under fixed-ratio schedules of reinforcement. The first purpose of the present work has been to study if differences in operant responding behavior may participate in the reported differences in morphine self-administration behavior between both inbred rat strains. To this end, we have analyzed the microstructure of responding obtained under a variable-interval (VI) of food reinforcement by calculating the inter-response time (IRT) for each rat strain. LEW rats exhibited shorter IRTs than F344 rats, suggesting that LEW rats may have an inherent high or compulsive operant responding activity. When subjects of both inbred rat strains were submitted to a schedule of morphine reinforcement of high responding requirements such as progressive ratio schedules, LEW rats also reached significantly higher breaking points and final response ratio than F344 rats for i.v. morphine self-administration. Given that there are neurochemical differences between both rat strains and that glutamatergic N-methyl-D-aspartate (NMDA) and dopaminergic D(1) receptors have been involved in operant responding behavior, a second purpose of this work has been to measure basal NMDA and D(1) receptor levels in these rat strains by quantitative receptor autoradiography. Compared to F344 rats, LEW rats showed higher basal NMDA receptor levels in frontal and cingulate cortex, caudate putamen, central amygdaloid nuclei, and intermediate white layer of superior colliculus, and higher basal D(1) receptor levels in several areas of hippocampus and thalamus, and substantia nigra pars reticulata. Taken together, these results suggest that an inherent high operant responding activity of LEW rats may have a role in the previous reported faster acquisition of opiate-reinforced behavior in operant self-administration paradigms under fixed-ratio schedules of reinforcement. In

  10. A genetic rat model of depression, Flinders Sensitive Line, has a lower density of 5-HT1A receptors, but a higher density of 5-HT1B receptors, compared to control rats

    PubMed Central

    Nishi, Kyoko; Kanemaru, Kazuya; Diksic, Mirko

    2008-01-01

    Deficiencies in brain serotonergic neurotransmission, which is in part associated with the alteration of brain serotonin (5-HT) receptors, have been proposed as part of a neurochemical imbalance in affective disorders, including depression. The drugs used for the treatment of these disorders generally act through and/or on the serotonergic system. Different animal models of depression have provided researchers with tools to obtain a better understanding of drug actions and possibilities to obtain insight into the neurochemical bases of these disorders. The measurements of the 5-HT1A and 5-HT1B receptor densities in a rat model of depression, Flinders Sensitive Line (FSL) rats, and comparisons with Sprague-Dawley (SPD) and Flinders Resistant Line (FRL) rats, are reported here. The receptor sites were quantified by autoradiography in more than twenty-five distinct brain regions known to have relatively large densities of respective sites. Some brain regions (e.g., dental gyrus, septal nucleus) were divided into several parts, according to previously known subdivisions, because of a substantial heterogeneity of these receptors. The densities in the FSL rats (“depressed” rats) were compared statistically to those in the SPD rats. In addition, comparisons were made to the densities in the FRL rats (rats not showing depressive symptoms). Comparisons were performed with the SPD and FRL rats because both of these strains have been used as control animals in studies of FSL rats. The results show that the densities of 5-HT1A receptors are not significantly different between the FSL and SPD rats, but they are significantly different from the FRL rats. 5-HT1A receptor density is significantly higher in the FRL rats than the SPD rats. The 5-HT1B receptors were significantly greater in the FSL rats than in either the SPD or FRL rats. In addition, the FRL rats have 5-HT1B receptor densities significantly lower in many brain regions than the SPD rats. The data presented here

  11. Subchronic feeding study with genetically modified stacked trait lepidopteran and coleopteran resistant (DAS-Ø15Ø7-1xDAS-59122-7) maize grain in Sprague-Dawley rats.

    PubMed

    Appenzeller, Laura M; Malley, Linda; Mackenzie, Susan A; Hoban, Denise; Delaney, Bryan

    2009-07-01

    DAS-Ø15Ø7-1xDAS-59122-7 (1507x59122) is a genetically modified (GM) maize hybrid that was produced by crossing of two GM maize inbreds; DAS-Ø15Ø7-1 and DAS-59122-7. This hybrid cross expresses four transgenic proteins: Cry1F and PAT (from DAS-Ø15Ø7-1) and Cry34Ab1/Cry35Ab1 and PAT (from DAS-59122-7) that confer resistance to lepidopteran and coleopteran pests and tolerance to the herbicidal active ingredient glufosinate-ammonium. The current subchronic feeding study was conducted in Sprague-Dawley rats to evaluate the potential health effects of long-term consumption of a rodent diet containing 1507x59122 maize grain compared with a diet containing maize grain from its near-isogenic control (091). Diets formulated with three unrelated non-GM commercial hybrids (3573, 35P12, 36G12) were also included for within study reference data. All diets contained 34% (w/wt) maize grain and were prepared according to the specifications of PMI((R)) Nutrition International, LLC Certified Rodent LabDiet((R)) 5002 (PMI((R)) 5002). Diets were fed ad libitum to rats for at least 92days. OECD 408 response variables from rats fed the 1507x59122 diet were compared with those from rats fed the 091 control diet. No toxicologically significant differences were observed in nutritional performance variables, clinical and neurobehavioral signs, ophthalmology, clinical pathology (hematology, clinical chemistry, coagulation, and urinalysis), organ weights, and gross and microscopic pathology between rats in the 091 and 1507x59122 treatment groups. The results from this study demonstrate that 1507x59122 maize grain is as safe and nutritious as non-GM maize grain and support the concept that crossing of two safe GM maize events results in production of a safe stacked GM event.

  12. Edible Safety Assessment of Genetically Modified Rice T1C-1 for Sprague Dawley Rats through Horizontal Gene Transfer, Allergenicity and Intestinal Microbiota

    PubMed Central

    Zhao, Kai; Ren, Fangfang; Han, Fangting; Liu, Qiwen; Wu, Guogan; Xu, Yan; Zhang, Jian; Wu, Xiao; Wang, Jinbin; Li, Peng; Shi, Wei; Zhu, Hong; Lv, Jianjun; Zhao, Xiao; Tang, Xueming

    2016-01-01

    In this study, assessment of the safety of transgenic rice T1C-1 expressing Cry1C was carried out by: (1) studying horizontal gene transfer (HGT) in Sprague Dawley rats fed transgenic rice for 90 d; (2) examining the effect of Cry1C protein in vitro on digestibility and allergenicity; and (3) studying the changes of intestinal microbiota in rats fed with transgenic rice T1C-1 in acute and subchronic toxicity tests. Sprague Dawley rats were fed a diet containing either 60% GM Bacillus thuringiensis (Bt) rice T1C-1 expressing Cry1C protein, the parental rice Minghui 63, or a basic diet for 90 d. The GM Bt rice T1C-1 showed no evidence of HGT between rats and transgenic rice. Sequence searching of the Cry1C protein showed no homology with known allergens or toxins. Cry1C protein was rapidly degraded in vitro with simulated gastric and intestinal fluids. The expressed Cry1C protein did not induce high levels of specific IgG and IgE antibodies in rats. The intestinal microbiota of rats fed T1C-1 was also analyzed in acute and subchronic toxicity tests by DGGE. Cluster analysis of DGGE profiles revealed significant individual differences in the rats' intestinal microbiota. PMID:27706188

  13. The accelerated post-infarction progression of cardiac remodelling is associated with genetic changes in an untreated streptozotocin-induced diabetic rat model.

    PubMed

    Song, Guang-Yuan; Wu, Yong-Jian; Yang, Yue-Jin; Li, Jian-Jun; Zhang, Hong-Liang; Pei, Han-Jun; Zhao, Zhen-Yan; Zeng, Zeng-Hua; Hui, Ru-Tai

    2009-10-01

    The mechanism by which diabetes mellitus exacerbates myocardial injury and the incidence of heart failure after acute myocardial infarction (AMI), remains unclear. We studied the severity of cardiac dysfunction and time-dependent gene expression in a hyperglycaemic rat model with AMI. The diabetic model was produced by injection of streptozotocin in Sprague-Dawley rats. Ten weeks after induction of diabetes, AMI was induced by ligation of the left anterior descending coronary artery. Cardiac function and left ventricular (LV) dimensions were evaluated using two-dimensional echocardiography. Structural changes were assessed by histological examination. Gene expression profile was documented by using affymetrix genechip U230 2.0 array and real time-PCR. During 56 days post-AMI, lower survival rates, worse LV function, more severe fibrosis, and larger LV diameters were identified in diabetic rats compared with non-diabetic rats. A total 1221 genes involved in processes, such as glucose metabolism, fatty acid metabolism, extracellular matrix, and apoptosis, were found to be differentially expressed between diabetic and non-diabetic rats, of these 770 were up-regulated and 451 down-regulated. Up-regulation of the genes was found 1-2 weeks earlier in diabetic rats than in non-diabetic rats. The present data suggest that hyperglycaemia up-regulates remodelling-related genes, which may be responsible for the worse outcomes in diabetics than in non-diabetics after AMI.

  14. Genetic Counseling

    MedlinePlus

    ... Home > Pregnancy > Before or between pregnancies > Genetic counseling Genetic counseling E-mail to a friend Please fill ... a genetic counselor in your area. What is genetic counseling? Genetic counseling helps you understand how genes , ...

  15. Assessment of Glial Scar, Tissue Sparing, Behavioral Recovery and Axonal Regeneration following Acute Transplantation of Genetically Modified Human Umbilical Cord Blood Cells in a Rat Model of Spinal Cord Contusion

    PubMed Central

    Mukhamedshina, Yana O.; Garanina, Ekaterina E.; Masgutova, Galina A.; Galieva, Luisa R.; Sanatova, Elvira R.; Chelyshev, Yurii A.; Rizvanov, Albert A.

    2016-01-01

    Objective and Methods This study investigated the potential for protective effects of human umbilical cord blood mononuclear cells (UCB-MCs) genetically modified with the VEGF and GNDF genes on contusion spinal cord injury (SCI) in rats. An adenoviral vector was constructed for targeted delivery of VEGF and GDNF to UCB-MCs. Using a rat contusion SCI model we examined the efficacy of the construct on tissue sparing, glial scar severity, the extent of axonal regeneration, recovery of motor function, and analyzed the expression of the recombinant genes VEGF and GNDF in vitro and in vivo. Results Transplantation of UCB-MCs transduced with adenoviral vectors expressing VEGF and GDNF at the site of SCI induced tissue sparing, behavioral recovery and axonal regeneration comparing to the other constructs tested. The adenovirus encoding VEGF and GDNF for transduction of UCB-MCs was shown to be an effective and stable vehicle for these cells in vivo following the transplantation into the contused spinal cord. Conclusion Our results show that a gene delivery using UCB-MCs-expressing VEGF and GNDF genes improved both structural and functional parameters after SCI. Further histological and behavioral studies, especially at later time points, in animals with SCI after transplantation of genetically modified UCB-MCs (overexpressing VEGF and GDNF genes) will provide additional insight into therapeutic potential of such cells. PMID:27003408

  16. Leptin Deficiency and Its Effects on Tibial and Vertebral Bone Mechanical Properties in Mature Genetically Lean and Obese JCR:LA-Corpulent Rats.

    PubMed

    Reimer, Raylene A; Lamothe, Jeremy M; Zernicke, Ronald F

    2012-01-01

    Leptin signaling deficient rodents have emerged as models of obesity/insulin resistance syndrome. Altered leptin signaling, however, can affect axial and appendicular bone geometrical properties differently, and, thus, we hypothesized that leptin-deficiency would differentially influence mechanical properties of vertebrae and tibiae compared to lean rats. Mature (9 mo) leptin receptor deficient obese (cp/cp; n = 8) and lean (+/?; n = 7) male JCR:LA-corpulent rats were used to test that hypothesis. Tibiae and the sixth lumbar vertebrae (L(6)) were scanned with micro-CT and were broken in three point-bending (tibiae) or axial loading (L(6)). Supporting the hypothesis, vertebrae and tibiae were differentially affected by leptin signaling deficiency. Tibiae, but not vertebrae, were significantly shorter in obese rats and achieved a significantly greater load (>18%), displacement (>15%), and stress (>18%) at the proportional limit, relative to the lean rats. Conversely, L(6) in obese rats had significantly reduced displacement (>25%) and strain (>32%) at proportional limit, relative to the lean rats. Those combined results suggest that the etiology and duration of obesity may be important determinants of bone mechanical properties, and axial and appendicular bones may be affected differently.

  17. Leptin Deficiency and Its Effects on Tibial and Vertebral Bone Mechanical Properties in Mature Genetically Lean and Obese JCR:LA-Corpulent Rats

    PubMed Central

    Reimer, Raylene A.; LaMothe, Jeremy M.; Zernicke, Ronald F.

    2012-01-01

    Leptin signaling deficient rodents have emerged as models of obesity/insulin resistance syndrome. Altered leptin signaling, however, can affect axial and appendicular bone geometrical properties differently, and, thus, we hypothesized that leptin-deficiency would differentially influence mechanical properties of vertebrae and tibiae compared to lean rats. Mature (9 mo) leptin receptor deficient obese (cp/cp; n = 8) and lean (+/?; n = 7) male JCR:LA-corpulent rats were used to test that hypothesis. Tibiae and the sixth lumbar vertebrae (L6) were scanned with micro-CT and were broken in three point-bending (tibiae) or axial loading (L6). Supporting the hypothesis, vertebrae and tibiae were differentially affected by leptin signaling deficiency. Tibiae, but not vertebrae, were significantly shorter in obese rats and achieved a significantly greater load (>18%), displacement (>15%), and stress (>18%) at the proportional limit, relative to the lean rats. Conversely, L6 in obese rats had significantly reduced displacement (>25%) and strain (>32%) at proportional limit, relative to the lean rats. Those combined results suggest that the etiology and duration of obesity may be important determinants of bone mechanical properties, and axial and appendicular bones may be affected differently. PMID:22888408

  18. [Genetics and genetic counseling].

    PubMed

    Izzi, Claudia; Liut, Francesca; Dallera, Nadia; Mazza, Cinzia; Magistroni, Riccardo; Savoldi, Gianfranco; Scolari, Francesco

    2016-01-01

    Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most frequent genetic disease, characterized by progressive development of bilateral renal cysts. Two causative genes have been identified: PKD1 and PKD2. ADPKD phenotype is highly variable. Typically, ADPKD is an adult onset disease. However, occasionally, ADPKD manifests as very early onset disease. The phenotypic variability of ADPKD can be explained at three genetic levels: genic, allelic and gene modifier effects. Recent advances in molecular screening for PKD gene mutations and the introduction of the new next generation sequencing (NGS)- based genotyping approach have generated considerable improvement regarding the knowledge of genetic basis of ADPKD. The purpose of this article is to provide a comprehensive review of the genetics of ADPKD, focusing on new insights in genotype-phenotype correlation and exploring novel clinical approach to genetic testing. Evaluation of these new genetic information requires a multidisciplinary approach involving a nephrologist and a clinical geneticist.

  19. IL-1β is induced in reactive astrocytes in the somatosensory cortex of rats with genetic absence epilepsy at the onset of spike-and-wave discharges, and contributes to their occurrence.

    PubMed

    Akin, Demet; Ravizza, Teresa; Maroso, Mattia; Carcak, Nihan; Eryigit, Tugba; Vanzulli, Ilaria; Aker, Rezzan Gülhan; Vezzani, Annamaria; Onat, Filiz Yılmaz

    2011-12-01

    Interleukin (IL)-1β plays a crucial role in the mechanisms of limbic seizures in rodent models of temporal lobe epilepsy. We addressed whether activation of the IL-1β signaling occurs in rats with genetic absence epilepsy (GAERS) during the development of spike-and-wave discharges (SWDs). Moreover, we studied whether inhibition of IL-1β biosynthesis in GAERS could affect SWD activity. IL-1β expression and glia activation were studied by immunocytochemistry in the forebrain of GAERS at postnatal days (PN)14, PN20, and PN90 and in age-matched non-epileptic control Wistar rats. In PN14 GAERS, when no SWDs have developed yet, IL-1β immunostaining was undetectable, and astrocytes and microglia showed a resting phenotype similar to control Wistar rats. In 3 out of 9 PN20 GAERS, IL-1β was observed in activated astrocytes of the somatosensory cortex; the cytokine expression was associated with the occurrence of immature-type of SWDs. In all adult PN90 GAERS, when mature SWDs are established, IL-1β was observed in reactive astrocytes of the somatosensory cortex but not in adjacent cortical areas or in extra-cortical regions. An age-dependent c-fos activation was found in the somatosensory cortex of GAERS with maximal levels reached in PN90 rats; c-fos was also induced in some thalamic nuclei in PN20 and PN90 GAERS. Inhibition of IL-1β biosynthesis in PN90 GAERS by 4-day systemic administration of a specific ICE/Caspase-1 blocker, significantly reduced both SWD number and duration. These results show that IL-1β is induced in reactive astrocytes of the somatosensory cortex of GAERS at the onset of SWDs. IL-1β has pro-ictogenic properties in this model, and thus it may play a contributing role in the mechanisms underlying the occurrence of absence seizures. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. A 90-day subchronic feeding study of genetically modified maize expressing Cry1Ac-M protein in Sprague-Dawley rats.

    PubMed

    Liu, Pengfei; He, Xiaoyun; Chen, Delong; Luo, Yunbo; Cao, Sishuo; Song, Huan; Liu, Ting; Huang, Kunlun; Xu, Wentao

    2012-09-01

    The cry1Ac-M gene, coding one of Bacillus thuringiensis (Bt) crystal proteins, was introduced into maize H99 × Hi IIB genome to produce insect-resistant GM maize BT-38. The food safety assessment of the BT-38 maize was conducted in Sprague-Dawley rats by a 90-days feeding study. We incorporated maize grains from BT-38 and H99 × Hi IIB into rodent diets at three concentrations (12.5%, 25%, 50%) and administered to Sprague-Dawley rats (n=10/sex/group) for 90 days. A commercialized rodent diet was fed to an additional group as control group. Body weight, feed consumption and toxicological response variables were measured, and gross as well as microscopic pathology were examined. Moreover, detection of residual Cry1Ac-M protein in the serum of rats fed with GM maize was conducted. No death or adverse effects were observed in the current feeding study. No adverse differences in the values of the response variables were observed between rats that consumed diets containing GM maize BT-38 and non-GM maize H99 × Hi IIB. No detectable Cry1Ac-M protein was found in the serum of rats after feeding diets containing GM maize for 3 months. The results demonstrated that BT-38 maize is as safe as conventional non-GM maize.

  1. The characteristics of hepatic Gsα-cAMP axis in HSHF diet-fed obese insulin resistance rats and genetic diabetic mice.

    PubMed

    Xue, Nina; Wei, Chen; Zhang, Lihong; Liu, Hongying; Wang, Xiaojuan; Wang, Lili

    2017-03-04

    Stimulatory G protein α-subunit (Gsα) mediated cyclic adenosine monophosphate (cAMP) signal is required for elevated hepatic glucose production (HGP) in diabetic patients. However, it remains obscure of the exact characteristics of hepatic Gsα-cAMP signal axis (including Gsα, glucagon receptor, β2-adrenergic receptor, cAMP, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) in insulin resistance (IR) and type 2 diabetes mellitus (T2DM). In current study, we investigated the changing characteristics of hepatic Gsα-cAMP signal axis and blood glucose in high-sugar-high-fat (HSHF)-diet-induced IR wistar rats and db/db diabetic mice. As expected, the HSHF-diet rats were characterized by hyperinsulinemia, hyperglycemia and impaired glucose tolerance. According to a threshold (1.7) of HOMA-R, the process of IR in HSHF-diet rats could be divided into slight and high IR stages, with the week-23 as the cut-off point. In early slight IR stage, key molecules expressions of hepatic Gsα-cAMP signal axis in HSHF-diet rats were up-regulated with significantly elevated fasting blood glucose (FBG) from 18 to 23 weeks. Unexpectedly, in high IR stage, hepatic Gsα-cAMP signal axis was recovered comparatively to that of normal chow-diet rats, and no significant differences in FBG levels were found. However, in diabetic db/db mice, up-regulation of hepatic Gsα-cAMP signal axis was responsible for its severely increased fasting hyperglycaemia. Our data revealed a positive correlation between hepatic Gsα-cAMP signal axis and FBG in slight IR stage of HSHF-diet rats and diabetic db/db mice. The current finding thus suggested hepatic Gsα-cAMP signal axis plays a central role in regulating of FBG during the occurrence and development of T2DM.

  2. Medical genetics

    SciTech Connect

    Nora, J.J.; Fraser, F.C.

    1989-01-01

    This book presents a discussion of medical genetics for the practitioner treating or counseling patients with genetic disease. It includes a discussion of the relationship of heredity and diseases, the chromosomal basis for heredity, gene frequencies, and genetics of development and maldevelopment. The authors also focus on teratology, somatic cell genetics, genetics and cancer, genetics of behavior.

  3. Effect of ME-3451-106, an aqueous extract of Stichaster striatus with inhibitory activity of voluntary alcohol intake, in genetically drinker rats: Isolation and identification of the active fraction.

    PubMed

    Font, M; Bilbeny, N; Contreras, S; Paeile, C; García, H

    2006-04-21

    The aqueous extract obtained from Stichaster striatus Müller & Troschel (Asteroidea, Stichasteridae) has been shown to possess activity as an alcohol appetite inhibitor after oral administration in a rat model with a genetically established excessive appetite for alcohol (Wistar rats, lineage UChB). A significant decrease in the consumption of ethanol was observed (unrelated to a possible disulfiram effect) without a change in the normal food or water intake during the experimentation period. A bio-guided fractionation of the extract was carried out in order to identify the most active fraction, in which the presence of a group of natural endogenous polyamines in undetermined proportions is suspected. Our hypothesis was to relate the activity obtained for the original ME-3451-106 extract with the presence of these polyamines in the extract in question. The activity shown by a series of commercially available polyamines (putrescine (Pu), spermidine (SPD) and spermine (SP)) in inhibiting voluntary ethanol intake lends support to our hypothesis. The extract was selected on the basis of oral tradition, which claimed that the consumption of a "soup" obtained by boiling starfish, later identified as Stichaster striatus, prevented the appearance of alcoholism in laborers on properties entrusted to the Jesuit order during the middle period of the Spanish conquest of America (17-18th century).

  4. Genetic control of HgCl2-induced IgE and autoimmunity by a 117-kb interval on rat chromosome 9 through CD4 CD45RChigh T cells.

    PubMed

    Pedros, C; Papapietro, O; Colacios, C; Casemayou, A; Bernard, I; Garcia, V; Lagrange, D; Mariamé, B; Andreoletti, O; Fournié, G J; Saoudi, A

    2013-06-01

    Gold or mercury salts trigger a dramatic IgE response and a CD4 T-cell-dependent nephropathy in Brown-Norway (BN), but not in Lewis (LEW) rats. We previously identified the 1.1-Mb Iresp3 (immunoglobin response QTL3) locus on chromosome 9 that controls these gold salt-triggered immune disorders. In the present work, we investigated the genetic control of HgCl(2)-induced immunological disorders and assessed the relative contribution of the CD45RC(high) and CD45RC(low) CD4 T-cell subpopulations in this control. By using interval-specific congenic lines, we narrowed down Iresp3 locus to 117-kb and showed that BN rats congenic for the LEW 117-kb were protected from HgCl(2)-triggered IgE response and nephropathy. This 117-kb interval also controls CD45RC expression by CD4 T cells and the ability of CD45RC(high) CD4 T cells to trigger the autoimmune disorders resulting from HgCl(2) administration. This 117-kb region contains four genes, including Vav1, a strong candidate gene according to its cellular function and exclusive expression in hematopoietic cells. Thus, this study highlights the role of the CD45RC(high) CD4 T-cell subpopulation in the opposite susceptibility of BN and LEW rats to HgCl(2)-triggered immune disorders and identifies a 117-kb interval on chromosome 9 that has a key role in their functions.

  5. Genetic Dissection of a Blood Pressure Quantitative Trait Locus on Rat Chromosome 1 and Gene Expression Analysis Identifies SPON1 as a Novel Candidate Hypertension Gene

    PubMed Central

    Clemitson, Jenny-Rebecca; Dixon, Richard J.; Haines, Steve; Bingham, Andrew J.; Patel, Bhakti R.; Hall, Laurence; Lo, Ming; Sassard, Jean; Charchar, Fadi J.; Samani, Nilesh J.

    2007-01-01

    A region with a major effect on blood pressure is located on rat chromosome 1. We have previously isolated this region in reciprocal congenic strains (WKY.SHR-Sa and SHR.WKY-Sa) derived from a cross of the spontaneously hypertensive rat (SHR) with the Wistar-Kyoto rat (WKY) and shown that there are two distinct BP quantitative trait loci (QTLs), BP1 and BP2, in this region. Sisa1, a congenic sub-strain from the SHR.WKY-Sa animals carrying an introgressed segment of 4.3Mb, contains BP1. Here, we report further dissection of BP1 by the creation of two new mutually exclusive congenic sub-strains (Sisa1a and Sisa1b) and interrogation of candidate genes by expression profiling and targeted transcript sequencing. Only one of the sub-strains (Sisa1a) continued to demonstrate a BP difference but with a reduced introgressed segment of 3Mb. Exonic sequencing of the twenty genes located in the Sisa1a region did not identify any major differences between SHR and WKY. However, microarray expression profiling of whole kidney samples and subsequent quantitative RT-PCR identified a single gene, Spon1 that exhibited significant differential expression between the WKY and SHR genotypes at both 6 and 24 weeks of age. Western blot analysis confirmed an increased level of the Spon1 gene product in SHR kidneys. Spon1 belongs to a family of genes with anti-angiogenic properties. These findings justify further investigation of this novel positional candidate gene in BP control in hypertensive rat models and humans. PMID:17332427

  6. Medical genetics

    SciTech Connect

    Jorde, L.B.; Carey, J.C.; White, R.L.

    1995-10-01

    This book on the subject of medical genetics is a textbook aimed at a very broad audience: principally, medical students, nursing students, graduate, and undergraduate students. The book is actually a primer of general genetics as applied to humans and provides a well-balanced introduction to the scientific and clinical basis of human genetics. The twelve chapters include: Introduction, Basic Cell Biology, Genetic Variation, Autosomal Dominant and Recessive Inheritance, Sex-linked and Mitochondrial Inheritance, Clinical Cytogenetics, Gene Mapping, Immunogenetics, Cancer Genetics, Multifactorial Inheritance and Common Disease, Genetic Screening, Genetic Diagnosis and Gene Therapy, and Clinical Genetics and Genetic Counseling.

  7. Time-frequency dynamics during sleep spindles on the EEG in rodents with a genetic predisposition to absence epilepsy (WAG/Rij rats)

    NASA Astrophysics Data System (ADS)

    Hramov, Alexander E.; Sitnikova, Evgenija Y.; Pavlov, Alexey N.; Grubov, Vadim V.; Koronovskii, Alexey A.; Khramova, Marina V.

    2015-03-01

    Sleep spindles are known to appear spontaneously in the thalamocortical neuronal network of the brain during slow-wave sleep; pathological processes in the thalamocortical network may be the reason of the absence epilepsy. The aim of the present work is to study developed changes in the time-frequency structure of sleep spindles during the progressive development of the absence epilepsy in WAG/Rij rats. EEG recordings were made at age 7 and 9 months. Automatic recognition and subsequent analysis of sleep spindles on the EEG were performed using the continuous wavelet transform. The duration of epileptic discharges and the total duration of epileptic activity were found to increase with age, while the duration of sleep spindles, conversely, decreased. In terms of the mean frequency, sleep spindles could be divided into three classes: `slow' (mean frequency 9.3Hz), `medium' (11.4Hz), and `fast' (13.5Hz). Slow and medium (transitional) spindles in five-month-old animals showed increased frequency from the beginning to the end of the spindle. The more intense the epilepsy is, the shorter are the durations of spindles of all types. The mean frequencies of `medium' and `fast' spindles were higher in rats with more intense signs of epilepsy. Overall, high epileptic activity in WAG/Rij rats was linked with significant changes in spindles of the transitional type, with less marked changes in the two traditionally identified types of spindle, slow and fast.

  8. Studies on the genetic linkage of bilirubin and androsterone UDP-glucuronyltransferases by cross-breeding of two mutant rat strains.

    PubMed Central

    Nagai, F; Homma, H; Tanase, H; Matsui, M

    1988-01-01

    Gunn rats, which have defects in bilirubin and 4-nitrophenol UDP-glucuronyltransferases (GT), were crossed with LA Wistar rats with a defect in androsterone GT. The F1 hybrids showed normal GT activities towards androsterone, bilirubin and 4-nitrophenol, demonstrating that Gunn and LA ('low activity') Wistar rats inherit a homozygous dominant trait for androsterone GT and bilirubin GT respectively. The F2 progeny showed four different combinations of bilirubin and androsterone GT activities: defects in both GT activities, a single defect in bilirubin GT activity, a single defect in androsterone GT activity and two normal GT activities. They were segregated in the approximate ratio of 1:3:3:9, which is compatible with Mendel's Principle of Independent Assortment. These results provide evidence that androsterone GT and bilirubin GT are located on different chromosomes. In the F2 generation, defective bilirubin and 4-nitrophenol GT activities were not segregated, indicating that these two mutant genes are closely linked on the same chromosome. PMID:3138978

  9. Genetic algorithms

    NASA Technical Reports Server (NTRS)

    Wang, Lui; Bayer, Steven E.

    1991-01-01

    Genetic algorithms are mathematical, highly parallel, adaptive search procedures (i.e., problem solving methods) based loosely on the processes of natural genetics and Darwinian survival of the fittest. Basic genetic algorithms concepts are introduced, genetic algorithm applications are introduced, and results are presented from a project to develop a software tool that will enable the widespread use of genetic algorithm technology.

  10. Genetic Counseling

    MedlinePlus

    ... Genetic Counseling Genomic Testing Pathogen Genomics Epidemiology Resources Genetic Counseling Recommend on Facebook Tweet Share Compartir In ... informed decisions about testing and treatment. Reasons for Genetic Counseling There are many reasons that people go ...

  11. The Kampo medicines Orengedokuto, Bofutsushosan and Boiogito have different activities to regulate gene expressions in differentiated rat white adipocytes: comprehensive analysis of genetic profiles.

    PubMed

    Yamakawa, Jun-ichi; Ishigaki, Yasuhito; Takano, Fumihide; Takahashi, Takashi; Yoshida, Junko; Moriya, Junji; Takata, Takanobu; Tatsuno, Takanori; Sasaki, Kenroh; Ohta, Tomihisa; Takegami, Tsutomu; Yoshizaki, Fumihiko

    2008-11-01

    Three Kampo medicines, Boiogito (BOT), Bofutsushosan (BTS) and Orengedokuto (OGT), used for obese patients were investigated for their effects on adipogenesis in cultured rat white adipocytes. Administration of the three extracts suppressed adipogenesis in concentration-dependent manners (1-100 microg/ml) without any cytotoxicity. Changes in mRNA expression levels were analyzed using a Rat 230 2.0 Affymetrix GeneChip microarray system. DNA microarray analysis (total probe set: 31099) using cDNAs prepared from adipocytes revealed that BOT, BTS and OGT increased the expression of 133-150 genes and decreased the expression of 42-110 genes by > or =2-fold. We identified 329 downregulated genes and 189 upregulated genes among a total set of 514 probes (overlap: 4). Overall, genes related to cellular movement, cell death, cell growth/differentiation and immune responses were the most downregulated, while those related to lipid metabolism and cell signaling were the most upregulated. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assays were conducted to confirm the microarray results. Analysis of the clustering profiles of the microarray results revealed that BOT and BTS changed the expression levels of similar genes mainly involved in small molecule biochemistry and cell differentiation, while OGT altered 10 genes related to lipid metabolism, in contrast to the effects of BOT and BTS. We also measured mRNA expression levels of seven selected genes highly contributing to the lipid metabolism by using semiquantitative RT-PCR assay, that were acetyl-Coenzyme A carboxylase alpha (ACACA), AE binding protein 1 (AEBP1), patatin-like phospholipase domain containing 8 (PNPLA8), secretoglobin (SCGB1A1), adrenergic (ADRB3), adiponectin (ADIPOQ), monoglyceride lipase (MGLL). Beta-actin (ACTB) gene was used as an endogenous internal standard. The present findings indicate that these three herbal extracts have the potential to prevent adipogenesis in rat

  12. URINARY CALCULI IN GERMFREE RATS

    PubMed Central

    Gustafsson, Bengt E.; Norman, Arne

    1962-01-01

    In a colony of germfree rats 50 per cent of the males had urinary calculi composed of calcium citrate and calcium oxalate. Genetically closely related conventional animals on the same sterilized diet did not present a single case of stone formation. The tendency to calculus formation disappeared when germfree animals were contaminated with the intestinal flora from conventional rats. The calculus formation can readily be explained by the high calcium, high citrate, and high pH of the urine. This pattern was changed to that of conventional rats when the germfree rats were infected with intestinal microorganisms. PMID:13903130

  13. 50-kHz chirping (laughter?) in response to conditioned and unconditioned tickle-induced reward in rats: effects of social housing and genetic variables.

    PubMed

    Panksepp, J; Burgdorf, J

    2000-10-01

    In these studies the incidence of conditioned and unconditioned 50-kHz ultrasonic vocalizations (USVs) in young rats was measured in response to rewarding manual tickling by an experimenter. We found that isolate-housed animals vocalize much more then socially housed ones, and when their housing conditions are reversed, they gradually shift their vocalization tendencies. Isolate-housed animals also show quicker acquisition of instrumental tasks for tickling, and exhibit less avoidance of tickling as compared to socially housed Ss. Isolate-housed animals also show rapid acquisition of 50-kHz USVs to a conditioned stimulus that predicts tickle reward, while socially housed animals do not. We successfully bred for high and low vocalization rates in response to tickling within four generations. The high tickle line showed quicker acquisition of an instrumental task for, as well as less avoidance of, tickling as compared to the random and low tickle lines. They also played more. Lastly, we found that the glutamate antagonist MK-801 can reduce tickle-induced 50-kHz USVs, but is resistant to opioid, dopamine and cholinergic stimulant and blocking agents. Overall, these results suggest that tickle evoked 50-kHz USVs may be a useful behavioral marker of positive social affect in rats. Difficulties with such concepts are also discussed.

  14. Anti-anhedonic effect of deep brain stimulation of the prefrontal cortex and the dopaminergic reward system in a genetic rat model of depression: an intracranial self-stimulation paradigm study.

    PubMed

    Rea, Ellis; Rummel, Julia; Schmidt, Timo T; Hadar, Ravit; Heinz, Andreas; Mathé, Aleksander A; Winter, Christine

    2014-01-01

    One of the two core symptoms of major depression (MD), whether uni- or bipolar, is the inability to experience pleasure, suggested to be triggered by dysregulation within the brain reward system. In recent years, deep brain stimulation (DBS) has evolved as a potential tool to modulate pathological neural activity; stimulation of the subgenual cingulate (Cg25) has been shown to reduce depressive symptoms, including anhedonia. In rodents, the ventromedial prefrontal cortex (vmPFC) is likely to represent the correlate of Cg25 and accordingly, stimulation of vmPFC reduces anhedonia-like behavior in rats. The present study addresses the question of whether the anti-anhedonic effect of vmPFC-DBS is mediated by the brain reward system. Rats of the Flinders Sensitive Line (FSL), a validated genetic animal model of depression, and its controls, the Flinders Resistant Line (FRL), were stimulated in the vmPFC and tested in the forced swim test (FST), sucrose consumption test (SCT) and the intracranial self-stimulation (ICSS) paradigm. The curve-shift paradigm of ICSS was used in combination with vmPFC-DBS, d-amphetamine and fluoxetine to quantify reward-facilitating or -attenuating treatment effects. Our findings support anti-depressive efficacy of vmPFC-DBS with respect to despair- and anhedonia-like behavior, as shown in the FST and SCT, respectively. However, DBS did not elicit reward-facilitating or reward-attenuating effects on ICSS behavior. These data suggest that it is unlikely that the anti-anhedonic effect of vmPFC-DBS depends on the mesolimbic dopaminergic reward system. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Rhythm and blues: animal models of epilepsy and depression comorbidity

    PubMed Central

    Epps, S. Alisha; Weinshenker, David

    2014-01-01

    Clinical evidence shows a strong, bidirectional comorbidity between depression and epilepsy that is associated with decreased quality of life and responsivity to pharmacotherapies. At present, the neurobiological underpinnings of this comorbidity remain hazy. To complicate matters, anticonvulsant drugs can cause mood disturbances, while antidepressant drugs can lower seizure threshold, making it difficult to treat patients suffering from both depression and epilepsy. Animal models have been created to untangle the mechanisms behind the relationship between these disorders and to serve as screening tools for new therapies targeted to treat both simultaneously. These animal models are based on chemical interventions (e.g. pentylenetetrazol, kainic acid, pilocarpine), electrical stimulations (e.g. kindling, electroshock), and genetic/selective breeding paradigms (e.g. Genetically Epilepsy-Prone Rats (GEPRs), Genetic Absence Epilepsy Rat from Strasbourg (GAERS), WAG/Rij rats, Swim Lo-Active rats (SwLo)). Studies on these animal models point to some potential mechanisms that could explain epilepsy and depression comorbidity, such as various components of the dopaminergic, noradrenergic, serotonergic, and GABAergic systems, as well as key brain regions, like the amygdala and hippocampus. These models have also been used to screen possible therapies. The purpose of the present review is to highlight the importance of animal models in research on comorbid epilepsy and depression and to explore the contributions of these models to our understanding of the mechanisms and potential treatments for these disorders. PMID:22940575

  16. Rhythm and blues: animal models of epilepsy and depression comorbidity.

    PubMed

    Epps, S Alisha; Weinshenker, David

    2013-01-15

    Clinical evidence shows a strong, bidirectional comorbidity between depression and epilepsy that is associated with decreased quality of life and responsivity to pharmacotherapies. At present, the neurobiological underpinnings of this comorbidity remain hazy. To complicate matters, anticonvulsant drugs can cause mood disturbances, while antidepressant drugs can lower seizure threshold, making it difficult to treat patients suffering from both depression and epilepsy. Animal models have been created to untangle the mechanisms behind the relationship between these disorders and to serve as screening tools for new therapies targeted to treat both simultaneously. These animal models are based on chemical interventions (e.g. pentylenetetrazol, kainic acid, pilocarpine), electrical stimulations (e.g. kindling, electroshock), and genetic/selective breeding paradigms (e.g. genetically epilepsy-prone rats (GEPRs), genetic absence epilepsy rat from Strasbourg (GAERS), WAG/Rij rats, swim lo-active rats (SwLo)). Studies on these animal models point to some potential mechanisms that could explain epilepsy and depression comorbidity, such as various components of the dopaminergic, noradrenergic, serotonergic, and GABAergic systems, as well as key brain regions, like the amygdala and hippocampus. These models have also been used to screen possible therapies. The purpose of the present review is to highlight the importance of animal models in research on comorbid epilepsy and depression and to explore the contributions of these models to our understanding of the mechanisms and potential treatments for these disorders. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. An Early Function during Transcription for the Yeast mRNA Export Factor Dbp5p/Rat8p Suggested by Its Genetic and Physical Interactions with Transcription Factor IIH Components

    PubMed Central

    Estruch, Francisco; Cole, Charles N.

    2003-01-01

    The yeast DEAD-box protein Dbp5p/Rat8p is an essential factor for mRNA export and shuttles between the nucleus and the cytoplasm. It is concentrated at the cytoplasmic fibrils of the nuclear pore complex where it interacts with several nucleoporins. On the basis of this localization, it has been suggested that it might participate in a terminal step of RNA export, the release from the mRNA of proteins that accompany the mRNA during translocation through nuclear pores. In this report, we present evidence linking Dbp5p to transcription. Two different screens identified genetic interactions between DBP5 and genes involved in early transcription events, initiation and promoter clearance. Mutations of transcription proteins expected to impair transcription act as suppressors of dbp5 mutants, whereas those that may act to increase transcription are synthetically lethal with dbp5 mutations. We also show that growth and mRNA export in dbp5 mutant strains are dependent on the carboxy-terminal domain of the RNA pol II largest subunit. Finally, we show that Dbp5p associates physically with components of transcription factor IIH. Because these interactions affect not only growth but also mRNA export, they are likely to reflect a functional relationship between Dbp5p and the transcription machinery. Together, our results suggest a nuclear role for Dbp5 during the early steps of transcription. PMID:12686617

  18. Genetic Disorders

    MedlinePlus

    ... This can cause a medical condition called a genetic disorder. You can inherit a gene mutation from ... during your lifetime. There are three types of genetic disorders: Single-gene disorders, where a mutation affects ...

  19. Genetic counseling

    MedlinePlus

    ... this page: //medlineplus.gov/ency/patientinstructions/000510.htm Genetic counseling To use the sharing features on this ... cystic fibrosis or Down syndrome. Who May Want Genetic Counseling? It is up to you whether or ...

  20. Genetic Manipulation

    ERIC Educational Resources Information Center

    Klein, David

    1973-01-01

    Knowledge of genetic manipulations opens the door to ambitious possibilities of inhabiting the world with genetically perfect human beings. Legal, technological and social problems are involved. Attempts must be made to identify hereditary complaints in individuals. (PS)

  1. Genetic Mapping

    MedlinePlus

    ... Genetic Education Resources for Teachers Genomic Careers National DNA Day Online Education Kit Online Genetics Education Resources ... prevalent. Using various laboratory techniques, the scientists isolate DNA from these samples and examine it for unique ...

  2. New Genetics

    MedlinePlus

    ... Organisms RNA Interference The New Genetics is a science education booklet explains the role of genes in health and disease, the basics of DNA and its molecular cousin RNA, and new directions in genetic research. ...

  3. Genetic modification and genetic determinism

    PubMed Central

    Resnik, David B; Vorhaus, Daniel B

    2006-01-01

    In this article we examine four objections to the genetic modification of human beings: the freedom argument, the giftedness argument, the authenticity argument, and the uniqueness argument. We then demonstrate that each of these arguments against genetic modification assumes a strong version of genetic determinism. Since these strong deterministic assumptions are false, the arguments against genetic modification, which assume and depend upon these assumptions, are therefore unsound. Serious discussion of the morality of genetic modification, and the development of sound science policy, should be driven by arguments that address the actual consequences of genetic modification for individuals and society, not by ones propped up by false or misleading biological assumptions. PMID:16800884

  4. Genetic modification and genetic determinism.

    PubMed

    Resnik, David B; Vorhaus, Daniel B

    2006-06-26

    In this article we examine four objections to the genetic modification of human beings: the freedom argument, the giftedness argument, the authenticity argument, and the uniqueness argument. We then demonstrate that each of these arguments against genetic modification assumes a strong version of genetic determinism. Since these strong deterministic assumptions are false, the arguments against genetic modification, which assume and depend upon these assumptions, are therefore unsound. Serious discussion of the morality of genetic modification, and the development of sound science policy, should be driven by arguments that address the actual consequences of genetic modification for individuals and society, not by ones propped up by false or misleading biological assumptions.

  5. Imaging Genetics

    ERIC Educational Resources Information Center

    Munoz, Karen E.; Hyde, Luke W.; Hariri, Ahmad R.

    2009-01-01

    Imaging genetics is an experimental strategy that integrates molecular genetics and neuroimaging technology to examine biological mechanisms that mediate differences in behavior and the risks for psychiatric disorder. The basic principles in imaging genetics and the development of the field are discussed.

  6. Imaging Genetics

    ERIC Educational Resources Information Center

    Munoz, Karen E.; Hyde, Luke W.; Hariri, Ahmad R.

    2009-01-01

    Imaging genetics is an experimental strategy that integrates molecular genetics and neuroimaging technology to examine biological mechanisms that mediate differences in behavior and the risks for psychiatric disorder. The basic principles in imaging genetics and the development of the field are discussed.

  7. Influence of exercise on NA- and Hsp72-induced release of IFNγ by the peritoneal suspension of macrophages and lymphocytes from genetically obese Zucker rats.

    PubMed

    Martín-Cordero, L; García, J J; Hinchado, M D; Bote, E; Ortega, E

    2013-03-01

    Regular physical exercise is recognized as a nonpharmacological therapeutic strategy in the treatment of metabolic syndrome, and has been proposed for improving obesity, diabetic status, insulin resistance, and immune response. The aim of the present study was to evaluate the effect of a regular exercise program (treadmill running, 5 days/week for 14 weeks at 35 cm/s for 35 min in the last month) on the release of the pro-inflammatory cytokine interferon gamma (IFNγ) by peritoneal cells (macrophages and lymphocytes) from obese Zucker rats (fa/fa) in response to noradrenaline (NA) and heat shock proteins of 72 kDa (Hsp72), and the possible adaptation due to training for a bout acute exercise (a single session of 25-35 min at 35 cm/s). In healthy (lean Fa/fa) and obese animals, peritoneal cells released greater concentrations of IFNγ in response to Hsp72 and lower concentrations in response to NA. The regular exercise training protocol, evaluated in the obese animals, produced a clear change in the regulation of the release of IFNγ. Peritoneal immune cells from trained animals released more IFNγ in response to NA, but there was a reduction in the release of IFNγ in response to Hsp72. In the obese animals, regular exercise caused a change in the inhibitory effect of NA (which now becomes stimulatory) and the stimulatory effect of Hsp72e (which now becomes inhibitory) in relation to the release of IFNγ. This reflects that Hsp72, induced by the prior release of NA following exercise-induced stress, plays a role in the homeostatic balance of release of IFNγ by peritoneal immune cells in obese animals during exercise.

  8. Pharmacokinetics of Dietary Cancer Chemopreventive Compound Dibenzoylmethane in the Rats and Impacts of Nanoemulsion and Genetic knockout of Nrf2 on its Disposition

    PubMed Central

    Lin, Wen; Hong, Jin-Liern; Shen, Guoxiang; Wu, Rachel T.; Wu, Yuwen; Huang, Mou-Tuan; Newmark, Harold L.; Huang, Qingrong; Khor, Tin Oo; Heimbach, Tycho; Kong, Ah-Ng

    2012-01-01

    The pharmacokinetic disposition of a dietary cancer chemopreventive compound dibenzoylmethane (DBM) was studied in male Sprague-Dawley rats after intravenous (i.v.) and oral (p.o.) administrations. Following a single i.v. bolus dose, the mean plasma clearance (CL) of DBM was low as compared to the hepatic blood flow. DBM displayed a high volume of distribution (Vss). The elimination terminal t1/2 was long. The mean CL, Vss and AUC0-∞/dose were similar between the i.v. 10 and 10 mg/kg doses. After single oral doses (10, 50, and 250 mg/kg), the absolute oral bioavailability (F*) of DBM was 7.4 to 13.6%. The increase in AUC was not proportional to the oral doses, suggesting non-linearity. In silico prediction of oral absorption also demonstrated low DBM absorption in vivo. An oil-in-water nanoemulsion containing DBM was formulated to potentially overcome low F* due to poor water solubility of DBM, with enhanced oral absorption. Finally, to examine the role of Nrf2 on the pharmacokinetics of DBM since DBM activates the Nrf2-dependent detoxification pathways, the Nrf2 wild-type (+/+) mice and Nrf2 knockout (−/−) mice were utilized. There was an increased systemic plasma exposure of DBM in Nrf2 (−/−) mice, suggesting that Nrf2 genotype could also play a role in the pharmacokinetic disposition of DBM. Taken together, our results show that DBM has low oral bioavailability which could be due in part to poor water-solubility and this could be overcome by nanotechnology-based drug delivery system and furthermore Nrf2 genotype could also play a role in the pharmacokinetics of DBM. PMID:21341276

  9. Transgenic Rat Models of Huntington's Disease.

    PubMed

    Carreira, João Casaca; Jahanshahi, Ali; Zeef, Dagmar; Kocabicak, Ersoy; Vlamings, Rinske; von Hörsten, Stephan; Temel, Yasin

    2015-01-01

    Several animal models for Huntington's disease (HD) have been created in order to investigate mechanisms of disease, and to evaluate the potency of novel therapies. Here, we describe the characteristics of the two transgenic rat models: transgenic rat model of HD (fragment model) and the Bacterial Artificial Chromosome HD model (full-length model). We discuss their genetic, behavioural, neuropathological and neurophysiological features.

  10. Genetic barcodes

    DOEpatents

    Weier, Heinz -Ulrich G

    2015-08-04

    Herein are described multicolor FISH probe sets termed "genetic barcodes" targeting several cancer or disease-related loci to assess gene rearrangements and copy number changes in tumor cells. Two, three or more different fluorophores are used to detect the genetic barcode sections thus permitting unique labeling and multilocus analysis in individual cell nuclei. Gene specific barcodes can be generated and combined to provide both numerical and structural genetic information for these and other pertinent disease associated genes.

  11. Genetic Alliance

    MedlinePlus

    ... educate consumers around appropriate testing and public health services, and help individuals navigate the complex health care delivery system. Highlights Genetic Alliance Internship Program Learn about ...

  12. Genetics of experimental hypertension.

    PubMed

    Dominiczak, A F; Clark, J S; Jeffs, B; Anderson, N H; Negrin, C D; Lee, W K; Brosnan, M J

    1998-12-01

    Experimental models of genetic hypertension are used to develop paradigms to study human essential hypertension while removing some of the complexity inherent in the study of human subjects. Since 1991 several quantitative trait loci responsible for blood pressure regulation have been identified in various rat crosses. More recently, a series of interesting quantitative trait loci influencing cardiac hypertrophy, stroke, metabolic syndrome and renal damage has also been described. It is recognized that the identification of large chromosomal regions containing a quantitative trait locus is only a first step towards gene identification. The next step is the production of congenic strains and substrains to confirm the existence of the quantitative trait locus and to narrow down the chromosomal region of interest. Several congenic strains have already been produced, with further refinement of the methodology currently in progress. The ultimate goal is to achieve positional cloning of the causal gene, a task which has so far been elusive. There are several areas of cross-fertilization between experimental and human genetics of hypertension, with a successful transfer of two loci directly from rats to humans and with new pharmacogenetic approaches which may be utilized in both experimental and clinical settings.

  13. Genetic Engineering

    ERIC Educational Resources Information Center

    Phillips, John

    1973-01-01

    Presents a review of genetic engineering, in which the genotypes of plants and animals (including human genotypes) may be manipulated for the benefit of the human species. Discusses associated problems and solutions and provides an extensive bibliography of literature relating to genetic engineering. (JR)

  14. Genetic algorithms

    SciTech Connect

    Grefenstette, J.J.

    1994-12-31

    Genetic algorithms solve problems by using principles inspired by natural population genetics: They maintain a population of knowledge structures that represent candidate solutions, and then let that population evolve over time through competition and controlled variation. GAs are being applied to a wide range of optimization and learning problems in many domains.

  15. Genetic Counseling.

    ERIC Educational Resources Information Center

    Exceptional Parent, 1987

    1987-01-01

    Information is presented on a number of tests used in genetic counseling (e.g., genetic evaluation, chromosome evaluation, consideration of multifactorial conditions, prenatal testing, and chorionic villus sampling) which help parents with one disabled child make family planning decisions. (CB)

  16. Genetic Engineering

    ERIC Educational Resources Information Center

    Phillips, John

    1973-01-01

    Presents a review of genetic engineering, in which the genotypes of plants and animals (including human genotypes) may be manipulated for the benefit of the human species. Discusses associated problems and solutions and provides an extensive bibliography of literature relating to genetic engineering. (JR)

  17. Genetic principles

    Treesearch

    Ronald P. Overton; David T. Funk

    1989-01-01

    Tree growth is a function of both environment and genetic makeup. All forest management activities during a rotation from establishment to harvest affect the genetic composition and the environment of a stand. Silvicultural practices which fail to take both of these factors into account will reduce forest productivity.

  18. Arthropod Genetics.

    ERIC Educational Resources Information Center

    Zumwalde, Sharon

    2000-01-01

    Introduces an activity on arthropod genetics that involves phenotype and genotype identification of the creature and the construction process. Includes a list of required materials and directions to build a model arthropod. (YDS)

  19. RNA genetics

    SciTech Connect

    Domingo, E. ); Holland, J.J. . Dept. of Biology); Ahlquist, P. . Dept. of Plant Pathology)

    1988-01-01

    This book contains the proceedings on RNA genetics: Retroviruses, Viroids, and RNA recombination, Volume 2. Topics covered include: Replication of retrovirus genomes, Hepatitis B virus replication, and Evolution of RNA viruses.

  20. Genetic Counseling

    PubMed Central

    Reid, Kathryn J.; Sakati, Nadia; Prichard, Lorraine L.; Schneiderman, Lawrence J.; Jones, Oliver W.; Dixson, Barbara K.

    1976-01-01

    The geographic distribution of County Health Department clinic facilities in the state of California has made it readily possible to establish a regionalized program for genetic counseling services, using public health nurses as a major source of case-finding. From both consumer and health professional standpoints, regionalized satellite genetic counseling clinics have been successful, and in particular, the effectiveness of public health nurses in identifying clinical genetic problems is readily apparent. Long-term follow-up reinforcement of genetic counseling appears to be an important conclusion from these studies. It is our suggestion that reinforcement of counseling would best be accomplished through the health team member (physician, nurse and so forth) following the patient or family rather than through the consulting geneticist. PMID:946335

  1. Genetics (image)

    MedlinePlus

    ... chromosomes to their child, 22 autosomal and 1 sex chromosome. The inheritance of genetic diseases, abnormalities, or traits ... chromosome the abnormal gene resides on (autosomal or sex chromosome), and by whether the gene itself is dominant ...

  2. Ciona Genetics

    PubMed Central

    Veeman, Michael T.; Chiba, Shota; Smith, William C.

    2010-01-01

    Ascidians, such as Ciona, are invertebrate chordates with simple embryonic body plans and small, relatively non-redundant genomes. Ciona genetics is in its infancy compared to many other model systems, but it provides a powerful method for studying this important vertebrate outgroup. Here we give basic methods for genetic analysis of Ciona, including protocols for controlled crosses both by natural spawning and by the surgical isolation of gametes; the identification and propagation of mutant lines; and strategies for positional cloning. PMID:21805273

  3. Genetic Screening

    PubMed Central

    Burke, Wylie; Tarini, Beth; Press, Nancy A.; Evans, James P.

    2011-01-01

    Current approaches to genetic screening include newborn screening to identify infants who would benefit from early treatment, reproductive genetic screening to assist reproductive decision making, and family history assessment to identify individuals who would benefit from additional prevention measures. Although the traditional goal of screening is to identify early disease or risk in order to implement preventive therapy, genetic screening has always included an atypical element—information relevant to reproductive decisions. New technologies offer increasingly comprehensive identification of genetic conditions and susceptibilities. Tests based on these technologies are generating a different approach to screening that seeks to inform individuals about all of their genetic traits and susceptibilities for purposes that incorporate rapid diagnosis, family planning, and expediting of research, as well as the traditional screening goal of improving prevention. Use of these tests in population screening will increase the challenges already encountered in genetic screening programs, including false-positive and ambiguous test results, overdiagnosis, and incidental findings. Whether this approach is desirable requires further empiric research, but it also requires careful deliberation on the part of all concerned, including genomic researchers, clinicians, public health officials, health care payers, and especially those who will be the recipients of this novel screening approach. PMID:21709145

  4. Genetic counseling.

    PubMed

    Pina-Neto, João Monteiro de

    2008-08-01

    The objective of this review of genetic counseling (GC) is to describe the current concepts and philosophical and ethical principles accepted by the great majority of countries and recommended by the World Health Organization, the stages of the process, its results and the psychological impact that a genetic disease has on a family. The concepts presented are based on an historical synthesis of the literature on GC since the 1930s until today, and the articles cited represent the most important research published which today provides the foundation for the theory and practice of GC. The modern definition of GC is a process of communication that deals with the human problems related with the occurrence of a genetic disease in a family. It is of fundamental importance that health professionals are aware of the psychological aspects triggered by genetic diseases and the ways in which these can be managed. In the field of human and medical genetics we are still living in a phase in which technical and scientific aspects predominate, with little emphasis on the study of emotional reactions and people's processes of adaptation to these diseases, which leads to clients having a low level of understanding of the events that have taken place, with negative consequences for family life and for society. The review concludes by discussing the need to refer families with genetic diseases for GC and the need for professionals working in this area to invest more in humanizing care and developing non-directive psychological GC techniques.

  5. Struvite Urolithiasis in Long-Evans Rats.

    PubMed

    Pang, Jassia; Borjeson, Tiffany M; Parry, Nicola M A; Fox, James G

    2015-12-01

    Struvite urinary calculi, which are composed of magnesium, ammonium, and phosphate, can cause complications including sepsis and renal failure. Struvite calculi were identified within the urinary bladder and renal pelvis of 2 Long-Evans rats that died within days after arrival from a commercial vendor. The remaining rats in the shipment were screened by physical examination, radiography, and ultrasonography, revealing an additional 2 animals that were clinically affected. These rats were euthanized, necropsied, and yielded similar findings to those from the first 2 rats. In addition, urine samples had an alkaline pH and contained numerous bacteria (predominantly Proteus mirabilis), leukocytes, and crystals. All calculi were composed completely of struvite. Another 7 rats in the shipment had alkaline urine with the presence of blood cells; 6 of these rats also had abundant struvite crystals, and P. mirabilis was cultured from the urine of 3 rats. Further investigation by the vendor identified 2 of 100 rats with struvite calculi from the same colony. Although no specific cause could be implicated, the fact that all the affected rats came from the same breeding area suggests a genetic or environmental triggering event; a contribution due to diet cannot be ruled out. Our findings suggest that the affected rats had metabolic disturbances coupled with bacterial infection that predisposed them to develop struvite calculi. During sudden increases of struvite urinary calculi cases in rats, urine cultures followed by appropriate surgical intervention and antibiotic therapy is warranted. Additional factors, including diet, merit attention as well.

  6. Genetic differences in hippocampal synaptic plasticity.

    PubMed

    Prakash, S; Ambrosio, E; Alguacil, L F; Del Olmo, N

    2009-06-30

    Synaptic plasticity is considered a physiological substrate for learning and memory [Lynch MA (2004) Long-term potentiation and memory. Physiol Rev 84:87-136] that contributes to maladaptive learning in drug addiction [Schoenbaum G, Roesch MR, Stalnaker TA (2006) Orbitofrontal cortex, decision-making and drug addiction. Trends Neurosci 29:116-124]. Many studies have revealed that drug addiction has a strong hereditary component [Kosten TA, Ambrosio E (2002) HPA axis function and drug addictive behaviors: insights from studies with Lewis and Fischer 344 inbred rats. Psychoneuroendocrinology 27:35-69; Uhl GR (2004) Molecular genetic underpinnings of human substance abuse vulnerability: likely contributions to understanding addiction as a mnemonic process. Neuropharmacology 47 (Suppl 1):140-147], however the contribution of the genetic background to drug-induced changes in synaptic plasticity has been scarcely studied. The present study reports on an analysis of long-term potentiation (LTP) and depotentiation in Lewis (LEW) and Fischer-344 (F344) rats, two inbred rat strains that show different proneness to drugs of abuse and are considered an experimental model of genetic vulnerability to addiction [Kosten TA, Ambrosio E (2002) HPA axis function and drug addictive behaviors: insights from studies with Lewis and Fischer 344 inbred rats. Psychoneuroendocrinology 27:35-69]. The induction of saturated-LTP was similar in LEW and F344 rats treated with saline or cocaine. However, only slices from LEW saline-treated rats showed the reversal of LTP; thus, the depotentiation of saturated-LTP was not observed in cocaine-injected LEW rats and in F344 animals (treated either with cocaine or saline). These results suggest significant differences in hippocampal synaptic plasticity between Lewis and Fischer 344 rats.

  7. [The delta-sleep inducing peptide and its effect on the electroencephalogram and power spectrum density in rats with metaphit-induced epilepsy].

    PubMed

    Stanojlovic, O; Zivanovic, D; Susic, V

    2001-01-01

    epilepsy thus providing an experimental model of choice for the studies of the mechanism of epilepsy development and blockade of NMDA/PCP receptors. In our previous studies a competitive NMDA antagonist CPP [9] and a noncompetitive antagonist MK-801 [8] were used. Non-competitive, selective NMDA antagonists MK-801, PCP and ketamin expressed a partial agonist motor action (myoclonic jerks, ataxia and tremor of the whole body) in audiogenic epilepsy prone mice. DSIP produced no harmful effects even when overdosed or any effect over "normality" [4, 5]. DSIP has a capacity of suppressing various forms of convulsive activity in different animal species. It was suggested that it exerts an anticonvulsant action by influencing neurotransmitter (dopaminergic, adrenergic, GABA-ergic) and neuromodulator (peptidergic) brain systems [12, 13]. Our results, together with the fact that DSIP penetrates through the blood brain barrier after systemic administration and that overdoses of this natural peptide produce no harmful effects, strongly suggest that it could be an important therapeutic agent for the treatment of sleep disturbances. Also, our data demonstrating reduction in incidence, severity and duration of seizure components, suggest that this agent might be a suitable candidate as an antiepileptic drug.

  8. Genetic screening

    PubMed Central

    Andermann, Anne; Blancquaert, Ingeborg

    2010-01-01

    Abstract OBJECTIVE To provide a primer for primary care professionals who are increasingly called upon to discuss the growing number of genetic screening services available and to help patients make informed decisions about whether to participate in genetic screening, how to interpret results, and which interventions are most appropriate. QUALITY OF EVIDENCE As part of a larger research program, a wide literature relating to genetic screening was reviewed. PubMed and Internet searches were conducted using broad search terms. Effort was also made to identify the gray literature. MAIN MESSAGE Genetic screening is a type of public health program that is systematically offered to a specified population of asymptomatic individuals with the aim of providing those identified as high risk with prevention, early treatment, or reproductive options. Ensuring an added benefit from screening, as compared with standard clinical care, and preventing unintended harms, such as undue anxiety or stigmatization, depends on the design and implementation of screening programs, including the recruitment methods, education and counseling provided, timing of screening, predictive value of tests, interventions available, and presence of oversight mechanisms and safeguards. There is therefore growing apprehension that economic interests might lead to a market-driven approach to introducing and expanding screening before program effectiveness, acceptability, and feasibility have been demonstrated. As with any medical intervention, there is a moral imperative for genetic screening to do more good than harm, not only from the perspective of individuals and families, but also for the target population and society as a whole. CONCLUSION Primary care professionals have an important role to play in helping their patients navigate the rapidly changing terrain of genetic screening services by informing them about the benefits and risks of new genetic and genomic technologies and empowering them to

  9. Models of primary generalized epilepsy.

    PubMed

    Hosford, D A

    1995-04-01

    The most important recent development in primary generalized epilepsy has been the use of in-vitro and in-vivo models to delineate the neuronal populations and intrinsic mechanisms, which generate the synchronized thalamocortical burst-firing of absence seizures. Candidate molecular mechanisms, which may be critically involved in the pathogenesis of absence seizures in selected animal models, include the following: altered biophysical properties of T-type calcium channels in the genetic absence epilepsy rat of Strasbourg (GAERS) model; increased numbers of gamma-aminobutyric acid, B subtype receptors in the lethargic mouse (lh/lh mouse) model; and changes in the subunit composition of gamma-aminobutyric acid, A subtype receptors in the GAERS model. Regarding generalized convulsive seizures, neuronal populations within the inferior and superior colliculi appear to regulate seizures in the genetic epilepsy-prone rat (GEPR) model, and subpopulations within the substantia nigra pars reticulata (SNR) appear to regulate seizures in the fluorothyl model. Deficiencies in the function of GABAergic and noradrenergic receptors may underlie generalized convulsive seizures in the GEPR model.

  10. Autotomy following nerve injury: genetic factors in the development of chronic pain.

    PubMed

    Inbal, R; Devor, M; Tuchendler, O; Lieblich, I

    1980-12-01

    Several weeks following transection and ligation of the hind limb nerves in rats, the animals often attack their anaesthetic foot ("autotomy"). This behaviour is thought to reflect a sensory pathology analogous to anaesthesia dolorosa. We report here that the extent of autotomy varies greatly in genetically different populations of rats. Rats of one population, LC2, showed high autotomy levels; rats of another, LC1, showed very low autotomy levels. The main genetic difference between these two populations is the presence of inbred Lewis rat stock in the LC1 population. Pure Lewis strain rats proved to have very low autotomy levels. Thus, constitutional differences between different rat populations effect the extent of autotomy. These data may bear on the fact that after seemingly identical nerve injuries, some humans develop chronic pain syndromes and others do not. Our rat strains may provide a model for investigating the physiological basis of constitutional susceptibility to chronic pain.

  11. Genetic Counseling

    MedlinePlus

    ... test results and your baby’s risk for genetic conditions. Your counselor works with you and your health care provider to help you make decisions about your baby’s health. Refers you to medical ... that focus on your baby’s condition. A support group is a group of people ...

  12. RNA genetics

    SciTech Connect

    Domingo, E. ); Holland, J.J. . Dept. of Biology); Ahlquist, P. . Dept. of Plant Pathology)

    1988-01-01

    This book contains the proceedings on RNA genetics: RNA-directed virus replication Volume 1. Topics covered include: Replication of the poliovirus genome; Influenza viral RNA transcription and replication; and Relication of the reoviridal: Information derived from gene cloning and expression.

  13. Genetic Recombination

    ERIC Educational Resources Information Center

    Whitehouse, H. L. K.

    1973-01-01

    Discusses the mechanisms of genetic recombination with particular emphasis on the study of the fungus Sordaria brevicollis. The study of recombination is facilitated by the use of mutants of this fungus in which the color of the ascospores is affected. (JR)

  14. Genetic Recombination

    ERIC Educational Resources Information Center

    Whitehouse, H. L. K.

    1973-01-01

    Discusses the mechanisms of genetic recombination with particular emphasis on the study of the fungus Sordaria brevicollis. The study of recombination is facilitated by the use of mutants of this fungus in which the color of the ascospores is affected. (JR)

  15. Genetic resistances

    USDA-ARS?s Scientific Manuscript database

    Genetic resistance often has been recognized as the most viable mean for limiting soil-borne diseases. In sugar beet, it is only for Beet necrotic yellow vein virus, i.e., rhizomania that a set of fairly different and effective, single-gene resistance is currently available, while for other soil-bor...

  16. Analysis of vkorc1 polymorphisms in Norway rats using the roof rat as outgroup

    PubMed Central

    2010-01-01

    Background Certain mutations in the vitamin K epoxide reductase subcomponent 1 gene (vkorc1) mediate rodent resistance to warfarin and other anticoagulants. Testing for resistance often involves analysis of the vkorc1. However, a genetic test for the roof rat (Rattus rattus) has yet to be developed. Moreover, an available roof rat vkorc1 sequence would enable species identification based on vkorc1 sequence and the evaluation of natural selection on particular vkorc1 polymorphisms in the Norway rat (R. norvegicus). Results We report the coding sequence, introns and 5' and 3' termini for the vkorc1 gene of roof rats (R. r. alexandrinus and R. r. frugivorus) from Uganda, Africa. Newly designed PCR primers now enable genetic testing of the roof rat and Norway rat. Only synonymous and noncoding polymorphisms were found in roof rats from Uganda. Both nominal subspecies of roof rats were indistinguishable from each other but were distinct from R. losea and R. flavipectus; however, the roof rat also shares at least three coding sequence polymorphisms with R. losea and R. flavipectus. Many of recently published vkorc1 synonymous and non-synonymous single nucleotide polymorphisms (SNPs) in Norway rats are likely SNPs from roof rats and/or other Rattus species. Tests applied to presumably genuine Norway rat vkorc1 SNPs are consistent with a role for selection in two populations carrying the derived Phe63Cys and Tyr139Cys mutations. Conclusion Geographic mapping of vkorc1 SNPs in roof rats should be facilitated by our report. Our assay should be applicable to most species of Rattus, which are intermediate in genetic distance from roof and Norway rats. Vkorc1-mediated resistance due to non-synonymous coding SNPs is not segregating in roof rats from Uganda. By using the roof rat sequence as a reference vkorc1, SNPs now can be assigned to the correct rat species with more confidence. Sampling designs and genotyping strategies employed so far have helped detect candidate mutations

  17. Analysis of vkorc1 polymorphisms in Norway rats using the roof rat as outgroup.

    PubMed

    Díaz, Juan C; Song, Ying; Moore, Anthony; Borchert, Jeff N; Kohn, Michael H

    2010-05-24

    Certain mutations in the vitamin K epoxide reductase subcomponent 1 gene (vkorc1) mediate rodent resistance to warfarin and other anticoagulants. Testing for resistance often involves analysis of the vkorc1. However, a genetic test for the roof rat (Rattus rattus) has yet to be developed. Moreover, an available roof rat vkorc1 sequence would enable species identification based on vkorc1 sequence and the evaluation of natural selection on particular vkorc1 polymorphisms in the Norway rat (R. norvegicus). We report the coding sequence, introns and 5' and 3' termini for the vkorc1 gene of roof rats (R. r. alexandrinus and R. r. frugivorus) from Uganda, Africa. Newly designed PCR primers now enable genetic testing of the roof rat and Norway rat. Only synonymous and noncoding polymorphisms were found in roof rats from Uganda. Both nominal subspecies of roof rats were indistinguishable from each other but were distinct from R. losea and R. flavipectus; however, the roof rat also shares at least three coding sequence polymorphisms with R. losea and R. flavipectus. Many of recently published vkorc1 synonymous and non-synonymous single nucleotide polymorphisms (SNPs) in Norway rats are likely SNPs from roof rats and/or other Rattus species. Tests applied to presumably genuine Norway rat vkorc1 SNPs are consistent with a role for selection in two populations carrying the derived Phe63Cys and Tyr139Cys mutations. Geographic mapping of vkorc1 SNPs in roof rats should be facilitated by our report. Our assay should be applicable to most species of Rattus, which are intermediate in genetic distance from roof and Norway rats. Vkorc1-mediated resistance due to non-synonymous coding SNPs is not segregating in roof rats from Uganda. By using the roof rat sequence as a reference vkorc1, SNPs now can be assigned to the correct rat species with more confidence. Sampling designs and genotyping strategies employed so far have helped detect candidate mutations underlying vkorc1-mediated

  18. Invasive Predators Deplete Genetic Diversity of Island Lizards

    PubMed Central

    Gasc, Amandine; Duryea, M. C.; Cox, Robert M.; Kern, Andrew; Calsbeek, Ryan

    2010-01-01

    Invasive species can dramatically impact natural populations, especially those living on islands. Though numerous examples illustrate the ecological impact of invasive predators, no study has examined the genetic consequences for native populations subject to invasion. Here we capitalize on a natural experiment in which a long-term study of the brown anole lizard (Anolis sagrei) was interrupted by rat invasion. An island population that was devastated by rats recovered numerically following rat extermination. However, population genetic analyses at six microsatellite loci suggested a possible loss of genetic diversity due to invasion when compared to an uninvaded island studied over the same time frame. Our results provide partial support for the hypothesis that invasive predators can impact the genetic diversity of resident island populations. PMID:20706576

  19. Rat retinal transcriptome

    PubMed Central

    Kozhevnikova, Oyuna S.; Korbolina, Elena E.; Ershov, Nikita I.; Kolosova, Natalia G.

    2013-01-01

    Pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, remains poorly understood due to the paucity of animal models that fully replicate the human disease. Recently, we showed that senescence-accelerated OXYS rats develop a retinopathy similar to human AMD. To identify alterations in response to normal aging and progression of AMD-like retinopathy, we compared gene expression profiles of retina from 3- and 18-mo-old OXYS and control Wistar rats by means of high-throughput RNA sequencing (RNA-Seq). We identified 160 and 146 age-regulated genes in Wistar and OXYS retinas, respectively. The majority of them are related to the immune system and extracellular matrix turnover. Only 24 age-regulated genes were common for the two strains, suggestive of different rates and mechanisms of aging. Over 600 genes showed significant differences in expression between the two strains. These genes are involved in disease-associated pathways such as immune response, inflammation, apoptosis, Ca2+ homeostasis and oxidative stress. The altered expression for selected genes was confirmed by qRT-PCR analysis. To our knowledge, this study represents the first analysis of retinal transcriptome from young and old rats with biologic replicates generated by RNA-Seq technology. We can conclude that the development of AMD-like retinopathy in OXYS rats is associated with an imbalance in immune and inflammatory responses. Aging alters the expression profile of numerous genes in the retina, and the genetic background of OXYS rats has a profound impact on the development of AMD-like retinopathy. PMID:23656783

  20. Rapid genetic restoration of a keystone species exhibiting delayed demographic response

    USDA-ARS?s Scientific Manuscript database

    Genetic founder effects are often expected when animals colonize restored habitat in fragmented landscapes, but empirical data on genetic responses to restoration are limited. We examined the genetic response of banner-tailed kangaroo rats (Dipodomys spectabilis) to landscape-scale grassland restor...

  1. Human genetics

    SciTech Connect

    Carlson, E.A.

    1984-01-01

    This text provides full and balanced coverage of the concepts requisite for a thorough understanding of human genetics. Applications to both the individual and society are integrated throughout the lively and personal narrative, and the essential principles of heredity are clearly presented to prepare students for informed participation in public controversies. High-interest, controversial topics, including recombinant DNA technology, oncogenes, embryo transfer, environmental mutagens and carcinogens, IQ testing, and eugenics encourage understanding of important social issues.

  2. Mitochondrial genetics

    PubMed Central

    Chinnery, Patrick Francis; Hudson, Gavin

    2013-01-01

    Introduction In the last 10 years the field of mitochondrial genetics has widened, shifting the focus from rare sporadic, metabolic disease to the effects of mitochondrial DNA (mtDNA) variation in a growing spectrum of human disease. The aim of this review is to guide the reader through some key concepts regarding mitochondria before introducing both classic and emerging mitochondrial disorders. Sources of data In this article, a review of the current mitochondrial genetics literature was conducted using PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). In addition, this review makes use of a growing number of publically available databases including MITOMAP, a human mitochondrial genome database (www.mitomap.org), the Human DNA polymerase Gamma Mutation Database (http://tools.niehs.nih.gov/polg/) and PhyloTree.org (www.phylotree.org), a repository of global mtDNA variation. Areas of agreement The disruption in cellular energy, resulting from defects in mtDNA or defects in the nuclear-encoded genes responsible for mitochondrial maintenance, manifests in a growing number of human diseases. Areas of controversy The exact mechanisms which govern the inheritance of mtDNA are hotly debated. Growing points Although still in the early stages, the development of in vitro genetic manipulation could see an end to the inheritance of the most severe mtDNA disease. PMID:23704099

  3. Detection of rat hepatitis E virus in wild Norway rats (Rattus norvegicus) and Black rats (Rattus rattus) from 11 European countries.

    PubMed

    Ryll, René; Bernstein, Samuel; Heuser, Elisa; Schlegel, Mathias; Dremsek, Paul; Zumpe, Maxi; Wolf, Sandro; Pépin, Michel; Bajomi, Daniel; Müller, Gabi; Heiberg, Ann-Charlotte; Spahr, Carina; Lang, Johannes; Groschup, Martin H; Ansorge, Hermann; Freise, Jona; Guenther, Sebastian; Baert, Kristof; Ruiz-Fons, Francisco; Pikula, Jiri; Knap, Nataša; Tsakmakidis, Ιoannis; Dovas, Chrysostomos; Zanet, Stefania; Imholt, Christian; Heckel, Gerald; Johne, Reimar; Ulrich, Rainer G

    2017-09-01

    Rat hepatitis E virus (HEV) is genetically only distantly related to hepeviruses found in other mammalian reservoirs and in humans. It was initially detected in Norway rats (Rattus norvegicus) from Germany, and subsequently in rats from Vietnam, the USA, Indonesia, China, Denmark and France. Here, we report on a molecular survey of Norway rats and Black rats (Rattus rattus) from 12 European countries for ratHEV and human pathogenic hepeviruses. RatHEV-specific real-time and conventional RT-PCR investigations revealed the presence of ratHEV in 63 of 508 (12.4%) rats at the majority of sites in 11 of 12 countries. In contrast, a real-time RT-PCR specific for human pathogenic HEV genotypes 1-4 and a nested broad-spectrum (NBS) RT-PCR with subsequent sequence determination did not detect any infections with these genotypes. Only in a single Norway rat from Belgium a rabbit HEV-like genotype 3 sequence was detected. Phylogenetic analysis indicated a clustering of all other novel Norway and Black rat-derived sequences with ratHEV sequences from Europe, the USA and a Black rat-derived sequence from Indonesia within the proposed ratHEV genotype 1. No difference in infection status was detected related to age, sex, rat species or density of human settlements and zoological gardens. In conclusion, our investigation shows a broad geographical distribution of ratHEV in Norway and Black rats from Europe and its presence in all settlement types investigated. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Genetic Testing (For Parents)

    MedlinePlus

    ... Habits for TV, Video Games, and the Internet Genetic Testing KidsHealth > For Parents > Genetic Testing Print A ... blood, skin, bone, or other tissue is needed. Genetic Testing During Pregnancy For genetic testing before birth, ...

  5. Cancer Genetics Services Directory

    MedlinePlus

    ... Services Directory Cancer Prevention Overview Research NCI Cancer Genetics Services Directory This directory lists professionals who provide services related to cancer genetics (cancer risk assessment, genetic counseling, genetic susceptibility testing, ...

  6. Integration of the Rat Recombination and EST Maps in the Rat Genomic Sequence and Comparative Mapping Analysis With the Mouse Genome

    PubMed Central

    Wilder, Steven P.; Bihoreau, Marie-Thérèse; Argoud, Karène; Watanabe, Takeshi K.; Lathrop, Mark; Gauguier, Dominique

    2004-01-01

    Inbred strains of the laboratory rat are widely used for identifying genetic regions involved in the control of complex quantitative phenotypes of biomedical importance. The draft genomic sequence of the rat now provides essential information for annotating rat quantitative trait locus (QTL) maps. Following the survey of unique rat microsatellite (11,585 including 1648 new markers) and EST (10,067) markers currently available, we have incorporated a selection of 7952 rat EST sequences in an improved version of the integrated linkage-radiation hybrid map of the rat containing 2058 microsatellite markers which provided over 10,000 potential anchor points between rat QTL and the genomic sequence of the rat. A total of 996 genetic positions were resolved (avg. spacing 1.77 cM) in a single large intercross and anchored in the rat genomic sequence (avg. spacing 1.62 Mb). Comparative genome maps between rat and mouse were constructed by successful computational alignment of 6108 mapped rat ESTs in the mouse genome. The integration of rat linkage maps in the draft genomic sequence of the rat and that of other species represents an essential step for translating rat QTL intervals into human chromosomal targets. PMID:15060020

  7. [Genetic amniocentesis].

    PubMed

    Violante Díaz, M; Carrillo Hinojosa, M; García Necoechea, M P; Escobedo Aguirre, F; Lowenberg Favela, E; Ahued Ahued, J R

    1989-04-01

    179 patients were studied by genetic amniocentesis (GA) in sessions of 3 punctures each. This was done in order to follow a prenatal diagnosis (PD) program and study amniotic fluid at the Hospital Regional 20 de Novembre (ISSSTE) between May 1983 and December 1987. The parameters taken were: age, indications, number of sessions, number punctures, echosonographic studies for gestational age, placental insertion, punction site, amniotic fluid volume, blood contamination, failures and handling of the patient. A low incidence of abortion is reported. We don't have cases of dripping of amniotic fluid or transvaginal haemorrhage. Multiple insertion of the needle and placental or vessel lesions of the cord, as causes of a fetal death are still argued if we have in mind avoiding chances; we didn't have those complications in our cases. The percent is low if there are not previous spontaneous abortions. 79% of the amniotic fluid samples were sent between the 15th and 17th weeks of pregnancy. For alpha fetus protein determination 12 and for biochemical studies 1, specially for beta-galactosidase level. This was done at the Biomedical Investigation Institute of the National Autonomous University of Mexico (in parents with generalized gangliosidosis GM1). Even though results were good, the technique has still risks and complications. An ultrasonic study of the procedures made by physicians with trustable experience is needed. Our country has the need to create more Prenatal Genetic Diagnosis Centers.

  8. Hepatitis E virus genotype 3 in wild rats, United States.

    PubMed

    Lack, Justin B; Volk, Kylie; Van Den Bussche, Ronald A

    2012-08-01

    The role of rodents in the epidemiology of zoonotic hepatitis E virus (HEV) infection has been a subject of considerable debate. Seroprevalence studies suggest widespread HEV infection in commensal Rattus spp. rats, but experimental transmission has been largely unsuccessful and recovery of zoonotic genotype 3 HEV RNA from wild Rattus spp. rats has never been confirmed. We surveyed R. rattus and R. norvegicus rats from across the United States and several international populations by using a hemi-nested reverse transcription PCR approach. We isolated HEV RNA in liver tissues from 35 of 446 rats examined. All but 1 of these isolates was relegated to the zoonotic HEV genotype 3, and the remaining sequence represented the recently discovered rat genotype from the United States and Germany. HEV-positive rats were detected in urban and remote localities. Genetic analyses suggest all HEV genotype 3 isolates obtained from wild Rattus spp. rats were closely related.

  9. A genetic engineering approach to genetic algorithms.

    PubMed

    Gero, J S; Kazakov, V

    2001-01-01

    We present an extension to the standard genetic algorithm (GA), which is based on concepts of genetic engineering. The motivation is to discover useful and harmful genetic materials and then execute an evolutionary process in such a way that the population becomes increasingly composed of useful genetic material and increasingly free of the harmful genetic material. Compared to the standard GA, it provides some computational advantages as well as a tool for automatic generation of hierarchical genetic representations specifically tailored to suit certain classes of problems.

  10. Establishment of a novel dwarf rat strain: cartilage calcification insufficient (CCI) rats.

    PubMed

    Tanaka, Masami; Watanabe, Minoru; Yokomi, Izuru; Matsumoto, Naoki; Sudo, Katsuko; Satoh, Hitoshi; Igarashi, Tsuneo; Seki, Azusa; Amano, Hitoshi; Ohura, Kiyoshi; Ryu, Kakei; Shibata, Shunichi; Nagayama, Motohiko; Tanuma, Jun-ichi

    2015-01-01

    Rats with dwarfism accompanied by skeletal abnormalities, such as shortness of the limbs, tail, and body (dwarf rats), emerged in a Jcl-derived Sprague-Dawley rat colony maintained at the Institute for Animal Experimentation, St. Marianna University Graduate School of Medicine. Since the dwarfism was assumed to be due to a genetic mutation based on its frequency, we bred the dwarf rats and investigated their characteristics in order to identify the causative factors of their phenotypes and whether they could be used as a human disease model. One male and female that produced dwarf progeny were selected, and reproduction was initiated by mating the pair. The incidence of dwarfism was 25.8% among the resultant litter, and dwarfism occurred in both genders, suggesting that it was inherited in an autosomal recessive manner. At 12 weeks of age, the body weights of the male and female dwarf rats were 40% and 57% of those of the normal rats, respectively. In soft X-ray radiographic and histological examinations, shortening and hypoplasia of the long bones, such as the tibia and femur, were observed, which were suggestive of endochondral ossification abnormalities. An immunohistochemical examination detected an aggrecan synthesis disorder, which might have led to delayed calcification and increased growth plate thickening in the dwarf rats. We hypothesized that the principal characteristics of the dwarf rats were systemically induced by insufficient cartilage calcification in their long bones; thus, we named them cartilage calcification insufficient (CCI) rats.

  11. Establishment of a novel dwarf rat strain: cartilage calcification insufficient (CCI) rats

    PubMed Central

    TANAKA, Masami; WATANABE, Minoru; YOKOMI, Izuru; MATSUMOTO, Naoki; SUDO, Katsuko; SATOH, Hitoshi; IGARASHI, Tsuneo; SEKI, Azusa; AMANO, Hitoshi; OHURA, Kiyoshi; RYU, Kakei; SHIBATA, Shunichi; NAGAYAMA, Motohiko; TANUMA, Jun-ichi

    2014-01-01

    Rats with dwarfism accompanied by skeletal abnormalities, such as shortness of the limbs, tail, and body (dwarf rats), emerged in a Jcl-derived Sprague-Dawley rat colony maintained at the Institute for Animal Experimentation, St. Marianna University Graduate School of Medicine. Since the dwarfism was assumed to be due to a genetic mutation based on its frequency, we bred the dwarf rats and investigated their characteristics in order to identify the causative factors of their phenotypes and whether they could be used as a human disease model. One male and female that produced dwarf progeny were selected, and reproduction was initiated by mating the pair. The incidence of dwarfism was 25.8% among the resultant litter, and dwarfism occurred in both genders, suggesting that it was inherited in an autosomal recessive manner. At 12 weeks of age, the body weights of the male and female dwarf rats were 40% and 57% of those of the normal rats, respectively. In soft X-ray radiographic and histological examinations, shortening and hypoplasia of the long bones, such as the tibia and femur, were observed, which were suggestive of endochondral ossification abnormalities. An immunohistochemical examination detected an aggrecan synthesis disorder, which might have led to delayed calcification and increased growth plate thickening in the dwarf rats. We hypothesized that the principal characteristics of the dwarf rats were systemically induced by insufficient cartilage calcification in their long bones; thus, we named them cartilage calcification insufficient (CCI) rats. PMID:25736479

  12. Genetic risks and genetic model specification.

    PubMed

    Zheng, Gang; Zhang, Wei; Xu, Jinfeng; Yuan, Ao; Li, Qizhai; Gastwirth, Joseph L

    2016-08-21

    Genetic risks and genetic models are often used in design and analysis of genetic epidemiology studies. A genetic model is defined in terms of two genetic risk measures: genotype relative risk and odds ratio. The impacts of choosing a risk measure on the resulting genetic models are studied in the power to detect association and deviation from Hardy-Weinberg equilibrium in cases using genetic relative risk. Extensive simulations demonstrate that the power of a study to detect associations using odds ratio is lower than that using relative risk with the same value when other parameters are fixed. When the Hardy-Weinberg equilibrium holds in the general population, the genetic model can be inferred by the deviation from Hardy-Weinberg equilibrium in only cases. Furthermore, it is more efficient than that based on the deviation from Hardy-Weinberg equilibrium in all cases and controls. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Genetics Home Reference: microphthalmia

    MedlinePlus

    ... including clouding of the lens of the eye ( cataract ) and a narrowed opening of the eye (narrowed ... Genetic Testing Registry: Anophthalmia/Microphthalmia Genetic Testing Registry: Cataract, congenital, with microphthalmia Genetic Testing Registry: Cataract, microphthalmia ...

  14. Genetics Home Reference

    MedlinePlus

    ... MENU Toggle navigation Home Page Search Share: Email Facebook Twitter Home Health Conditions Genes Chromosomes & mtDNA Resources Help Me Understand Genetics Genetics Home Reference provides consumer-friendly information about the effects of genetic variation ...

  15. Applying the New Genetics

    ERIC Educational Resources Information Center

    Sorenson, James

    1976-01-01

    New developments in the prediction and treatment of genetic diseases are presented. Genetic counseling and the role of the counselor, and rights of individuals to reproduce versus societal impact of genetic disorders, are discussed. (RW)

  16. Applying the New Genetics

    ERIC Educational Resources Information Center

    Sorenson, James

    1976-01-01

    New developments in the prediction and treatment of genetic diseases are presented. Genetic counseling and the role of the counselor, and rights of individuals to reproduce versus societal impact of genetic disorders, are discussed. (RW)

  17. Anti-epileptic effects of focal micro-injection of excitatory amino acid antagonists.

    PubMed

    Meldrum, B; Millan, M; Patel, S; de Sarro, G

    1988-01-01

    The role of excitatory synaptic activity at various brain regions in the development and spread of seizure activity has been investigated by the focal microinjection of 2-amino-7-phosphono-heptanoate (2-APH), a selective antagonist at the N-methyl-D-aspartate preferring receptor, or gamma-D-glutamyl-aminomethyl sulphonate (GAMS), a partially selective antagonist at the kainate receptor. In genetically epilepsy prone rats the seizure response to a loud sound in most effectively suppressed by focal injections of 2-APH, 0.1-1.0 nmol, in the inferior colliculus. Protection is also seen after injections of 2-APH, 25 nmoles, in the substantia nigra (pars reticulata) or the midbrain reticular formation. Motor limbic seizures induced by pilocarpine, 380 mg/kg intraperitoneally, are prevented by prior injection into the substantia nigra, pars reticulata, or the entopeduncular nucleus, of 2-APH, 10 nmol or 10 pmol, respectively. Similar protection follows the injection of 2-APH, 1-5 pmol in the piriform cortex. The convulsant effects of pilocarpine are also blocked by the focal injection of GAMS, 10 nmol in the entopeduncular nucleus. This experimental approach can indicate critical sites at which seizure activity is initiated in particular models (e.g., inferior colliculus in sound-induced seizures, and piriform cortex in limbic seizures) and the pathways controlling seizure expression, such as the basal ganglia outputs. It also identifies specific receptors at which anticonvulsant drugs may operate.

  18. Genetic aspects and genetic epidemiology of parasomnias.

    PubMed

    Hublin, Christer; Kaprio, Jaakko

    2003-10-01

    Parasomnias are undesirable phenomena associated with sleep. Many of them run in families, and genetic factors have been long suggested to be involved in their occurrence. This article reviews the present knowledge of the genetics of the major classical behavioral parasomnias as well as present results from genetic epidemiological studies. The level and type of evidence for genetic effects varies much from parasomnia to parasomnia. The genetic factors are best established in enuresis, with several linkages to chromosomal loci, but their functions are not so far known. Environmental causes and gene-environment interactions are most probably also of great importance in the origin of complex traits or disorders such as parasomnias.

  19. The emerging role for rat models in gene discovery

    PubMed Central

    Dwinell, Melinda R.; Lazar, Jozef; Geurts, Aron M.

    2011-01-01

    Rat models have been used for many decades to study physiological and pathophysiological mechanisms. Prior to the release of the rat genome and new technologies for targeting gene manipulation, the rat had been the underdog in the genomics era, despite the abundance of physiological data compared to the mouse. The overarching goal of biomedical research is to improve health and advance medical science. Translating human disease gene discovery and validation in the rat, through the use of emerging technologies and integrated tools and databases, is providing power to understand the genetics, environmental influences, and biology of disease. In this review, we will briefly outline the rat models, bioinformatic tools, and technologies that are changing the landscape of translational research. The strategies used to translate disease traits to genes to function, and ultimately, to improve human health will be discussed. Finally, our perspectives on how rat models will continue to positively impact biomedical research will be provided. PMID:21732192

  20. MWF rats with spontaneous albuminuria inherit a reduced efficiency of nephron induction during early nephrogenesis in comparison to SHR rats.

    PubMed

    Schulte, Leonard; Schulz, Angela; Unland, Johannes; Schulz, Herbert; Hubner, Norbert; Schmidt-Ott, Kai M; Kreutz, Reinhold

    2012-10-01

    A congenital nephron deficit has been linked to the progression of arterial hypertension and to the development of chronic kidney disease. The Munich Wistar Frömter (MWF) inbred rat develops hypertension, progressive albuminuria, and exhibits an inherited nephron deficit of about 27% compared to spontaneously hypertensive rats (SHRs) with low-grade albuminuria. Introgression of rat chromosome (RNO)6 from SHRs into MWF rats markedly suppresses albuminuria and abolishes the nephron deficit in 4-week-old MWF-6 rats. Differences in early nephrogenesis may account for the nephron deficit in MWF rats. We compared ureteric bud branching morphogenesis and nephron induction in E15.5-E16.0 stage-matched rat embryos between MWF rats, SHRs, and consomic MWF-6 rats. Comparative analysis of three-dimensional reconstructions of the ureteric bud tree suggested normal qualitative branching morphogenesis. Surprisingly, the number of ureteric bud tips was higher in MWF rats compared to SHRs (+22%; P = 0.004). However, the nephron number induced per ureteric bud tip was markedly lower in MWF rats compared to SHRs (-46%; P < 0.0001). This deficit was partially corrected in MWF-6 rats (+18% vs. MWF; P = 0.02). In gene expression analysis of 59 candidate genes involved in kidney development, hepatocyte growth factor (Hgf) gene expression was significantly reduced in embryonic kidneys of MWF and MWF-6 rats (approximately -70%; P < 0.004) compared to SHRs. These results suggest a reduced efficiency of nephron induction in MWF rats during the early stages of nephrogenesis that is partially dependent on genetic loci on RNO6. In addition, Hgf that maps to RNO4 may represent an interesting candidate gene that contributes to the nephron deficit in MWF rats.

  1. Germline transmission of a novel rat embryonic stem cell line derived from transgenic rats.

    PubMed

    Men, Hongsheng; Bauer, Beth A; Bryda, Elizabeth C

    2012-09-20

    Germline-competent rat embryonic stem (ES) cell lines are important resources for the creation of mutant rat models using ES-cell-based gene targeting technology. The ability to isolate germline-competent ES cell lines from any rat strain, including genetically modified strains, would allow for more sophisticated genetic manipulations without extensive breeding. Sprague Dawley (SD) males carrying an enhanced green fluorescent protein (EGFP) transgene were used as the founder animals for the derivation of ES cell lines. A number of ES cell lines were established and subjected to rigorous quality control testing that included assessment of pluripotency factor expression, karyotype analysis, and pathogen/sterility testing. Two male ES cell lines, SD-Tg.EC1/Rrrc and SD-Tg.EC8/Rrrc, were injected into blastocysts recovered from a cross of Dark Agouti (DA) males with SD females. Resulting chimeric animals were bred with wild-type SD mates to verify the germline transmissibility of the ES cell lines by identifying pups carrying the ES cell line-derived EGFP transgene. While both ES cell lines gave rise to chimeric animals, only SD-Tg.EC1 was germline competent. This confirms the feasibility of deriving germline-competent ES cell lines from transgenic rat strains and provides a novel ES cell line with a stable green fluorescent protein (GFP) reporter for future genetic manipulations to create new rat models.

  2. Autism-related behavioral phenotypes in an inbred rat substrain.

    PubMed

    Zhang-James, Yanli; Yang, Li; Middleton, Frank A; Yang, Lina; Patak, Jameson; Faraone, Stephen V

    2014-08-01

    Behavioral and genetic differences among Wistar-Kyoto (WKY) rats from different vendors and different breeders have long been observed, but generally overlooked. In our prior work, we found that two closely related WKY substrains, the WKY/NCrl and WKY/NHsd rats, differ in a small percentage of their genome which appeared to be highly enriched for autism risk genes. Although both substrains have been used widely in studies of hypertension, attention deficit/hyperactivity disorder (ADHD) and depression, they have not been tested for any autism-related behavioral phenotypes. Furthermore, these two substrains have often been used interchangeably in previous studies; no study has systematically examined the phenotypic differences that could be attributed by their small yet potentially meaningful genetic differences. In this paper we compared these two substrains on a battery of neurobehavioral tests. Although two substrains were similar in locomotor activity, WKY/NCrl rats were significantly different from WKY/NHsd rats in the elevated plus maze test, as well as measures of social interaction and ultrasonic vocalization. These strains were also compared with Sprague Dawley (SD) rats, a common outbred strain, and spontaneous hypertensive rats (SHR), an inbred rat model for ADHD and hypertension, which were derived from the same ancestor strain as the WKY strains. Our behavioral findings suggest that WKY/NCrl rats may be useful as a model autism spectrum disorders due to their lower social interest, lower ultrasonic vocalization and higher anxiety levels when WKY/NHsd rats are used as the control strain. Given the small genetic difference between the two inbred substrains, future studies to identify the exact gene and sequence variants that differ between the two may be useful for identifying the genetic mechanisms underlying these behaviors.

  3. Diversity of mitochondrial Ca²⁺ signaling in rat neonatal cardiomyocytes: evidence from a genetically directed Ca²⁺ probe, mitycam-E31Q.

    PubMed

    Haviland, Sarah; Cleemann, Lars; Kettlewell, Sarah; Smith, Godfrey L; Morad, Martin

    2014-09-01

    I(Ca)-gated Ca(2+) release (CICR) from the cardiac SR is the main mechanism mediating the rise of cytosolic Ca(2+), but the extent to which mitochondria contribute to the overall Ca(2+) signaling remains controversial. To examine the possible role of mitochondria in Ca(2+) signaling, we developed a low affinity mitochondrial Ca(2+) probe, mitycam-E31Q (300-500 MOI, 48-72h) and used it in conjunction with Fura-2AM to obtain simultaneous TIRF images of mitochondrial and cytosolic Ca(2+) in cultured neonatal rat cardiomyocytes. Mitycam-E31Q staining of adult feline cardiomyocytes showed the typical mitochondrial longitudinal fluorescent bandings similar to that of TMRE staining, while neonatal rat cardiomyocytes had a disorganized tubular or punctuate appearance. Caffeine puffs produced rapid increases in cytosolic Ca(2+) while simultaneously measured global mitycam-E31Q signals decreased more slowly (increased mitochondrial Ca(2+)) before decaying to baseline levels. Similar, but oscillating mitycam-E31Q signals were seen in spontaneously pacing cells. Withdrawal of Na(+) increased global cytosolic and mitochondrial Ca(2+) signals in one population of mitochondria, but unexpectedly decreased it (release of Ca(2+)) in another mitochondrial population. Such mitochondrial Ca(2+) release signals were seen not only during long lasting Na(+) withdrawal, but also when Ca(2+) loaded cells were exposed to caffeine-puffs, and during spontaneous rhythmic beating. Thus, mitochondrial Ca(2+) transients appear to activate with a delay following the cytosolic rise of Ca(2+) and show diversity in subpopulations of mitochondria that could contribute to the plasticity of mitochondrial Ca(2+) signaling.

  4. Rats! Oh No, Not Rats!

    ERIC Educational Resources Information Center

    Strong, Gary E.

    1987-01-01

    Examples of problems encountered in a new library building--including rats and humidity--and a description of the library's collections provide a framework for this presentation of the California State Library's emergency management planning. Current preservation efforts are documented and the library's disaster and security plans are described.…

  5. Rats! Oh No, Not Rats!

    ERIC Educational Resources Information Center

    Strong, Gary E.

    1987-01-01

    Examples of problems encountered in a new library building--including rats and humidity--and a description of the library's collections provide a framework for this presentation of the California State Library's emergency management planning. Current preservation efforts are documented and the library's disaster and security plans are described.…

  6. Interactive Genetics Tutorial Project.

    ERIC Educational Resources Information Center

    Wisconsin Univ., Madison. Dept. of Curriculum and Instruction.

    The Interactive Genetics Tutorial (IGT) project and the Intelligent Tutoring System for the IGT project named MENDEL supplement genetics instruction in biology courses by providing students with experience in designing, conducting, and evaluating genetics experiments. The MENDEL software is designed to: (1) simulate genetics experiments that…

  7. The genetics of immunity.

    PubMed

    Lazzaro, Brian P; Schneider, David S

    2014-06-17

    In this commentary, Brian P. Lazzaro and David S. Schneider examine the topic of the Genetics of Immunity as explored in this month's issues of GENETICS and G3: Genes|Genomes|Genetics. These inaugural articles are part of a joint Genetics of Immunity collection (ongoing) in the GSA journals.

  8. Marked genomic heterogeneity of rat hepatitis E virus strains in Indonesia demonstrated on a full-length genome analysis.

    PubMed

    Mulyanto; Suparyatmo, Joseph Benedictus; Andayani, I Gusti Ayu Sri; Khalid; Takahashi, Masaharu; Ohnishi, Hiroshi; Jirintai, Suljid; Nagashima, Shigeo; Nishizawa, Tsutomu; Okamoto, Hiroaki

    2014-01-22

    Rat hepatitis E virus (HEV) strains have recently been isolated in several areas of Germany, Vietnam, the United States, Indonesia and China. However, genetic information regarding these rat HEV strains is limited. A total of 369 wild rats (Rattus rattus) captured in Central Java (Solo) and on Lombok Island, Indonesia were tested for the presence of rat HEV-specific antibodies and RNA. Overall, 137 rats (37.1%) tested positive for rat anti-HEV antibodies, while 97 (26.3%) had rat HEV RNA detectable on reverse transcription-PCR with primers targeting the ORF1-ORF2 junctional region. The 97 HEV strains recovered from these viremic rats were 76.3-100% identical to each other in an 840-nucleotide sequence and 75.4-88.4% identical to the rat HEV strains reported in Germany and Vietnam. Five representative Indonesian strains, one from each of five phylogenetic clusters, whose entire genomic sequence was determined, were segregated into three genetic groups (a German type, Vietnamese type and novel type), which differed from each other by 19.5-23.5 (22.0 ± 1.7)% over the entire genome. These results suggest the presence of at least three genetic groups of rat HEV and indicate the circulation of polyphyletic strains of rat HEV belonging to three distinct genetic groups in Indonesia. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Genetics and genomic medicine.

    PubMed

    Bogaard, Kali; Johnson, Marlene

    2009-01-01

    Genetics is playing an increasingly important role in the diagnosis, monitoring and treatment of diseases, and the expansion of genetics into health care has generated the field of genomic medicine. Health care delivery is shifting away from general diagnostic evaluation toward a generation of therapeutics based on a patient's genetic makeup. Meanwhile, the scientific community debates how best to incorporate genetics and genomic medicine into practice. While obstacles remain, the ultimate goal is to use information generated from the study of human genetics to improve disease treatment, cure and prevention. As the use of genetics in medical diagnosis and treatment increases, health care workers will require an understanding of genetics and genomic medicine.

  10. Obesity-resistant S5B rats showed great cocaine conditioned place preference than the obesity-prone OM rats

    SciTech Connect

    Thanos, P.K.; Wang, G.; Thanos, P.K..; Kim, R.; Cho, J.; Michaelides, M.; Anderson, B.J.; Primeaux, S.D.; Bray, G.A.; Wang, G.-J.; Robinson, J.K.; Volkow, N.D.

    2010-12-01

    Dopamine (DA) and the DA D2 receptor (D2R) are involved in the rewarding and conditioned responses to food and drug rewards. Osborne-Mendel (OM) rats are genetically prone and S5B/P rats are genetically resistant to obesity when fed a high-fat diet. We hypothesized that the differential sensitivity of these two rat strains to natural rewards may also be reflected in sensitivity to drugs of abuse. Therefore, we tested whether OM and S5B/P rats showed a differential preference to cocaine using conditioned place preference (CPP). To also evaluate whether there is specific involvement of the D2R in this differential conditioning sensitivity, we then tested whether the D2R agonist bromocriptine (BC) would differentially affect the effects of cocaine in the two strains. OM and S5B/P rats were conditioned with cocaine (5 or 10 mg/kg) in one chamber and saline in another for 8 days. Rats were then tested for cocaine preference. The effects of BC (0.5, 1, 5, 10, 20 mg/kg) on cocaine preference were then assessed in subsequent test sessions. OM rats did not show a significant preference for the cocaine-paired chamber on test day. Only the S5B/P rats showed cocaine CPP. Later treatment with only the highest dose of BC resulted in reduced cocaine CPP in S5B/P rats when treated with 5 mg/kg cocaine and in OM rats treated with 10 mg/kg cocaine. Our results indicated that obesity-resistant S5B rats showed greater cocaine CPP than the obesity-prone OM rats. These findings do not support a theory of common vulnerability for reinforcer preferences (food and cocaine). However, they show that BC reduced cocaine conditioning effects supporting at least a partial regulatory role of D2R in conditioned responses to drugs.

  11. How Are Genetic Conditions Diagnosed?

    MedlinePlus

    ... Consultation How are genetic conditions diagnosed? How are genetic conditions diagnosed? A doctor may suspect a diagnosis ... and advocacy resources. For more information about diagnosing genetic conditions: Genetics Home Reference provides information about genetic ...

  12. Update: Biochemistry of Genetic Manipulation.

    ERIC Educational Resources Information Center

    Barker, G. R.

    1983-01-01

    Various topics on the biochemistry of genetic manipulation are discussed. These include genetic transformation and DNA; genetic expression; DNA replication, repair, and mutation; technology of genetic manipulation; and applications of genetic manipulation. Other techniques employed are also considered. (JN)

  13. Update: Biochemistry of Genetic Manipulation.

    ERIC Educational Resources Information Center

    Barker, G. R.

    1983-01-01

    Various topics on the biochemistry of genetic manipulation are discussed. These include genetic transformation and DNA; genetic expression; DNA replication, repair, and mutation; technology of genetic manipulation; and applications of genetic manipulation. Other techniques employed are also considered. (JN)

  14. Bioactive constituents from chinese natural medicines. XXIV. Hypoglycemic effects of Sinocrassula indica in sugar-loaded rats and genetically diabetic KK-A(y) mice and structures of new acylated flavonol glycosides, sinocrassosides A(1), A(2), B(1), and B(2).

    PubMed

    Yoshikawa, Masayuki; Wang, Tao; Morikawa, Toshio; Xie, Haihui; Matsuda, Hisashi

    2007-09-01

    The methanolic extract from the whole plant of Sinocrassula indica (Crassulaceae) was found to inhibit the increase in serum glucose levels in oral administration of sucrose and glucose in rats at a dose of 250 mg/kg (p.o.). However, the extract did not inhibit the increase in serum glucose levels after intraperitoneal administration of glucose in these animals but did partly inhibit the gastric emptying. On the other hand, this extract significantly inhibited the increase in serum glucose levels after administration for 2 weeks in KK-A(y) mice, a genetically type II diabetic mice, at a dose of 250 mg/kg/d (p.o.) without significant changes of the weights of body, liver, and visceral fat. From the extract, four new acylated flavonol glycosides, sinocrassosides A(1), A(2), B(1), and B(2), were isolated together with 11 flavonoids and 2 megastigmanes. The absolute stereostructures of the four new compounds were elucidated on the basis of chemical and physicochemical evidence.

  15. Pulmonary Transcriptional Response to Ozone in Healthy and Cardiovascular Compromised Rat Models

    EPA Science Inventory

    The genetic cardiovascular disease (CVD) and associated metabolic impairments can influence the lung injury from inhaled pollutants. We hypothesized that comparative assessment of global pulmonary expression profile of healthy and CVD-prone rat models will provide mechanistic ins...

  16. EXPRESSION PROFILING OF FIVE RAT STRAINS REVEAL TRANSCRIPTIONAL MODES IN THE ANTIGEN PROCESSING PATHWAY

    EPA Science Inventory

    Comparative gene expression profiling of rat strains with genetic predisposition to diverse cardiovascular diseases can help decode the transcriptional program that governs cellular behavior. We hypothesized that co-transcribed, intra-pathway, functionally coherent genes can be r...

  17. Pulmonary Transcriptional Response to Ozone in Healthy and Cardiovascular Compromised Rat Models

    EPA Science Inventory

    The genetic cardiovascular disease (CVD) and associated metabolic impairments can influence the lung injury from inhaled pollutants. We hypothesized that comparative assessment of global pulmonary expression profile of healthy and CVD-prone rat models will provide mechanistic ins...

  18. EXPRESSION PROFILING OF FIVE RAT STRAINS REVEAL TRANSCRIPTIONAL MODES IN THE ANTIGEN PROCESSING PATHWAY

    EPA Science Inventory

    Comparative gene expression profiling of rat strains with genetic predisposition to diverse cardiovascular diseases can help decode the transcriptional program that governs cellular behavior. We hypothesized that co-transcribed, intra-pathway, functionally coherent genes can be r...

  19. Heterogeneous stock rat: a unique animal model for mapping genes influencing bone fragility.

    PubMed

    Alam, Imranul; Koller, Daniel L; Sun, Qiwei; Roeder, Ryan K; Cañete, Toni; Blázquez, Gloria; López-Aumatell, Regina; Martínez-Membrives, Esther; Vicens-Costa, Elia; Mont, Carme; Díaz, Sira; Tobeña, Adolf; Fernández-Teruel, Alberto; Whitley, Adam; Strid, Pernilla; Diez, Margarita; Johannesson, Martina; Flint, Jonathan; Econs, Michael J; Turner, Charles H; Foroud, Tatiana

    2011-05-01

    Previously, we demonstrated that skeletal mass, structure and biomechanical properties vary considerably among 11 different inbred rat strains. Subsequently, we performed quantitative trait loci (QTL) analysis in four inbred rat strains (F344, LEW, COP and DA) for different bone phenotypes and identified several candidate genes influencing various bone traits. The standard approach to narrowing QTL intervals down to a few candidate genes typically employs the generation of congenic lines, which is time consuming and often not successful. A potential alternative approach is to use a highly genetically informative animal model resource capable of delivering very high resolution gene mapping such as Heterogeneous stock (HS) rat. HS rat was derived from eight inbred progenitors: ACI/N, BN/SsN, BUF/N, F344/N, M520/N, MR/N, WKY/N and WN/N. The genetic recombination pattern generated across 50 generations in these rats has been shown to deliver ultra-high even gene-level resolution for complex genetic studies. The purpose of this study is to investigate the usefulness of the HS rat model for fine mapping and identification of genes underlying bone fragility phenotypes. We compared bone geometry, density and strength phenotypes at multiple skeletal sites in HS rats with those obtained from five of the eight progenitor inbred strains. In addition, we estimated the heritability for different bone phenotypes in these rats and employed principal component analysis to explore relationships among bone phenotypes in the HS rats. Our study demonstrates that significant variability exists for different skeletal phenotypes in HS rats compared with their inbred progenitors. In addition, we estimated high heritability for several bone phenotypes and biologically interpretable factors explaining significant overall variability, suggesting that the HS rat model could be a unique genetic resource for rapid and efficient discovery of the genetic determinants of bone fragility. Copyright

  20. Genetic engineering compared to natural genetic variations.

    PubMed

    Arber, Werner

    2010-11-30

    By comparing strategies of genetic alterations introduced in genetic engineering with spontaneously occurring genetic variation, we have come to conclude that both processes depend on several distinct and specific molecular mechanisms. These mechanisms can be attributed, with regard to their evolutionary impact, to three different strategies of genetic variation. These are local nucleotide sequence changes, intragenomic rearrangement of DNA segments and the acquisition of a foreign DNA segment by horizontal gene transfer. Both the strategies followed in genetic engineering and the amounts of DNA sequences thereby involved are identical to, or at least very comparable with, those involved in natural genetic variation. Therefore, conjectural risks of genetic engineering must be of the same order as those for natural biological evolution and for conventional breeding methods. These risks are known to be quite low. There is no scientific reason to assume special long-term risks for GM crops. For future agricultural developments, a road map is designed that can be expected to lead, by a combination of genetic engineering and conventional plant breeding, to crops that can insure food security and eliminate malnutrition and hunger for the entire human population on our planet. Public-private partnerships should be formed with the mission to reach the set goals in the coming decades.

  1. Establishment of rat embryonic stem cells and making of chimera rats.

    PubMed

    Ueda, Shinobu; Kawamata, Masaki; Teratani, Takumi; Shimizu, Taku; Tamai, Yoshitaka; Ogawa, Hiromasa; Hayashi, Katsuyuki; Tsuda, Hiroyuki; Ochiya, Takahiro

    2008-07-30

    The rat is a reference animal model for physiological studies and for the analysis of multigenic human diseases such as hypertension, diabetes, neurological disorders, and cancer. The rats have long been used in extensive chemical carcinogenesis studies. Thus, the rat embryonic stem (rES) cell is an important resource for the study of disease models. Attempts to derive ES cells from various mammals, including the rat, have not succeeded. Here we have established two independent rES cells from Wister rat blastocysts that have undifferentiated characters such as Nanog and Oct3/4 genes expression and they have stage-specific embryonic antigen (SSEA) -1, -3, -4, and TRA-1-81 expression. The cells were successfully cultured in an undifferentiated state and can be possible over 18 passages with maintaining more than 40% of normal karyotype. Their pluripotent potential was confirmed by the differentiation into derivatives of the endoderm, mesoderm, and ectoderm. Most importantly, the rES cells are capable of producing chimera rats. Therefore, we established pluripotent rES cell lines that are widely used to produce genetically modified experimental rats for study of human diseases.

  2. Phenotypic Characterization of LEA Rat: A New Rat Model of Nonobese Type 2 Diabetes

    PubMed Central

    Okamura, Tadashi; Pei, Xiang Yuan; Miyoshi, Ichiro; Shimizu, Yukiko; Takanashi-Yanobu, Rieko; Mototani, Yasumasa; Kanai, Takao; Satoh, Jo; Kimura, Noriko; Kasai, Noriyuki

    2013-01-01

    Animal models have provided important information for the genetics and pathophysiology of diabetes. Here we have established a novel, nonobese rat strain with spontaneous diabetes, Long-Evans Agouti (LEA) rat derived from Long-Evans (LE) strain. The incidence of diabetes in the males was 10% at 6 months of age and 86% at 14 months, while none of the females developed diabetes. The blood glucose level in LEA male rats was between 200 and 300 mg/dl at 120 min according to OGTT. The glucose intolerance in correspondence with the impairment of insulin secretion was observed in male rats, which was the main cause of diabetes in LEA rats. Histological examination revealed that the reduction of β-cell mass was caused by progressive fibrosis in pancreatic islets in age-dependent manner. The intracytoplasmic hyaline droplet accumulation and the disappearance of tubular epithelial cell layer associated with thickening of basement membrane were evident in renal proximal tubules. The body mass index and glycaemic response to exogenous insulin were comparable to those of control rats. The unique characteristics of LEA rat are a great advantage not only to analyze the progression of diabetes, but also to disclose the genes involved in type 2 diabetes mellitus. PMID:23691528

  3. Comparison Of Cardiovascular Characteristics In Normotensive And Hypertensive Rat Strains.

    PubMed

    Zemancíková, Anna; Török, Jozef

    2015-01-01

    Hypertensive rats serve as valuable tools for studies of dysregulations in cardiovascular functions before and during pathological elevation of blood pressure. They exhibit many defects in structure and function of heart and vessels which are often related to severity of hypertension. The relationship of blood pressure level and manifestation of aberrations in selected cardiovascular and metabolic parameters were determined in 20-week-old normotensive Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and in their F1 offspring borderline hypertensive rats (BHR), and also in normotensive Wistar rats which are genetically less compatible with the other mentioned rat strains. Systolic blood pressure and heart rate were measured in conscious rats by the non-invasive tail-cuff method. At the end of the treatment, rats were sacrificed, relative weight of their left heart ventricle and liver were determined and plasma concentration of glucose and triglycerides were measured. Thoracic aorta and superior mesenteric artery were isolated and prepared for isometric tension recording. Neurogenic contractions were elicited by electrical stimulation of perivascular adrenergic nerves. The level of systolic blood pressure in WKY rats (106.0 ± 0.4 mmHg), BHR (149.5 ± 2.5 mmHg) and SHR (186.4 ± 3.9 mmHg) corresponded with the impairment of acetylcholine-induced relaxation of isolated thoracic aorta and with the increase in sensitivity of contractile responses to exogenous noradrenaline and to electrical stimulation of perivascular adrenergic nerves in mesenteric artery. However, rats of the normotensive strain Wistar (118.1 ± 2.0 mmHg) exhibited arterial contractions similar to those obtained in hypertensive rats. Wistar rats had also the highest relative liver weight and plasma triglyceride concentration. These observations indicate that when comparing non-related rat strains the higher magnitude of arterial contractions and abnormal lipid parameters may not

  4. [Advances in genetic modification technologies].

    PubMed

    Zhang, Baixue; Sun, Qixin; Li, Haifeng

    2015-08-01

    Genetic modification technology is a new molecular tool for targeted genome modification. It includes zinc finger nucleases (ZFN) technology, transcription activator-like effector nucleases (TALEN) technology and clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) (CRISPR-Cas) nucleases technology. All of these nucleases create DNA double-strand breaks (DSB) at chromosomal targeted sites and induce cell endogenous mechanisms that are primarily repaired by the non-homologous end joining (NHEJ) or homologous recombination (HR) pathway, resulting in targeted endogenous gene knock-out or exogenous gene insertion. In recent years, genetic modification technologies have been successfully applied to bacteria, yeast, human cells, fruit fly, zebra fish, mouse, rat, livestock, cynomolgus monkey, Arabidopsis, rice, tobacco, maize, sorghum, wheat, barley and other organisms, showing its enormous advantage in gene editing field. Especially, the newly developed CRISPR-Cas9 system arose more attention because of its low cost, high effectiveness, simplicity and easiness. We reviewed the principles and the latest research progress of these three technologies, as well as prospect of future research and applications.

  5. Genetic defects of iron transport.

    PubMed

    Bannerman, R M

    1976-09-01

    Five genetic traits in man and laboratory animals have major effects on iron transport. The heterogeneous condition, hemochromatosis, in some families appears to segregate as a Mendelian trait, and is associated with defective control of intestinal iron absorption. In the very rare human autosomal recessive trait, atransferrinemia, there is an almost total lack of transferrin and gross maldistribution of iron through the body. In mice, sex-linked anemia (an X-linked recessive trait) causes iron deficiency through defective iron absorption, at the "exit" step; a similar defect probably exists in placental iron transfer. In microcytic anemia of mice, an autosomal recessive trait, iron absorption is also impaired because of a defect of iron entry into cells, which is probably generalized. Belgrade rat anemia, less understood at present, also may involve a major disorder of iron metabolism. Study of these mutations has provided new knowledge of iron metabolism and its genetic control Their phenotypic interaction with nutritional factors, especially the form and quantity of iron in the diet, may provide new insights for the study of nutrition.

  6. Rats of hypertensive ISIAH strain are resistant to the development of metabolic syndrome induced by high-fat diet.

    PubMed

    Dushkin, M I; Khrapova, M V; Kovshik, G G; Chasovskikh, M I; Selyatitskaya, V G; Palchikova, N A

    2014-03-01

    We studied the influence of high-fat diet on the development of metabolic syndrome in rats of hypertensive ISIAH strain and normotensive WAG strain. In contrast to ISIAH rats, high-fat diet in WAG rats led visceral obesity, glucose tolerance, and dyslipidemia. DNA-binding activity of the peroxisome proliferator-activated receptor α (PPARα) decreased in the liver of WAG rats and increased in ISIAH rats. Blood levels of TNF-α, IL-6, and corticosterone increased more significantly in WAG rats. Corticosterone content in the adrenal glands was more markedly reduced in WAG rats. High-fat diet had no effect on BP in ISIAH and WAG rats. It was concluded that ISIAH rats can be used as a genetic model in studies of the mechanism of resistance to the metabolic syndrome.

  7. The local effect of octreotide on mechanical pain sensitivity is more sensitive in DA rats than DA.1U rats.

    PubMed

    Yao, Fan-Rong; Wang, Hui-Sheng; Guo, Yuan; Zhao, Yan

    2016-02-01

    A recent study by the authors indicated that major histocompatibility complex (MHC) genes are associated with the differences in basal pain sensitivity and in formalin model between Dark-Agouti (DA) and novel congenic DA.1U rats, which have the same genetic background as DA rats except for the u alleles of MHC. The objective of the present study is to investigate whether there is a difference in the pristane-induced arthritis (PIA) model and local analgesic effect of octreotide (OCT) between DA and DA.1U rats. The hindpaw mechanical withdrawal threshold (MWT) and heat withdrawal latency (HWL) were observed. The C unit firings of the tibial nerve evoked by non-noxious and noxious toe movements were recorded by electrophysiological methods in normal and PIA models in DA and DA.1U rats before and after local OCT administration. The expression of somatostatin receptor 2A (SSTR2A) was observed by immunohistochemistry. The results demonstrate that DA rats have a higher mechanical sensitivity than DA.1U rats after PIA. Local OCT administration significantly elevated MWT in DA rats under normal and PIA sate, but not in DA.1U rats. The electrophysiological experiments showed OCT significantly attenuated the firings of C units evoked by non-noxious and noxious stimulation in DA rats more than those in DA.1U rats both in normal and PIA states. In addition, the expression of SSTR2A in the dorsal horn of the spinal cord was significantly higher in DA than in DA.1U rats. All of the findings suggest a higher local analgesic effect of OCT in DA rats than DA.1U rats, which might be associated with the MHC genes.

  8. Genetically engineered foods

    MedlinePlus

    ... a cell of another plant or animal. Function Genetic engineering can be done with plants, animals, or bacteria and other very small organisms. Genetic engineering allows scientists to move desired genes from one ...

  9. Genetics Home Reference

    MedlinePlus

    Skip Navigation Bar Home Current Issue Past Issues Genetics Home Reference Past Issues / Spring 2007 Table of ... of this page please turn Javascript on. The Genetics Home Reference (GHR) Web site — ghr.nlm.nih. ...

  10. Genetic Disease Foundation

    MedlinePlus

    ... Newly Diagnosed Patients There are over 6,000 genetic disorders that can be passed down through the ... mission to help prevent, manage and treat inherited genetic diseases. View our latest News Brief here . You ...

  11. Latest Research: Genetic Links

    MedlinePlus

    ... Current Issue Past Issues Feature: Vision Latest Research: Genetic Links Past Issues / Summer 2008 Table of Contents ... laboratories is one way the NEI is expanding genetic testing of eye diseases. Photo courtesy of National ...

  12. Genetics of Hearing Loss

    MedlinePlus

    ... in Latin America Information For… Media Policy Makers Genetics of Hearing Loss Recommend on Facebook Tweet Share ... of hearing loss in babies is due to genetic causes. There are also a number of things ...

  13. Genetics and Man

    ERIC Educational Resources Information Center

    Carter, C. O.

    1973-01-01

    Can genetic evolution be controlled by man in a manner which does not violate a civilized, humane, and democratic ethos? The genetics of health and illhealth and of normal variation are discussed with respect to this question. (PEB)

  14. Genetics Home Reference: SADDAN

    MedlinePlus

    ... PDF Open All Close All Description SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) is a ... Genetic Testing (1 link) Genetic Testing Registry: Severe achondroplasia with developmental delay and acanthosis nigricans Other Diagnosis ...

  15. Genetic Testing for ALS

    MedlinePlus

    ... Some medical centers may require a neurological exam, psychological assessment and counseling before predictive testing. If a person in the family with ALS has a negative genetic test result (no identified genetic mutation), testing family members ...

  16. Genetics Home Reference: otulipenia

    MedlinePlus

    ... Facebook Share on Twitter Your Guide to Understanding Genetic Conditions Search MENU Toggle navigation Home Page Search ... Conditions Genes Chromosomes & mtDNA Resources Help Me Understand Genetics Home Health Conditions otulipenia otulipenia Enable Javascript to ...

  17. Frontotemporal Dementia: Genetics

    MedlinePlus

    ... Calendar of Events Fundraising Events Conferences Press Releases Genetics of FTD After receiving a diagnosis of FTD ... that recent advances in science have brought the genetics of FTD into much better focus. In 2012, ...

  18. Genetic Brain Disorders

    MedlinePlus

    A genetic brain disorder is caused by a variation or a mutation in a gene. A variation is a different form ... mutation is a change in a gene. Genetic brain disorders affect the development and function of the ...

  19. About Genetic Counselors

    MedlinePlus

    ... While most genetic counseling is provided in-person, access to genetic counselors is expanding, and many now provide consultation services by telephone, videoconferencing, and the internet, or offer education and support in group settings. ...

  20. Software For Genetic Algorithms

    NASA Technical Reports Server (NTRS)

    Wang, Lui; Bayer, Steve E.

    1992-01-01

    SPLICER computer program is genetic-algorithm software tool used to solve search and optimization problems. Provides underlying framework and structure for building genetic-algorithm application program. Written in Think C.

  1. Genomes and phenomes of a population of outbred rats and its progenitors

    PubMed Central

    Baud, Amelie; Guryev, Victor; Hummel, Oliver; Johannesson, Martina; Baud, Amelie; Guryev, Victor; Hummel, Oliver; Johannesson, Martina; Hermsen, Roel; Stridh, Pernilla; Graham, Delyth; McBride, Martin W; Foroud, Tatiana; Calderari, Sophie; Diez, Margarita; Ockinger, Johan; Beyeen, Amennai D; Gillett, Alan; Abdelmagid, Nada; Guerreiro-Cacais, Andre Ortlieb; Jagodic, Maja; Tuncel, Jonatan; Norin, Ulrika; Beattie, Elisabeth; Huynh, Ngan; Miller, William H; Koller, Daniel L; Alam, Imranul; Falak, Samreen; Osborne-Pellegrin, Mary; Martinez-Membrives, Esther; Canete, Toni; Blazquez, Gloria; Vicens-Costa, Elia; Mont-Cardona, Carme; Diaz-Moran, Sira; Tobena, Adolf; Zelenika, Diana; Saar, Kathrin; Patone, Giannino; Bauerfeind, Anja; Bihoreau, Marie-Therese; Heinig, Matthias; Lee, Young-Ae; Rintisch, Carola; Schulz, Herbert; Wheeler, David A; Worley, Kim C; Muzny, Donna M; Gibbs, Richard A; Lathrop, Mark; Lansu, Nico; Toonen, Pim; Ruzius, Frans Paul; de Bruijn, Ewart; Hauser, Heidi; Adams, David J; Keane, Thomas; Atanur, Santosh S; Aitman, Tim J; Flicek, Paul; Malinauskas, Tomas; Jones, E Yvonne; Ekman, Diana; Lopez-Aumatell, Regina; Dominiczak, Anna F; Holmdahl, Rikard; Olsson, Tomas; Gauguier, Dominique; Hubner, Norbert; Fernandez-Teruel, Alberto; Cuppen, Edwin; Mott, Richard; Flint, Jonathan; Flint, Jonathan

    2014-01-01

    Finding genetic variants that contribute to phenotypic variation is one of the main challenges of modern genetics. We used an outbred population of rats (Heterogeneous Stock, HS) in a combined sequence-based and genetic mapping analysis to identify sequence variants and genes contributing to complex traits of biomedical relevance. Here we describe the sequences of the eight inbred progenitors of the HS and the variants that segregate between them. We report the genotyping of 1,407 HS rats, and the collection from 2,006 rats of 195 phenotypic measures that are relevant to models of anxiety, type 2 diabetes, hypertension and osteoporosis. We make available haplotype dosages for the 1,407 genotyped rats, since genetic mapping in the HS is best carried out by reconstructing each HS chromosome as a mosaic of the progenitor genomes. Finally, we have deposited an R object that makes it easy to incorporate our sequence data into any genetic study of HS rats. Our genetic data are available for both Rnor3.4 and Rnor5.0 rat assemblies. PMID:25977769

  2. Genomes and phenomes of a population of outbred rats and its progenitors.

    PubMed

    Baud, Amelie; Guryev, Victor; Hummel, Oliver; Johannesson, Martina; Flint, Jonathan

    2014-01-01

    Finding genetic variants that contribute to phenotypic variation is one of the main challenges of modern genetics. We used an outbred population of rats (Heterogeneous Stock, HS) in a combined sequence-based and genetic mapping analysis to identify sequence variants and genes contributing to complex traits of biomedical relevance. Here we describe the sequences of the eight inbred progenitors of the HS and the variants that segregate between them. We report the genotyping of 1,407 HS rats, and the collection from 2,006 rats of 195 phenotypic measures that are relevant to models of anxiety, type 2 diabetes, hypertension and osteoporosis. We make available haplotype dosages for the 1,407 genotyped rats, since genetic mapping in the HS is best carried out by reconstructing each HS chromosome as a mosaic of the progenitor genomes. Finally, we have deposited an R object that makes it easy to incorporate our sequence data into any genetic study of HS rats. Our genetic data are available for both Rnor3.4 and Rnor5.0 rat assemblies.

  3. Behavioral genetics and taste

    PubMed Central

    Boughter, John D; Bachmanov, Alexander A

    2007-01-01

    This review focuses on behavioral genetic studies of sweet, umami, bitter and salt taste responses in mammals. Studies involving mouse inbred strain comparisons and genetic analyses, and their impact on elucidation of taste receptors and transduction mechanisms are discussed. Finally, the effect of genetic variation in taste responsiveness on complex traits such as drug intake is considered. Recent advances in development of genomic resources make behavioral genetics a powerful approach for understanding mechanisms of taste. PMID:17903279

  4. Genetics in psychiatry.

    PubMed

    Umesh, Shreekantiah; Nizamie, Shamshul Haque

    2014-04-01

    Today, psychiatrists are focusing on genetics aspects of various psychiatric disorders not only for a future classification of psychiatric disorders but also a notion that genetics would aid in the development of new medications to treat these disabling illnesses. This review therefore emphasizes on the basics of genetics in psychiatry as well as focuses on the emerging picture of genetics in psychiatry and their future implications.

  5. Genetics in psychiatry

    PubMed Central

    Umesh, Shreekantiah; Nizamie, Shamshul Haque

    2014-01-01

    Today, psychiatrists are focusing on genetics aspects of various psychiatric disorders not only for a future classification of psychiatric disorders but also a notion that genetics would aid in the development of new medications to treat these disabling illnesses. This review therefore emphasizes on the basics of genetics in psychiatry as well as focuses on the emerging picture of genetics in psychiatry and their future implications. PMID:25400339

  6. Introductory molecular genetics

    SciTech Connect

    Edwards-Moulds, J.

    1986-01-01

    This book begins with an overview of the current principles of genetics and molecular genetics. Over this foundation, it adds detailed and specialized information: a description of the translation, transcription, expression and regulation of DNA and RNA; a description of the manipulation of genetic material via promoters, enhancers, and gene splicing; and a description of cloning techniques, especially those for blood group genes. The last chapter looks to the impact of molecular genetics on transfusion medicine.

  7. Genetics of psoriasis.

    PubMed

    Mahil, Satveer K; Capon, Francesca; Barker, Jonathan N

    2015-01-01

    Psoriasis is a common and debilitating immune-mediated skin disease with a complex genetic basis. Genetic studies have provided critical insights into the pathogenesis of disease. This article focuses on the results of genetic association studies, which provide evidence that psoriasis susceptibility genes are involved in innate and adaptive immunity and skin barrier functions. The potential for disease stratification and the development of more effective treatments with fewer side effects using genetic data are highlighted.

  8. Gene Targeting in the Rat: Advances and Opportunities

    PubMed Central

    Jacob, Howard J.; Lazar, Jozef; Dwinell, Melinda R.; Moreno, Carol; Geurts, Aron M.

    2010-01-01

    The rat has long been a model favored by physiologists, pharmacologists, and neuroscientists. However, over the last two decades, many investigators in these fields have turned to the mouse because of its gene modification technologies and extensive genomic resources. While the genomic resources of the rat have nearly caught-up, gene targeting has lagged far behind, limiting the value of the rat for many investigators. In the last two years, advances in transposon- and zinc finger nuclease-mediated gene knockout as well as the establishment and culturing of embryonic and inducible pluripotent stem cells have created new opportunities for rat genetic research. Here, we provide a high-level description and potential uses of these new technologies for investigators using the rat for biomedical research. PMID:20869786

  9. EXACERBATED MECHANICAL ALLODYNIA IN RATS WITH DEPRESSION-LIKE BEHAVIOR

    PubMed Central

    Zeng, Qing; Wang, Shuxing; Lim, Grewo; Yang, Liling; Mao, Ji; Sung, Backil; Chang, Yang; Lim, Jeong-Ae; Guo, Gongshe; Mao, Jianren

    2008-01-01

    Although a clinical connection between pain and depression has long been recognized, how these two conditions interact remains unclear. Here we report that both mechanical allodynia and depression-like behavior were significantly exacerbated after peripheral nerve injury in Wistar-Kyoto (WKY) rats, a genetic variation of Wistar rats with demonstrable depression-like behavior. Administration of melatonin into the anterior cingular cortex contralateral to peripheral nerve injury prevented the exacerbation of mechanical allodynia with a concurrent improvement of depression-like behavior in WKY rats. Moreover, there was a lower plasma melatonin concentration and a lower melatonin receptor expression in the anterior cingular cortex in WKY rats than in Wistar rats. These results suggest that there exists a reciprocal relationship between mechanical allodynia and depression-like behavior and the melotoninergic system in the anterior cingular cortex might play an important role in the interaction between pain and depression. PMID:18289511

  10. Clonic Seizures in GAERS Rats after Oral Administration of Enrofloxacin

    PubMed Central

    Bauquier, Sebastien H; Jiang, Jonathan L; Lai, Alan; Cook, Mark J

    2016-01-01

    The aim of this study was to evaluate the effect of oral enrofloxacin on the epileptic status of Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Five adult female GAERS rats, with implanted extradural electrodes for EEG monitoring, were declared free of clonic seizures after an 8-wk observation period. Enrofloxacin was then added to their drinking water (42.5 mg in 750 mL), and rats were observed for another 3 days. The number of spike-and-wave discharges and mean duration of a single discharge did not differ before and after treatment, but 2 of the 5 rats developed clonic seizures after treatment. Enrofloxacin should be used with caution in GAERS rats because it might induce clonic seizures. PMID:27298247

  11. Generation of transgenic rats through induced pluripotent stem cells.

    PubMed

    Jiang, Ming-Gui; Li, Tianda; Feng, Chunjing; Fu, Rui; Yuan, Yan; Zhou, Quan; Li, Xin; Wan, Haifeng; Wang, Liu; Li, Wei; Xiao, Yamei; Zhao, Xiao-Yang; Zhou, Qi

    2013-09-20

    The rat is an important animal model for human disease research. Using inhibitors of glycogen synthase kinase 3 and MAPK signaling pathways, rat embryonic stem cells and rat induced pluripotent stem cells (riPSCs) have been derived. However, unlike rat embryonic stem cells, germ line competent riPSCs have only been derived from Wistar rats at low efficiency. Here, we found that an optimized induction medium containing knock-out serum replacement and vitamin C improved the rate and efficiency of riPSCs generation from Dark Agouti rat fibroblasts and Sertoli cells. riPSCs maintained an undifferentiated status for >30 passages and could differentiate into various cells types including germ cells when injected into rat blastocysts. Moreover, transgenic riPSCs could be generated through the PiggyBac transposon, which could be used to generate transgenic rats through germ line transmission. riPSCs can be used as a novel tool in genetic and genomic studies of the rat.

  12. Statistics for Learning Genetics

    ERIC Educational Resources Information Center

    Charles, Abigail Sheena

    2012-01-01

    This study investigated the knowledge and skills that biology students may need to help them understand statistics/mathematics as it applies to genetics. The data are based on analyses of current representative genetics texts, practicing genetics professors' perspectives, and more directly, students' perceptions of, and performance in, doing…

  13. Phenylketonuria Genetic Screening Simulation

    ERIC Educational Resources Information Center

    Erickson, Patti

    2012-01-01

    After agreeing to host over 200 students on a daylong genetics field trip, the author needed an easy-to-prepare genetics experiment to accompany the DNA-necklace and gel-electrophoresis activities already planned. One of the student's mothers is a pediatric physician at the local hospital, and she suggested exploring genetic-disease screening…

  14. Statistics for Learning Genetics

    ERIC Educational Resources Information Center

    Charles, Abigail Sheena

    2012-01-01

    This study investigated the knowledge and skills that biology students may need to help them understand statistics/mathematics as it applies to genetics. The data are based on analyses of current representative genetics texts, practicing genetics professors' perspectives, and more directly, students' perceptions of, and performance in, doing…

  15. Phenylketonuria Genetic Screening Simulation

    ERIC Educational Resources Information Center

    Erickson, Patti

    2012-01-01

    After agreeing to host over 200 students on a daylong genetics field trip, the author needed an easy-to-prepare genetics experiment to accompany the DNA-necklace and gel-electrophoresis activities already planned. One of the student's mothers is a pediatric physician at the local hospital, and she suggested exploring genetic-disease screening…

  16. Feline Genetics: Clinical Applications and Genetic Testing

    PubMed Central

    Lyons, Leslie A.

    2010-01-01

    DNA testing for domestic cat diseases and appearance traits is a rapidly growing asset for veterinary medicine. Approximately thirty-three genes contain fifty mutations that cause feline health problems or alterations in the cat’s appearance. A variety of commercial laboratories can now perform cat genetic diagnostics, allowing both the veterinary clinician and the private owner to obtain DNA test results. DNA is easily obtained from a cat via a buccal swab using a standard cotton bud or cytological brush, allowing DNA samples to be easily sent to any laboratory in the world. The DNA test results identify carriers of the traits, predict the incidence of traits from breeding programs, and influence medical prognoses and treatments. An overall goal of identifying these genetic mutations is the correction of the defect via gene therapies and designer drug therapies. Thus, genetic testing is an effective preventative medicine and a potential ultimate cure. However, genetic diagnostic tests may still be novel for many veterinary practitioners and their application in the clinical setting needs to have the same scrutiny as any other diagnostic procedure. This article will review the genetic tests for the domestic cat, potential sources of error for genetic testing, and the pros and cons of DNA results in veterinary medicine. Highlighted are genetic tests specific to the individual cat, which are a part of the cat’s internal genome. PMID:21147473

  17. Feline genetics: clinical applications and genetic testing.

    PubMed

    Lyons, Leslie A

    2010-11-01

    DNA testing for domestic cat diseases and appearance traits is a rapidly growing asset for veterinary medicine. Approximately 33 genes contain 50 mutations that cause feline health problems or alterations in the cat's appearance. A variety of commercial laboratories can now perform cat genetic diagnostics, allowing both the veterinary clinician and the private owner to obtain DNA test results. DNA is easily obtained from a cat via a buccal swab with a standard cotton bud or cytological brush, allowing DNA samples to be easily sent to any laboratory in the world. The DNA test results identify carriers of the traits, predict the incidence of traits from breeding programs, and influence medical prognoses and treatments. An overall goal of identifying these genetic mutations is the correction of the defect via gene therapies and designer drug therapies. Thus, genetic testing is an effective preventative medicine and a potential ultimate cure. However, genetic diagnostic tests may still be novel for many veterinary practitioners and their application in the clinical setting needs to have the same scrutiny as any other diagnostic procedure. This article will review the genetic tests for the domestic cat, potential sources of error for genetic testing, and the pros and cons of DNA results in veterinary medicine. Highlighted are genetic tests specific to the individual cat, which are a part of the cat's internal genome. Copyright © 2010 Elsevier Inc. All rights reserved.

  18. Strain differences in toxicity of oral cadmium intake in rats.

    PubMed

    Ninkov, Marina; Popov Aleksandrov, Aleksandra; Mirkov, Ivana; Demenesku, Jelena; Mileusnic, Dina; Jovanovic Stojanov, Sofija; Golic, Natasa; Tolinacki, Maja; Zolotarevski, Lidija; Kataranovski, Dragan; Brceski, Ilija; Kataranovski, Milena

    2016-10-01

    Influence of genetic background on toxicity of oral cadmium (Cd) administration (30 days, in drinking water; 5 ppm and 50 ppm of cadmium) was examined in Albino Oxford (AO) and Dark Agouti (DA) rats. Similar cadmium deposition was noted in gut and draining mesenteric lymph nodes (MLN) of both strains but intensity and/or the pattern of responses to cadmium in these tissues differ. Less intense intestinal damage and leukocyte infiltration was observed in gut of cadmium-exposed AO rats. While gut-associated lymph node cells of DA rats responded to cadmium with an increase of cell proliferation, oxidative activity, IFN-γ, IL-17 production and expression, no changes of these activities of MLN cells of cadmium-treated AO rats were observed. Spleen, which accumulated cadmium comparable to MLN, responded to metal by drop in cell viability and by reduced responsiveness of proliferation and cytokine production to stimulation in DA rats solely, which suggest tissue dependence of cadmium effects. More pronounced cadmium effects on MLN and spleen cells of DA rats (which accumulated similar cadmium doses as AO rats), showed greater susceptibility of this strain to cadmium. The results presented, for the first time, depict the influence of genetic background to effects of oral cadmium administration.

  19. Rat hepatitis E virus derived from wild rats (Rattus rattus) propagates efficiently in human hepatoma cell lines.

    PubMed

    Jirintai, Suljid; Tanggis; Mulyanto; Suparyatmo, Joseph Benedictus; Takahashi, Masaharu; Kobayashi, Tominari; Nagashima, Shigeo; Nishizawa,