Foetal haemoglobin elevation, unfavourable prognosis, and protective role of genetic variants HBG2 rs7482144, HBS1L-MYB rs9399137 and BCL11A rs4671393 in children with ALL.

In acute lymphoblastic leukaemia (ALL), elevated foetal haemoglobin (HbF) levels have been associated with the prognosis of patients. Genetic variants in HbF regulatory genes: BAF chromatin remodelling complex subunit (BCL11A), HBS1L-MYB transcriptional GTPase intergenic region (HBS1L-MYB), Krüppel-like factor 1 (KLF1), haemoglobin gamma subunit 2 (HBG2), haemoglobin gamma subunit 1 (HBG1), and haemoglobin subunit beta pseudogene 1 (HBBP1) are often associatedwith elevatedHbF concentration. This study investigated the association of genetic variants in HbF regulatory genes with HbF concentration, unfavourable prognosis, and outcome in children with ALL.We quantified HbF concentration and genotyped 17 genetic variants in 48 patients with ALL and 64 children without ALL as a reference group. HbF concentrationwas higher in patients than in the reference group (4.4%vs 1.4%), and 75%(n = 36) of thepatientshadHbF>2.5%.Unfavourable prognosis ALL was established in 68.8% (n = 33) of the patients. Variant HBG2 rs7482144 was associated with high HbF concentration (P = 0.015); while HBS1L-MYB rs9399137 (P = 0.001), HBG2 rs7482144 (P = 0.001) and the ß-globin genes HBG2, HBG1, and HBPP1 haplotypeTGC(P = 0.017) with unfavourable prognosisALL.Additionally, variantBCL11A rs4671393 showed a protective role (P = 0.0001). In conclusion, variants HBG2 rs7482144, HBS1L-MYB rs9399137 and BCL11A rs4671393 may play a significant role in ALL.

Genetic analysis of TMPRSS6 catalytic domain variants in Mexican patients with iron treatment refractoriness.

OBJECTIVE: To identify the TMPRSS6 gene variants in Mexican patients with iron treatment refractoriness, to describe hematological and iron profile parameters, and to use bioinformatic prediction and protein modeling tools to assess a possible biological impact for the detected missense variants. METHODS: Nineteen patients referred with iron treatment refractoriness were studied. Peripheral blood was collected to determine hematic cytometry, iron profile, hemoglobin electrophoresis, and quantification. Molecular screening was carried out for exons 15 through 18 of the TMPRSS6 gene by Sanger sequencing and for frequent thalassemia variants by amplification-refractory mutation system-polymerase chain reaction (PCR) and gap-PCR. The biological impact of the detected missense variants was assessed using bioinformatic prediction and protein modeling tools. RESULTS: We found 5 genetic variants in the matriptase-2 catalytic domain: 1 at intron-15/exon-16 junction (rs60484081) and 4 exonic, 3 missense (rs377054987, p.Gly626Asp; rs1384127820, p.Ser672Thr; rs855791, p.Val727Ala) and 1 synonymous (rs2235321, p.Tyr730=), with frequencies ranging from 0.18 to 0.53. No significant differences were observed in the hematological parameters or iron profile, considering type and number of variants. Bioinformatic predictions suggested a possible biological impact only for rs377054987. CONCLUSIONS: The TMPRSS6 variants observed in Mexican patients with oral iron treatment refractoriness have high frequencies; nevertheless, their relationship with hematological and iron profile parameters needs further research. The possible biological impact for rs377054987 is due to size and amino acid hydrophobicity changes and hydrogen bond modifications.

Association of Serum Fibroblast Growth Factor 23 and FGF23 Gene Variants with Chronic Kidney Disease in Patients with Type 2 Diabetes and Essential Hypertension.

INTRODUCTION: Fibroblast growth factor 23 (FGF23) gene variants could influence the production of FGF23 in subjects at risk for chronic kidney disease (CKD). Our purpose was to analyze the association of serum levels of FGF23 and two FGF23 gene variants with metabolic and renal function parameters in Mexican patients with Type 2 Diabetes (T2D) and/or essential hypertension (HTN). MATERIALS/METHODS: The study included 632 individuals diagnosed with T2D and/or HTN, of which 269 (43%) were diagnosed with CKD. FGF23 serum levels were determined and FGF23 gene variants rs11063112 and rs7955866 were genotyped. Genetic association analysis included binary and multivariate logistic regressions adjusted for age and sex. RESULTS: Patients with CKD were older, had higher systolic blood pressure, uric acid, and glucose levels than those without CKD. Also, patients with CKD had higher FGF23 levels (106 vs. 73 pg/mL p = 0.003). No correlation of any gene variants with FGF23 levels was found, but minor allele for rs11063112 and haplotype rs11063112A-rs7955866A were associated with low probability of CKD (Odds Ratio [OR] = 0.62 and 0.58, respectively). Conversely, the haplotype rs11063112T-rs7955866A was associated with increased FGF23 levels and risk for CKD (OR = 6.90). CONCLUSIONS: In addition to the traditional risk factors, levels of FGF23 are higher in Mexican patients with diabetes and/or essential hypertension and CKD, compared to those without renal damage. In contrast, the two minor alleles of two variants of the FGF23 gene, rs11063112 and rs7955866, as well as the haplotype carrying these two alleles, were found to be protective against renal disease in this Mexican patients' sample.

The Genetic Variant TNFA (rs361525) Is Associated with Increased Susceptibility to Developing Dengue Symptoms.

Dengue virus (DENV) is the causal agent of dengue fever. The symptoms and signs of dengue vary from febrile illness to hemorrhagic syndrome. IFITM3 and TNFA are genes of the innate immune system. Variants IFITM3 (rs12252 T>C) and TNFA (rs1800629 G > A and rs361525 G>A) might alter gene expression and change the course of the disease. Our first objective was to determine whether these variants were associated with the susceptibility and severity of dengue. The second was to assess the association of these variants with each symptom. We studied 272 cases with suspected dengue infection, of which 102 were confirmed dengue cases (DENV+) and 170 were dengue-like cases without DENV infection (DENV-). Samples of 201 individuals from the general population of Mexico were included as a reference. Genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism technique. Odds ratios and confidence intervals were calculated using Pearson's chi-square test and later adjusted for age and sex with a binary logistic regression model. Haldane correction is applied when necessary. We found a significantly higher frequency of the A allele of TNFA rs361525 in both the DENV+ and DENV- groups compared with the general population. Focusing on DENV+ and DENV-, the frequency of the A allele of TNFA rs361525 was higher in the DENV+ group. A broad spectrum of symptoms was related to the A allele of both TNFA variants. We conclude that TNFA rs361525 increases the susceptibility to symptomatic dengue but can also be associated with susceptibility to other dengue-like symptoms from unknown causes.

Low Expression of E-Cadherin and Cdh1 Variants Associated with Diffuse Gastric Cancer

ABSTRACT Background Reduced or null expression of E-cadherin protein is a frequent cause of diffuse gastric cancer (DGC). More than 50% of patients with DGC present somatic variants in CDH1 gene. Objectives The objectives of this study were to study E-cadherin expression and identify variants in the CDH1 gene in gastric tumors of patients with DGC. Methods We studied 18 Mexican DGC patients who attended a hospital of the Mexican Social Security Institute; E-cadherin expression was determined by immunohistochemistry, and variants were identified by Sanger sequencing in promoter and coding regions. Predictive analysis was performed using PolyPhen-2 and HOPE software. Results We found that 56% of DGC patients showed reduced expression of E-cadherin. All patients carried CDH1 variants; overall, 12 different CDH1 variants were identified. Predictive analysis revealed that the rs114265540 variant was probably damaging, with a value of 0.985, indicating a functional impact on the E-cadherin protein. Variants rs34939176 and rs33964119 were identified as risk factors for DGC (odds' ratios [OR] = 31.3, 95% CI 6.3-154.0, p < 0.001; OR = 6.1, 95% CI 2.0-19.0, p < 0.001, respectively) given their elevated frequency and by comparing it with those reported for MXL population in the 1000 Genomes Project database. Conclusions In this Mexican population, the percentage of diffuse gastric tumors with reduced expression of E-cadherin was similar to that reported in other populations. All gastric tumors of DGC patients studied had somatic CDH1 gene variants; however, the rs114265540, rs34939176, and rs33964119 variants were importantly related to DGC.

Low expression of E-Cadherin and CDH1 variants associated with diffuse gastric cancer.

Background: Reduced or null expression of E-cadherin protein is a frequent cause of diffuse gastric cancer (DGC). More than 50% of patients with DGC present somatic variants in CDH1 gene. Objectives: The objectives of this study were to study E-cadherin expression and identify variants in the CDH1 gene in gastric tumors of patients with DGC. Methods: We studied 18 Mexican DGC patients who attended a hospital of the Mexican Social Security Institute; E-cadherin expression was determined by immunohistochemistry, and variants were identified by Sanger sequencing in promoter and coding regions. Predictive analysis was performed using PolyPhen-2 and HOPE software. Results: We found that 56% of DGC patients showed reduced expression of E-cadherin. All patients carried CDH1 variants; overall, 12 different CDH1 variants were identified. Predictive analysis revealed that the rs114265540 variant was probably damaging, with a value of 0.985, indicating a functional impact on the E-cadherin protein. Variants rs34939176 and rs33964119 were identified as risk factors for DGC (odds' ratios [OR] = 31.3, 95% CI 6.3-154.0, p < 0.001; OR = 6.1, 95% CI 2.0-19.0, p < 0.001, respectively) given their elevated frequency and by comparing it with those reported for MXL population in the 1000 Genomes Project database. Conclusions: In this Mexican population, the percentage of diffuse gastric tumors with reduced expression of E-cadherin was similar to that reported in other populations. All gastric tumors of DGC patients studied had somatic CDH1 gene variants; however, the rs114265540, rs34939176, and rs33964119 variants were importantly related to DGC.

Role of the BMP6 protein in breast cancer and other types of cancer.

The BMP6 protein (Bone Morphogenetic Protein 6) is part of the superfamily of transforming growth factor-beta (TGF-ß) ligands, participates in iron homeostasis, inhibits invasion by increasing adhesions and cell-cell type interactions and induces angiogenesis directly on vascular endothelial cells. BMP6 is coded by a tumor suppressor gene whose subexpression is related to the development and cancer progression; during neoplastic processes, methylation is the main mechanism by which gene silencing occurs. This work presents a review on the role of BMP6 protein in breast cancer (BC) and other types of cancer. The studies carried out to date suggest the participation of the BMP6 protein in the epithelial-mesenchymal transition (EMT) phenotype, cell growth and proliferation; however, these processes are affected in a variable way in the different types of cancer, the methylated CpG sites in BMP6 gene promoter, as well as the interaction with other proteins could be the cause of such variation.

Predicting Pathogenicity of CDH1 Gene Variants in Patients with Early-onset Diffuse Gastric Cancer from Western Mexico

ABSTRACT Background: Early-onset diffuse gastric cancer (EODGC) occurs at or before 50 years of age. Pathogenic mutations and germline deletions in the CDH1 gene (E-cadherin) are well-documented genetic factors associated with the causes of EODGC. Objective: The objective of the study was to study CDH1 germline variants and their potential functional impact in patients with EODGC in a Mexican population. Methods: We studied seven EODGC patients from a biomedical research center in western Mexico. Variants were identified by Sanger sequencing and multiplex ligation-dependent probe amplification. The DeepSEA and SNPClinic v.1.0 software and the Ensembl (1000 Genomes Project, 1kGP) and ClinVar databases were used to predict functional single-nucleotide polymorphisms (SNPs). The genetic admixture of the Mexican patients was corroborated by 22 short tandem repeat loci genotyping and structure analysis. Results: We found 12 germline CDH1 variants in all EODGC patients, and all of them are considered as polymorphisms: rs34561447, rs5030625, rs16260, rs1330727101, rs28372783, rs942269593, rs3743674, rs1801552, rs34939176, rs33964119, rs3556654, and rs1801026. The prediction of regulatory SNPs in the promoter suggests a role for a retrovirus in EODGC that induces the transcription of interferon-related genes through toll-like receptor-interferon response factor 3 signaling, as three SNPs in the CDH1 promoter alter three binding sites for this transcription factor. In addition, SNPs rs28372783 and rs1801026 could alter upstream stimulatory factors 1 (USF1)/USF2-mediated telomerase-dependent lymphocyte activation in EODGC. Other interesting result is a CTCF-dependent shorter CDH1 isoform lacking exon 14, probably due to exon-skipping mediated by rs33964119. Conclusions: Classical pathogenic germline mutations in the CDH1 gene were not found in these 7 EODGC patients. However, the in silico approaches revealed the possible involvement of a retrovirus and a shorter E-cadherin isoform in EODGC. Nevertheless, further in vitro and in vivo assays are needed to confirm these predictions.

Molecular and Hematological Analysis of Alpha- and Beta-Thalassemia in a Cohort of Mexican Patients.

Introduction: Alpha- and beta-thalassemia are caused by reduced or absent synthesis of hemoglobin (Hb) subunits α and/or ß. HBA2, HBA1, and HBB mutations are the main cause of thalassemias. The aim of this article is to analyze molecular and hematological features of α- and ß-thal in a cohort of Mexican patients. Methods: One hundred forty-one thalassemia patients were studied. Peripheral blood was collected for blood cell count, electrophoresis, Hb quantification, and molecular testing. Molecular screening was performed by Gap-PCR, ARMS-PCR, Sanger sequencing, and MLPA. Results: Fifty-four patients had α-thal, 75 ß-thal, and 12 patients were complex cases, we observed 13 α- and 18 ß-thal alleles in 43 genotypes, -α3.7/αα and ßCd39C>T/ß were the most frequent. Four α-thal deletions (-Mex4 included HBA2 and HBA1, whereas (αα)Mex5, Mex6 and Mex7 involved MCS-R), a hereditary persistence of fetal hemoglobin-2 like (HPFH-2 like) deletion and six alleles not previously reported in Mexicans (α-59C>Tα, -α4.2, αPlasenciaα, ß-32C>T, ßInitCdA>C and ßFSCd71/72+A) were identified. Conclusion: The observed alleles denote the high heterogeneity and multiple origin admixture of Mexican population. Hematological data are consistent with genotypes, variability in simple carriers, from asymptomatic forms to mild or moderate anemia, was ascertained. We emphasize the importance to consider hematological parameters to establish adequate molecular screening strategies.

Predicting Pathogenicity of CDH1 Gene Variants in Patients with Early-onset Diffuse Gastric Cancer from Western Mexico.

BACKGROUND: Early-onset diffuse gastric cancer (EODGC) occurs at or before 50 years of age. Pathogenic mutations and germline deletions in the CDH1 gene (E-cadherin) are well-documented genetic factors associated with the causes of EODGC. OBJECTIVE: The objective of the study was to study CDH1 germline variants and their potential functional impact in patients with EODGC in a Mexican population. METHODS: We studied seven EODGC patients from a biomedical research center in western Mexico. Variants were identified by Sanger sequencing and multiplex ligation-dependent probe amplification. The DeepSEA and SNPClinic v.1.0 software and the Ensembl (1000 Genomes Project, 1kGP) and ClinVar databases were used to predict functional single-nucleotide polymorphisms (SNPs). The genetic admixture of the Mexican patients was corroborated by 22 short tandem repeat loci genotyping and structure analysis. RESULTS: We found 12 germline CDH1 variants in all EODGC patients, and all of them are considered as polymorphisms: rs34561447, rs5030625, rs16260, rs1330727101, rs28372783, rs942269593, rs3743674, rs1801552, rs34939176, rs33964119, rs3556654, and rs1801026. The prediction of regulatory SNPs in the promoter suggests a role for a retrovirus in EODGC that induces the transcription of interferon-related genes through toll-like receptor-interferon response factor 3 signaling, as three SNPs in the CDH1 promoter alter three binding sites for this transcription factor. In addition, SNPs rs28372783 and rs1801026 could alter upstream stimulatory factors 1 (USF1)/USF2-mediated telomerase-dependent lymphocyte activation in EODGC. Other interesting result is a CTCF-dependent shorter CDH1 isoform lacking exon 14, probably due to exon-skipping mediated by rs33964119. CONCLUSIONS: Classical pathogenic germline mutations in the CDH1 gene were not found in these 7 EODGC patients. However, the in silico approaches revealed the possible involvement of a retrovirus and a shorter E-cadherin isoform in EODGC. Nevertheless, further in vitro and in vivo assays are needed to confirm these predictions.

Hemoglobina Fannin-Lubbock I y II, dos variantes que comparten una mutación / Hemoglobin Fannin-Lubbock I and II, two variants sharing a mutation

Hemoglobin (Hb) Fannin-Lubbock I (beta119 [GH2]), GGC>GAC, Gly>Asp) and Hb Fannin-Lubbock II (beta111 [G13]), GTC>CTC, Val>Leu and beta 119 (GH2), GGC >GAC, Gly>Asp), share the mutation at position 119, both abnormal hemoglobins have similar fast electrophoretic mobility due the Gly>Asp change. Hb Fannin-Lubbock, is classified in the group of unstable hemoglobins, without alteration in their affinity for oxygen; the mutation at amino acid 119 and that of amino acid 111 participate in the interaction of the alpha1beta1 chains, with important links in the stability of the molecule, so that both substitutions could affect the stability of the molecule. Initially the instability of the variant was attributed to mutation 111, however, our group confirmed that the mutation at amino acid 119 is responsible for the instability to the molecule. In this paper, we analyze the first observations of Hb Fannin-Lubbock in 1976 and in 1982, the demonstration of Hb Fannin-Lubbock II by DNA sequencing as well as the evidence of two different mutations by DNA analysis, the Hb Fannin-Lubbock I observed mainly in families of Mexican origin and Hb Fannin-Lubbock II in families of Spanish origin, we also present the hematological characteristics of both types and the indirect evidence that the Hb Fannin-Lubbock I observed in a Mexican family and in a Hind

La hemoglobina (Hb) Fannin-Lubbock I (beta119 (GH2), GGC>GAC, Gly>Asp) y la Hb Fannin-Lubbock II (beta111 (G13), GTC>CTC, Val>Leu y beta119 (GH2), GGC>GAC, Gly>Asp), comparten la mutación en la posición 119, tienen movilidad electroforética rápida similar debida al cambio Gly>Asp. La Hb FanninLubbock se clasifica en el grupo de hemoglobinas inestables, sin alteración en su afinidad por el oxígeno; tanto la mutación en el aminoácido 119 como la del aminoácido 111 participan en la interacción de las cadenas alfa1beta1, por lo que ambas sustituciones podrían afectar la estabilidad de la molécula. Inicialmente la inestabilidad de la Hb se atribuyó a la mutación 111, sin embargo, nuestro grupo confirmó que la mutación en el aminoácido 119 es la responsable de la inestabilidad de la molécula. En este trabajo se analizan las primeras observaciones de la Hb Fannin-Lubbock en 1977 y en 1982, la demostración de la Hb Fannin-Lubbock II por secuenciación de ADN, así como la evidencia de dos mutaciones diferentes por análisis de ADN, la Hb Fannin-Lubbock I observada principalmente en familias de origen mexicano y la Hb Fannin-Lubbock II en familias de origen español, así como las características hematológicas de ambos tipos y la evidencia indirecta de que la Hb Fannin-Lubbock I observada en una familia mexicana y en una familia india se asocian con haplotipos beta distintos, lo que sugiere que surgieron por eventos mutacionales independientes

Control of food intake by MC4-R signaling in the lateral hypothalamus, nucleus accumbens shell and ventral tegmental area: interactions with ethanol.

The melanocortin system is involved in animal models of obesity and anorexia-cachexia and MC4 receptors (MC4-R) are currently a target system for the development of drugs aimed to treat obesity and eating disorders in humans. Previous evidence suggest that feeding peptides might lack their orexigenic activity while stimulate ethanol intake. The present study comparatively evaluated food intake (4-h interval) in Sprague-Dawley (SD) rats drinking ethanol (6% w/v, 2 bottle choice paradigm) (EE group) and ethanol-naïve (EN) rats in response to bilateral infusion of the selective MC4-R antagonist HS014 (0, 0.02 or 0.05 µg/0.5 µl/site) or the selective MC4-R agonist cyclo(NH-CH(2)-CH(2)-CO-His-d-Phe-Arg-Trp-Glu)-NH(2) (0, 0.75 or 1.5 µg/0.5 µl/site), into the lateral hypothalamus (LH), the nucleus accumbens (NAc), or the ventral tegmental area (VTA). The main findings in the study are: (1) LH-infusions of the MC4-R antagonist increased and the agonist reduced feeding and total calories consumed, while ethanol intake remained unaltered. (2) NAc- and VTA-infusions of the selective agonist reduced food, ethanol and total calories intake. (3) NAc- and VTA-infusions of the MC4-R antagonist increased feeding in EN rats, but not in EE animals which showed a mild increase in ethanol intake, while total calories consumed remained unaltered. Present data show that having ethanol available reduces feeding elicited by NAc and VTA-MC4-R blockade. Additionally, while MC4-R signaling in the LH appears to modulate homeostatic aspects of feeding, it may contribute to non-homeostatic aspects of ingestive behaviors in the VTA and the NAc.

One-way avoidance learning in female inbred Roman high- and low-avoidance rats: effects of bilateral electrolytic central amygdala lesions.

Female inbred Roman high- (RHA-I) and low- (RLA-I) avoidance rats show differences in one-way avoidance learning only when the task implies a highly aversive situation (1s in the "non-shock"-associated safe compartment, as opposed to 30s). These between-strain differences seem to depend on strain differences in emotionality, given that: (i) they are abolished by IP administration of the GABAergic anxiolytic diazepam (Torres et al. [32]) and (ii) avoidance responding appears to correlate with cellular density in the basolateral amygdala (Gómez et al. [9]). In the present study we further analyzed whether the implication of the amygdala in one-way avoidance depends on the experimental situation aversiveness (30s vs. 1s in safety). After bilateral electrolytic lesions (1mA; 20s) of the central amygdala (CeA), RHA-I and RLA-I rats were exposed to a danger compartment (where they received a warning signal - 88dB tone - followed by a 1mA electric foot-shock), and a safe compartment, where these stimuli were not presented. The number of trials needed to reach 5 consecutive avoidance responses was used as dependent variable. Sham lesioned RLA-I rats showed poorer performance than sham lesioned RHA-I rats only under the 1s condition. The CeA lesion disrupted the avoidance response only in 1s groups, abolishing the between-strain performance differences observed under this condition. These results indicate the implication of CeA in one-way avoidance performance, and suggest a reciprocal modulation of fear and reinforcement (i.e. fear relief) in this form of aversive learning.

Consummatory successive negative and anticipatory contrast effects in inbred Roman rats.

Three experiments were designed to study the performance of female inbred Roman High-(RHA-I) and Low-(RLA-I) Avoidance rats in a consummatory task in which successive negative (cSNC) and anticipatory contrast (cANC) effects were induced by changing the concentration of the sucrose solution used as reward. Both RHA-I and RLA-I rats showed a significant suppression of drinking (cSNC) when they were exposed to 32% sucrose in preshift phase and 4% in postshift phase, in comparison to RHA-I and RLA-I control groups always exposed to 4% sucrose (Experiment 1). By contrast, when the preshift-postshift reward discrepancy was reduced from 32-4 to 22-4 in Experiment 2, both strains showed a suppression of fluid intake on the first postshift trial, whereas only the more emotional RLA-I strain maintained this suppression on subsequent days. Finally, no consumption differences were observed between RHA-I and RLA-I rats exposed to brief daily access to 4% sucrose followed by access to 22% sucrose (cANC, Experiment 3). These results suggest that differences between the Roman rat strains in consummatory contrast paradigms can only be observed when the sucrose solution manipulation implies an incentive loss-attenuated emotional situation, but not when it occurs in an anticipatory manner.

One-way avoidance acquisition and cellular density in the basolateral amygdala: strain differences in Roman high- and low-avoidance rats.

The goal of the present experiment was to study the performance of inbred Roman high- (RHA-I) and low- (RLA-I) avoidance rats in one-way avoidance learning and to relate the behaviour of the animals to cellular density in the basolateral amygdala (BLA), a brain region related to fear and anxiety. Thus, females from both strains were exposed either to 30s or 1s in the safe place as a function of experimental condition, until they reached five consecutive avoidance responses. Thereafter, the rats were perfused, and their brains sectioned in 40microm coronal sections, stained with cresyl violet. The area (percentage of field) corresponding to the BLA structures was quantified by computerized-assisted image analysis. The results indicated that RLA-I showed a significantly poorer acquisition of the one-way avoidance task than did RHA-I rats, but only when safe time was the shortest (1s). In addition, the number of trials needed to reach the behavioural acquisition criterion was negatively correlated with BLA cellular density in RLA-I rats. These data suggest the possibility of relating behavioural and neuro-anatomical indexes, enabling exploration of the biological basis of fear/anxiety behaviours.

The partial reinforcement extinction effect (PREE) in female Roman high- (RHA-I) and low-avoidance (RLA-I) rats.

The present experiment was designed with the goal of studying the partial reinforcement extinction effect (PREE) in female inbred Roman high- (RHA-I) and low-avoidance (RLA-I) rats. Two groups of RHA-I and two of RLA-I food-deprived animals were placed in a straight alley where they were partially or continuously reinforced. Once the animals reached the acquisition criterion, they were exposed to an extinction phase where the reinforcement was omitted. During the extinction phase RHA-I animals continuously reinforced during acquisition exhibited more resistance to extinction than their RLA-I counterparts, whereas only RLA-I rats partially reinforced during acquisition showed an increased resistance to extinction in comparison to continuously reinforced control RLA-I rats, this PREE being absent in RHA-I animals. These results are discussed within the framework of PREE theories that account for this effect by using emotional mechanisms, as pertains to the repeatedly observed RHA-RLA differences in emotional reactivity.

Successive negative contrast effect in instrumental runway behaviour: a study with Roman high- (RHA) and Roman low- (RLA) avoidance rats.

It has been recently shown that Roman high- (RHA) and low- (RLA) avoidance rats show behavioural divergence in successive negative contrast (SNC) induced in one-way avoidance learning [Torres C, Cándido A, Escarabajal MD, de la Torre L, Maldonado A, Tobeña A, et al. Successive negative contrast effect in one-way avoidance learning in female roman rats. Physiol Behav 2005;85:377-82]. A 2-experiment study was conducted with the goal of analyzing whether these differences in SNC can also be extended to a different experimental paradigm. Food-deprived RHA and RLA female rats were exposed to a straight alley, recording the latency (DV) between leaving the start box and reaching the food available in the goal box at the end of the alley. To induce the SNC effect the amount of reinforcement received went from 12 pellets in the pre-shift phase to 1 pellet (Experiment 1) or 2 pellets (Experiment 2) in the postshift phase. The SNC effect appeared in both strains in Experiment 1, but only in RLA rats in Experiment 2. These results are discussed within the framework of SNC theories that account for this effect by using emotional mechanisms, as related to the differences in emotional reactivity seen between the RHA and RLA strains in a number of behavioural tests of fear/anxiety.

One-way avoidance learning and diazepam in female roman high-avoidance and low-avoidance rats.

The goal of this experiment was to study the influence of the time spent in the safe compartment (30 vs. 1 s) and of an intraperitoneal injection of diazepam (1 mg/kg vs. vehicle) on one-way avoidance learning, in inbred female roman high-avoidance and roman low-avoidance rats. Rats learned to run from a danger compartment, where they received a warning signal (88 dB tone) followed by a 1 mA electric footshock, to a safe compartment, where these stimuli were not presented. The number of trials needed to reach 10 consecutive avoidance responses was the dependent variable. Roman low-avoidance rats exposed to 1 s in the safe compartment showed poorer performance than their roman high-avoidance counterparts. These differences were not observed in rats exposed to 30 s in the safe place, and were abolished by the injection of diazepam. These results suggest the importance of fear and reinforcement in one-way avoidance learning and its usefulness for studying emotional processes underlying genetic or pharmacological manipulations.