A QTL on rat chromosome 7 modulates prepulse inhibition, a neuro-behavioral trait of ADHD, in a Lewis x SHR intercross

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a complex neuropsychiatric disorder with a substantial genetic component. The Spontaneously Hypertensive Rats (SHR), considered as a good animal model of ADHD, also show less anxiety-like behaviors than Lewis (LEW) rats. The use of these inbred rat strains led us to the mapping of two quantitative trait loci (QTL), named Ofil1 (on chromosome 4) and Ofil2 (on chromosome 7), related to locomotion in the central and aversive area of an open field. Herein, we examined whether LEW and SHR rats differ in the acoustic startle reflex, a test used to study the neurobiology of anxiety, and in the prepulse inhibition of the startle response, which is known to be impaired in ADHD patients. The effect of the two aforementioned loci on these behavioral responses was also studied. METHODS: For this latter purpose, rats deriving from an F2 intercross between the LEW and SHR strains were selected according to their genotype at markers flanking the QTLs and bred to obtain lines of rats homozygous LEW/LEW or SHR/SHR for each of the two loci, thus generating 4 genotypic combinations. RESULTS: The SHR rats displayed decreased startle and prepulse inhibition levels when compared to LEW rats. Ofil2 affected prepulse inhibition in female rats only. CONCLUSION: The results suggest that the LEW and SHR strains are appropriate for studying mechanisms of sensorimotor gating and indicate that the locus Ofil2 on rat chromosome 7 contain genes controlling prepulse inhibition, a neuro-behavioral trait of ADHD

Genetic Contribution to Initial and Progressive Alcohol Intake Among Recombinant Inbred Strains of Mice

We profiled individual differences in alcohol consumption upon initial exposure and during 5 weeks of voluntary alcohol intake in female mice from 39 BXD recombinant inbred strains and parents using the drinking in the dark (DID) method. In this paradigm, a single bottle of 20% (v/v) alcohol was presented as the sole liquid source for 2 or 4 h starting 3 h into the dark cycle. For 3 consecutive days mice had access to alcohol for 2 h followed by a 4th day of 4 h access and 3 intervening days where alcohol was not offered. We followed this regime for 5 weeks. For most strains, 2 or 4 h alcohol intake increased over the 5-week period, with some strains demonstrating greatly increased intake. There was considerable and heritable genetic variation in alcohol consumption upon initial early and sustained weekly exposure. Two different mapping algorithms were used to identify QTLs associated with alcohol intake and only QTLs detected by both methods were considered further. Multiple suggestive QTLs for alcohol intake on chromosomes (Chrs) 2, 6, and 12 were identified for the first 4 h exposure. Suggestive QTLs for sustained intake during later weeks were identified on Chrs 4 and 8. Thirty high priority candidate genes, including Entpd2, Per3, and Fto were nominated for early and sustained alcohol intake QTLs. In addition, a suggestive QTL on Chr 15 was detected for change in 2 h alcohol intake over the duration of the study and Adcy8 was identified as a strong candidate gene. Bioinformatic analyses revealed that early and sustained alcohol intake is likely driven by genes and pathways involved in signaling, and/or immune and metabolic function, while a combination of epigenetic factors related to alcohol experience and genetic factors likely drives progressive alcohol intake.Peer Reviewe

The cortisol response to ACTH in pigs, heritability and influence of corticosteroid-binding globulin

In the search for biological basis of robustness, this study aimed (i) at the determination of the heritability of the cortisol response to ACTH in juvenile pigs, using restricted maximum likelihood methodology applied to a multiple trait animal model, and (ii) at the study of the relationships between basal and stimulated cortisol levels with corticosteroid-binding globulin (CBG), IGF-I and haptoglobin, all important players in glucose metabolism and production traits. At 6 weeks of age, 298 intact male and female piglets from 30 litters (30 dams and 30 boars) were injected with 250 µg ACTH(1–24) (Synacthen). Blood was taken before ACTH injection to measure basal levels of cortisol, glucose, CBG, IGF-I and haptoglobin, and 60 min later to measure stimulated cortisol levels and glucose. Cortisol increased 2.8-fold after ACTH injection, with a high correlation between basal and stimulated levels (phenotypic correlation, rp=0.539; genetic correlation, rg=0.938). Post-ACTH cortisol levels were highly heritable (h2=0.684) and could therefore be used for genetic selection of animals with a more reactive hypothalamic–pituitary–adrenocortical axis. CBG binding capacity correlated with cortisol levels measured in basal conditions in males only. No correlation was found between CBG binding capacity and post-ACTH cortisol levels. Basal IGF-I concentration was positively correlated with BW at birth and weaning, and showed a high correlation with CBG binding capacity with a strong sexual dimorphism, the correlation being much higher in males than in females. Basal haptoglobin concentrations were negatively correlated with CBG binding capacity and IGF-I concentrations. Complex relationships were also found between circulating glucose levels and these different variables that have been shown to be related to glucose resistance in humans. These data are therefore valuable for the genetic selection of animals to explore the consequences on production and robustness traits, but also point at pigs as a relevant model to explore the underlying mechanisms of the metabolic syndrome including the contribution of genetic factors

Methodologies for Assessing Disease Tolerance in Pigs

Features of intensive farming can seriously threaten pig homeostasis, well-being and productivity. Disease tolerance of an organism is the adaptive ability in preserving homeostasis and at the same time limiting the detrimental impact that infection can inflict on its health and performance without affecting pathogen burden per se. While disease resistance (DRs ) can be assessed measuring appropriately the pathogen burden within the host, the tolerance cannot be quantified easily. Indeed, it requires the assessment of the changes in performance as well as the changes in pathogen burden. In this paper, special attention is given to criteria required to standardize methodologies for assessing disease tolerance (DT) in respect of infectious diseases in pigs. The concept is applied to different areas of expertise and specific examples are given. The basic physiological mechanisms of DT are reviewed. Disease tolerance pathways, genetics of the tolerance-related traits, stress and disease tolerance, and role of metabolic stress in DT are described. In addition, methodologies based on monitoring of growth and reproductive performance, welfare, emotional affective states, sickness behavior for assessment of disease tolerance, and methodologies based on the relationship between environmental challenges and disease tolerance are considered. Automated Precision Livestock Farming technologies available for monitoring performance, health and welfare-related measures in pig farms, and their limitations regarding DT in pigs are also presented. Since defining standardized methodologies for assessing DT is a serious challenge for biologists, animal scientists and veterinarians, this work should contribute to improvement of health, welfare and production in pigs

Transcriptome profiling of sheep granulosa cells and oocytes during early follicular development obtained by Laser Capture Microdissection

<p>Abstract</p> <p>Background</p> <p>Successful achievement of early folliculogenesis is crucial for female reproductive function. The process is finely regulated by cell-cell interactions and by the coordinated expression of genes in both the oocyte and in granulosa cells. Despite many studies, little is known about the cell-specific gene expression driving early folliculogenesis. The very small size of these follicles and the mixture of types of follicles within the developing ovary make the experimental study of isolated follicular components very difficult.</p> <p>The recently developed laser capture microdissection (LCM) technique coupled with microarray experiments is a promising way to address the molecular profile of pure cell populations. However, one main challenge was to preserve the RNA quality during the isolation of single cells or groups of cells and also to obtain sufficient amounts of RNA.</p> <p>Using a new LCM method, we describe here the separate expression profiles of oocytes and follicular cells during the first stages of sheep folliculogenesis.</p> <p>Results</p> <p>We developed a new tissue fixation protocol ensuring efficient single cell capture and RNA integrity during the microdissection procedure. Enrichment in specific cell types was controlled by qRT-PCR analysis of known genes: six oocyte-specific genes (<it>SOHLH2</it>, <it>MAEL</it>, <it>MATER</it>, <it>VASA</it>, <it>GDF9</it>, <it>BMP15</it>) and three granulosa cell-specific genes (<it>KL</it>, <it>GATA4</it>, <it>AMH</it>).</p> <p>A global gene expression profile for each follicular compartment during early developmental stages was identified here for the first time, using a bovine Affymetrix chip. Most notably, the granulosa cell dataset is unique to date. The comparison of oocyte vs. follicular cell transcriptomes revealed 1050 transcripts specific to the granulosa cell and 759 specific to the oocyte.</p> <p>Functional analyses allowed the characterization of the three main cellular events involved in early folliculogenesis and confirmed the relevance and potential of LCM-derived RNA.</p> <p>Conclusions</p> <p>The ovary is a complex mixture of different cell types. Distinct cell populations need therefore to be analyzed for a better understanding of their potential interactions. LCM and microarray analysis allowed us to identify novel gene expression patterns in follicular cells at different stages and in oocyte populations.</p

Molecular genetics of stress responses to increase robustness in the context of sustainable production

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Effect of selective agonist of serotonin 5-HT1A receptors on defensive behavior in mice with different predisposition to catalepsy

Chantier qualité GAInternational audienceWe studied the effect of activation of serotonin 5-HT1A receptors with selective agonist 8-OH-DPAT (0.1, 0.5, and 1.0 mg/kg) on intraspecies aggression and freezing reaction (catalepsy) in male mice of catalepsy-resistant AKR/J and two catalepsy-prone strains CBA/Lac and congenic AKR. CBA-D13Mit76. The latter strain differs from AKR strain only by terminal chromosome 13 fragment transferred from CBA strain and containing a locus determining predisposition to catalepsy and a gene encoding 5-HT1A receptor. 8-OH-DPAT in a low dose (0.1 mg/kg) affecting primarily presynaptic receptors suppressed aggressive behavior in CBA mice, but had no effect on the time of cataleptic freezing. At the same time, this dose of the drug produced no significant effect on aggression in AKR and AKR. CBA-D13Mit76 mice, but significantly attenuated freezing in AKR. CBA-D13Mit76 mice. High doses of 8-OH-DPAT (0.5 and 1 mg/kg) which affected mainly postsynaptic receptors inhibited catalepsy in CBA and AKR. CBA-D13Mit76 mice and in a dose of 1 mg/kg it suppressed aggression in all tested mouse strains. We concluded that the genome of the recipient strain (AKR) modulated the involvement of 5-HT1A receptors into the regulation of aggression and catalepsy in mice

Genetic determinism of cortisol levels in pig

The plasma cortisol levels measured one hour after injection of ACTH reflects the hypothalamic-pituitary-adrenocortical (HPA) axis activity. The test was performed on piglets at 6 weeks of age. It was investigated as a potential selection criterion to improve pig robustness. From a base population of Large White pigs, two divergent lines were derived for 3 generations of selection, one selected for a high cortisol level (H line), one for a low cortisol level (L line). All breeders, as well as unselected animals, were also genotyped on a 70kSNP chip. At the 3rd generation of selection, the divergence between the two lines was about 5 genetic standard deviations. The high heritability of the trait was confirmed (h² = 0.64 ± 0.03). The genetic correlations with individual body weights and growth rates measured during lactation, post weaning and finishing periods were very low except for the genetic correlation between cortisol level and post-weaning growth rate (rg=-0.22 ± 0.10). The genome-wide association study revealed a quantitative trait locus influencing post-ACTH cortisol level, located on chromosome 2. It was suggested that divergent selection modified the frequency of NR3C1 alleles, favouring the hypersensitive glucocorticoid receptor in the low line

Analyse génétique de la réponse à l'ACTH chez le porc, relation avec des caractères de robustesse

L'axe corticotrope est une composante majeure des régulations métaboliques et des mécanismes biologiques de l'adaptation. L'activité de l'axe corticotrope et sa fonction sont fortement influencées par des facteurs génétiques. Les expériences présentes ont été conçues pour tester l'hypothèse que la sélection génétique pour un axe corticotrope plus actif peut améliorer la robustesse des porcs. Les expériences ont été faites avec des porcs Large White en race pure. Nous avons d'abord confirmé que la réponse du cortisol à l'ACTH est hautement héritable (h2 = 0,68 ± 0,12) dans cette population et peut donc être utilisée pour réaliser une expérience de sélection divergente. Dès la deuxième génération, de grandes différences dans le caractère de sélection ont été obtenues (concentration plasmatique de cortisol post-ACTH : 84,8 vs 127,5 ng/ml dans les lignées basse et haute, respectivement, P 0,10) et 1,5 porcelet vivant de plus par portée (P = 0,06) dans la lignée haute de reproducteurs G1). Les concentrations élevées de cortisol ont eu une influence négative sur la croissance en post-sevrage (418 vs 394 g/jour, P = 0,0013) et en engraissement (799 vs 754 g/jour, P 0.10), and 1.5 more piglets born alive per litter (P = 0.06) in the high line). Higher cortisol concentrations had a negative influence on growth rate during both post-weaning (418 vs 394 g/jour, P = 0.0013) and fattening (799 vs 754 g/jour, P < 0.0001) but improved carcass composition (lean%: 58.8 vs 60.4, low vs high line P < 0,001). These results confirm that the adrenocortical axis activity has a contrasted influence on functional and production traits. They have to be confirmed in the third generation for a comprehensive evaluation of the interest of selecting a more active adrenocortical axis to obtain animals that are more robust