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Pig husbandry is known as an intensive breeding system, piglets being submitted to multiple stressful events such as early weaning, successive mixing, crowding and shipping. These stressors are thought to impair immune defences and might contribute, at least partly, to the prophylactic use of antibiotics. Robustness was recently defined as the ability of an individual to express a high-production potential in a wide variety of environmental conditions. Increasing robustness thus appears as a valuable option to improve resilience to stressors and could be obtained by selecting piglets upon their adrenocortical activity. In this study, we aimed at depicting the consequences of an acute social stress on the immune capacity of piglets genetically selected upon divergent hypothalamic-pituitary-adrenocortical (HPA) axis activity. For this purpose, we monitored neuroendocrine and immune parameters, in high- (HPA(hi)) and low- (HPAI(lo)) responders to ACTH, just before and immediately after a one-hour mixing with unfamiliar conspecifics. As expected, stressed piglets displayed higher levels of circulating cortisol and norepinephrine. Blood cell count analysis combined to flow cytometry revealed a stress-induced leukocyte mobilization in the bloodstream with a specific recruitment of CD8 alpha(+) lymphocytes. Besides, one-hour mixing decreased LPS-induced IL-8 and TNF alpha secretions in whole-blood assays (WBA) and reduced mononuclear cell phagocytosis. Altogether, our data demonstrate that acute social stress alters immune competence of piglets from both groups, and bring new insights in favour of good farming practices. While for most parameters high- and low-responders to ACTH behaved similarly, HPA(hi) piglets displayed higher number of CD4(+) CD8 alpha(-) T cells, as well as increased cytokine production in WBA (LPS-induced TNFa and PIL-induced IL-8), which could confer them increased resistance to pathogens. Finally, a principal component analysis including all parameters highlighted that overall stress effects were less pronounced on piglets with a strong HPA axis. Thus, selection upon adrenocortical axis activity seems to reduce the magnitude of response to stress and appears as a good tool to increase piglet robustness.

Notice à Reprendre pas de clé UT au 14 janvier 2018; Lethal yellow (AY) mutation causes obesity and type-2 diabetes in mice. Here we studied the effect of the AYmutation on the brain and behavior. The experiments were carried out on adult (11–12 weeks old) males of AY/amice and their wild-type littermates (a/a). Mice of AY/a and a/a genotypes did not differ in their home cageactivity, sleep, food and water consumption, learning ability in the Morris water maze, anxiety in the open fieldand elevated plus-maze, as well as in the level of monoamines, metabolites and some genes expression in thebrain. At the same time, the fat mass, depressive-like immobility in the forced swim and tail suspension testswere significantly increased in AY/a mice compared with a/a ones. Magnetic resonance imaging revealed asignificant reduction of cortex volume in AY/a mice. The level of mRNA of Ptpn5 gene encoding striatal enrichedtyrosine phosphatase in the frontal cortex of AY/a mice was significantly elevated compared with their wild-typelittermates. This is the first report on the alterations in the brain and behavior in the AY/a mouse line. It istempting to speculate that this mouse line can serve as a new and useful preclinical model to study neurobehavioralcomplications associated with obesity and type-2 diabetes

Domestication of wild animals alters the aggression towards humans, brain monoamines and coat pigmentation. Our aim is the interplay between aggression, brain monoamines and depigmentation. The Hedlund white mutation in the American mink is an extreme case of depigmentation observed in domesticated animals. The aggressive (-2.06 ± 0.03) and tame (+3.5 ± 0.1) populations of wild-type dark brown color (standard) minks were bred during 17 successive generations for aggressive or tame reaction towards humans, respectively. The Hedlund mutation was transferred to the aggressive and tame backgrounds to generate aggressive (-1.2 ± 0.1) and tame (+3.0 ± 0.2) Hedlund minks. Four groups of 10 males with equal expression of aggressive (-2) or tame (+5) behavior, standard or with the Hedlund mutation, were selected to study biogenic amines in the brain. Decreased levels of noradrenaline in the hypothalamus, but increased concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid and dopamine metabolite, homovanillic acid, in the striatum were measured in the tame compared with the aggressive standard minks. The Hedlund mutation increased noradrenaline level in the hypothalamus and substantia nigra, serotonin level in the substantia nigra and striatum and decreased dopamine concentration in the hypothalamus and striatum. Significant interaction effects were found between the Hedlund mutation and aggressive behavior on serotonin metabolism in the substantia nigra (P < 0.001), dopamine level in the midbrain (P < 0.01) and its metabolism in the striatum (P < 0.05). These results provide the first experimental evidence of the interplay between aggression, brain monoamines and the Hedlund mutation in the American minks.

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, r p=0.539; genetic correlation, r g=0.938). Post-ACTH cortisol levels were highly heritable (h 2=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.

The hypothalamic-pituitary-adrenocortical (HPA) axis is a major neuroendocrine system involved in the regulation of numerous physiological processes and in adaptation to stress. A wide range of variability can be observed in all the components of the system, and the contribution of genetic factors has been shown in the central regulation of the axis, the production of glucocorticoid hormones by the adrenal cortex, their bioavailability, and the efficiency of their action at the level of receptor and postreceptor mechanisms. Numerous molecular polymorphisms have been described that contribute to physiological variation as well as to HPA axis-related pathological conditions. Although most studies focus on single gene polymorphisms, future studies should aim to integrate the different sources of variation into a systems genetic model to take into account the strong interdependence of the different components of the axis.

Background HPA axis plays a major role in physiological homeostasis. It is also involved in stress and adaptive response to the environment. In farm animals in general and specifically in pigs, breeding strategies have highly favored production traits such as lean growth rate, feed efficiency and prolificacy at the cost of robustness. On the hypothesis that the HPA axis could contribute to the trade-off between robustness and production traits, we have designed this experiment to explore individual variation in the biological response to the main stress hormone, cortisol, in pigs. We used ACTH injections to trigger production of cortisol in 120 juvenile Large White (LW) pigs from 28 litters and the kinetics of the response was measured with biological variables and whole blood gene expression at 4 time points. A multilevel statistical analysis was used to take into account the longitudinal aspect of the data. Results Cortisol level reached its peak 1 h after ACTH injection. White blood cell composition was modified with a decrease of lymphocytes and monocytes and an increase of granulocytes (FDR

The exposure of animals to a variety of stressful events can induce behavioral and physiological responses, which can be modulated by anxiety levels. It is well recognized that genetic factors play a substantial role in both anxiety and stress reactivity. The present study examined the effect of exposure to 2,4,5-trimethylthiazoline (TMT), a component of fox feces, on nociception and corticosterone levels in Lewis (LEW) and Spontaneously Hypertensive (SHR) inbred rat strains (which display genetic differences in anxiety models such as the elevated plus-maze and open-field). The influence of two quantitative trait loci (QTL), named Ofil1 and Ofil2, which are known to affect emotionality in LEW versus SHR intercrosses on the responses to TMT was also investigated. LEW and SHR rats of both sexes displayed similar levels of behavioral and neuroendocrine responses after TMT exposure. As expected, TMT odor stress produced analgesia and enhanced corticosterone levels. Ofil1 on chromosome 4 affected stress-induced analgesia in males only. Ofil2 on chromosome 7 had no effect. The results suggest that behaviors measured in classical models of generalized anxiety and reactivity to stress produced by predator odors can be genetically dissociated. Finding a locus with an effect on the behavioral responses to stress represents the starting point in the search for genes responsible for stress-related traits.

Previous studies using the inbred rat strains Lewis (LEW) and spontaneously hypertensive rats (SHR) led to the mapping of two quantitative trait loci, named Ofil1 (on chromosome 4 of the rat) and Ofil2 (on chromosome 7), for open-field inner locomotion, a behavioral index of anxiety. Studies using other strains showed that the region next to Ofil1 influences measures of not only anxiety but also ethanol consumption. In view of the high prevalence of psychiatric disorders such as anxiety and alcoholism, as well as the comorbidity between them, the present study was designed to better characterize the contribution of these two loci to complex emotional and consummatory responses. Rats deriving from an F2 intercross between the LEW and the SHR strains were selected according to their genotype at markers flanking the loci Ofil1 and Ofil2 and bred to obtain lines of rats homozygous LEW/LEW or SHR/SHR for each of the two loci, thus generating four genotypic combinations. These selected animals as well as purebred LEW and SHR rats of both sexes were submitted to a battery of tests including measures of locomotor activity, anxiety, sweet and bitter taste reinforcement and ethanol intake. Lewis rats displayed more anxiety-like behavior and less ethanol intake than SHR rats. Ofil1 (on chromosome 4) affected both the activity in the center of the open field and ethanol drinking in females only. These results suggest that Ofil1 contains either linked genes with independent influences on anxiety-related responses and ethanol drinking or a pleiotropic gene with simultaneous effects on both traits.

Background: HPA axis plays a major role in physiological homeostasis. It is also involved in stress and adaptive response to the environment. In farm animals in general and specifically in pigs, breeding strategies have highly favored production traits such as lean growth rate, feed efficiency and prolificacy at the cost of robustness. On the hypothesis that the HPA axis could contribute to the trade-off between robustness and production traits, we have designed this experiment to explore individual variation in the biological response to the main stress hormone, cortisol, in pigs. We used ACTH injections to trigger production of cortisol in 120 juvenile Large White (LW) pigs from 28 litters and the kinetics of the response was measured with biological variables and whole blood gene expression at 4 time points. A multilevel statistical analysis was used to take into account the longitudinal aspect of the data. Results: Cortisol level reached its peak 1 h after ACTH injection. White blood cell composition was modified with a decrease of lymphocytes and monocytes and an increase of granulocytes (FDR < 0.05). Basal level of cortisol was correlated with birth and weaning weights. Microarray analysis identified 65 unique genes of which expression responded to the injection of ACTH (adjusted P < 0.05). These genes were classified into 4 clusters with distinctive kinetics in response to ACTH injection. The first cluster identified genes strongly correlated to cortisol and previously reported as being regulated by glucocorticoids. In particular, DDIT4, DUSP1, FKBP5, IL7R, NFKBIA, PER1, RGS2 and RHOB were shown to be connected to each other by the glucocorticoid receptor NR3C1. Most of the differentially expressed genes that encode transcription factors have not been described yet as being important in transcription networks involved in stress response. Their co-expression may mean co-regulation and they could thus provide new patterns of biomarkers of the individual sensitivity to cortisol. Conclusions: We identified 65 genes as biological markers of HPA axis activation at the gene expression level. These genes might be candidates for a better understanding of the molecular mechanisms of the stress response.

Chantier qualité GA; The hypothalamic-pituitary-adrenal (HPA) axis exerts a large range of effects on metabolism, the immune system, inflammatory processes, and brain functions. Together with the sympathetic nervous system, it is also the most important stress-responsive neuroendocrine system. Both systems influence production traits, carcass composition, and meat quality. The HPA axis may be a critical target for genetic selection of more robust animals. Indeed, numerous studies in various species have demonstrated the importance of genetic factors in shaping the individual HPA axis phenotype, and genetic polymorphism can be found at each level of the axis, including hormone production by the adrenal cortices under stimulation by adrenocorticotropic hormone (ACTH), hormone bioavailability, or receptor and postreceptor mechanisms. The aim of the present experiment was to extend these findings to the brain neurochemical systems involved in stress responses. To this end, a number of candidate genes were sequenced for molecular polymorphisms and their association was studied with stress neuroendocrine and production traits in a genetically diverse population consisting of 100 female pigs from an advanced intercross (F10-F12) between 2 highly divergent breeds, Large White (LW) and Meishan (MS). The LW breed has a high production potential for lean meat and a low HPA axis activity, and the MS breed has low growth rate, fat carcasses--but large litters of highly viable piglets--and a high HPA axis activity. Candidate genes were chosen in the catecholaminergic and serotonergic pathways, in the pituitary control of cortisol production, among genes previously demonstrated to be differentially expressed in ACTH-stimulated adrenal glands from LW and MS pigs, and in cortisol receptors. Sixty new polymorphisms were found. The association study with carcass and meat quality traits and with endocrine traits showed a number of significant results, such as monoamine oxidase (MAOA) polymorphisms with growth rate (P = 0.01); lean content and intramuscular fat (P < 0.01), which are the most important traits for carcass value; dopamine receptor D3 (DRD3) with carcass composition (P < 0.05); and vasopressin receptor 1B (AVPR1B) with meat quality traits (P ≤ 0.05). The effect of these polymorphisms on neuroendocrine parameters (eg DRD3 and HPA axis or AVPR1B and catecholamines) indicates information regarding their biological mechanism of action.

Chantier qualité GA; International audience; Robustness in farm animals was defined by Knap as ‘the ability to combine a high production potential with resilience to stressors, allowing for unproblematic expression of a high production potential in a wide variety of environmental conditions’. The importance of robustness-related traits in breeding objectives is progressively increasing towards the production of animals with a high production level in a wide range of climatic conditions and production systems, together with a high level of animal welfare. Current strategies to increase robustness include selection for ‘functional traits’, such as skeletal and cardiovascular integrity, disease resistance and mortality in various stages. It is also possible to use global evaluation of sensitivity to the environment (e.g. reaction norm analysis or canalization), but these techniques are difficult to implement in practice. The hypothalamic–pituitary– adrenocortical (HPA) axis is the most important stress-responsive neuroendocrine system. Cortisol (or corticosterone) released by the adrenal cortices exerts a large range of effects on metabolism, the immune system, inflammatory processes and brain function, for example. Large individual variations have been described in the HPA axis activity with important physiopathological consequences. In terms of animal production, higher cortisol levels have negative effects on growth rate and feed efficiency and increase the fat/lean ratio of carcasses. On the contrary, cortisol has positive effects on traits related to robustness and adaptation. For instance, newborn survival was shown to be directly related to plasma cortisol levels at birth, resistance to bacteria and parasites are increased in animals selected for a higher HPA axis response to stress, and tolerance to heat stress is better in those animals that are able to mount a strong stress response. Intense selection for lean tissue growth during the last decades has concomitantly reduced cortisol production, which may be responsible for the negative effects of selection on piglet survival. One strategy to improve robustness is to select animals with higher HPA axis activity. Several sources of genetic polymorphism have been described in the HPA axis. Hormone production by the adrenal cortices under stimulation by adrenocorticotropin hormone is a major source of individual differences. Several candidate genes have been identified by genomic studies and are currently under investigation. Bioavailability of hormones as well as receptor and post-receptor mechanisms are also subject to individual variation. Integration of these different sources of genetic variability will allow the development of a model for marker-assisted selection to improve animal robustness without negative side effects on production traits.

Chantier qualité GA; International audience; The neurotransmitter serotonin (5-HT) is involved in the regulation of mouse intermale aggression. Previously, it was shown that intensity of mouse intermale aggression was positively associated with activity of the key enzyme of 5-HT synthesis - tryptophan hydroxylase 2 (TPH2) in mouse brain. The aim of the present study was to investigate the effect of pharmacological activation or inhibition of 5-HT synthesis in the brain on intermale aggression in two mouse strains differing in the TPH2 activity: C57BL/6J (B6, high TPH2 activity, high aggressiveness) and CC57BR/Mv (BR, low TPH2 activity, low aggressiveness). Administration of 5-HT precursor L-tryptophan (300 mg/kg, i.p.) to BR mice significantly increased the 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in the midbrain as well as the number of attacks and their duration in the resident-intruder test. And vice versa, administration of TPH2 inhibitor p-chlorophenylalanine (pCPA) (300 mg/kg, i.p., for 3 consecutive days) to B6 mice dramatically reduced the 5-HT and 5-HIAA contents in brain structures and attenuated the frequency and the duration of aggressive attacks. At the same time, L-tryptophan or pCPA did not influence the percentage of aggressive mice and the attack latency reflecting the threshold of aggressive reaction. This result indicated that the intensity of intermale aggression, but not the threshold of aggressive reaction is positively dependent on 5-HT metabolism in mouse brain.

Chantier qualité GA; International audience; The concept of robustness refers to the combination of a high production potential and a low sensitivity to environmental perturbations. The importance of robustness-related traits in breeding objectives is progressively increasing toward the production of animals with a high production level in a wide range of climatic conditions and production systems, together with a high level of animal welfare. Current strategies to increase robustness include selection for "functional traits," such as skeletal and cardiovascular integrity, disease resistance, and mortality at various stages. It is also possible to use global evaluation of sensitivity to the environment (eg reaction norm analysis or canalization), but these techniques are difficult to implement in practice. The glucocorticoid hormones released by the adrenal cortex exert a wide range of effects on metabolism, the cardiovascular system, inflammatory processes, and brain function, for example. Protein catabolism toward energy production and storage (lipids and glycogen) supports their pivotal role in stress responses aiming at the adaptation and survival of individuals under strong environmental pressure. Large individual variations have been described in adrenocortical axis activity, with important physiopathological consequences. In terms of animal production, higher cortisol levels have negative effects on growth rate and feed efficiency and increase the fat:lean ratio of carcasses. On the contrary, cortisol has positive effects on functional traits and adaptation. Intense selection for lean tissue growth and more generally high protein output during the past decades has concomitantly reduced cortisol production, which may be responsible for the negative effects of selection on functional traits. In this paper, we review experimental evidence suggesting that the balance between production and functional traits was modified in favor of improved robustness by selecting animals with higher adrenocortical axis activity, as well as the molecular genetic tools that can be used to fine-tune this objective.

Chantier qualité GA; We 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.

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.

The High-Ethanol Preferring line of rats (HEP), recently selected by R.D. Myers, is characterised by a high voluntary consumption of alcohol (3-4 g/kg/day for males and 6-8 g/kg/day for females, when a 10% ethanol solution is available as a choice vs. water) and a high sensitivity to taste reinforcement (saccharin, quinine). Our previous data obtained with HEP rats showed no evidence of development of dependence after long-term sustained alcohol intake. In this study, we subjected these rats to several long-term administration protocols suggested to favour the development of alcohol dependence, including multiple alcohol concentrations or sweetened alcohol solutions (ethanol 10% or 20%+saccharin), and deprivation periods. The results showed no increase in alcohol consumption, no shift of preference for alcohol solutions when offered as a free choice vs. a preferred saccharin solution, and a very limited alcohol-deprivation effect when alcohol is made available after a period of deprivation, the three criteria used to demonstrate the development of dependence. Regardless of the method used, HEP rats failed to show dependence after long-term, heavy ethanol consumption. Resistance to ethanol dependence may in fact be genetically influenced and the HEP rat appears as a valuable model to search for factors involved in the transition from alcohol abuse to dependence.