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Early-life adversity may have programming effects on neuroendocrine and immune adaptation mechanisms in humans and socially living animals. Using a pig model, we investigated the effect of daily 2-h maternal and littermate deprivation from postnatal days 2-15, either alone (DA) or in a group of littermates (DG) on the neuroendocrine, immunological and behavioural responses of piglets challenged with the bacterial endotoxin lipopolysaccharide (LPS) on day 42. LPS increased plasma concentrations of cortisol, tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10) and induced typical signs of sickness in all piglets. DA+DG piglets showed stronger signs of sickness compared to control (C) piglets. Plasma TNF-α concentrations were significantly lower in DA+DG males. In addition, the TNF-α/IL-10 ratio was significantly lower in DA than in DG and C males. Gene expression analyses showed lower hypothalamic TNF-α mRNA expression and diminished mRNA expression of the mineralocorticoid receptor (MR) and IL-10 in the amygdala of DA+DG piglets in response to LPS. Interestingly, males showed a higher MR- and a lower IL-10 mRNA expression in the amygdala than females. The present data suggest that repeated maternal deprivation during early life may alter neuroendocrine and immune responses to acute endotoxaemia in a sex-specific manner.

Measuring heart reactions has become a widely used method for the assessment of emotions. Heart rate and its variability, which can quite easily be noninvasively recorded, reflect the inputs of the sympathetic and parasympathetic branches of the autonomous nervous system. We tested the hypothesis that frequent anticipation of a positive event results in an increased state of welfare in pigs, expressed as positive arousal in anticipation of announced feeding as well as lowered heart rate and augmented heart rate variability during resting periods. We used a controlled paradigm with 3 groups of young domestic pigs (Sus scrofa domestica). We compared frequent acoustic announcement of feed delivery (group 1: 3 feedings between 0730 h and 1030 h plus 3 feedings between 1200 h and 1530 h) with the same number of feedings as in group 1 but without a temporal relation to the sound (group 2) and with a fixed-schedule feeding (group 3: 2 feedings at 0600 h and 1500 h). Specific cardiac and behavioral reactions indicated short-term (1 min) anticipation in the conditioned group. In this group, heart rate increased (P < 0.001) mainly through vagal withdraw and behavior became more active (P < 0.001). Only the conditioned group displayed changing heart rate characteristics during the sound. Pigs in the frequent unpredictable feed group reacted to feed delivery with increased heart rates (P < 0.001), whereas the heart-rate characteristics of pigs with the fixed schedule were unchanged during the sound and while the other 2 treatment groups were feeding. Clear evidence for long-term anticipation (over the course of hours) was not present in the data. Comparisons between the 3 treatment groups suggested that in housing conditions where pigs cannot obtain feed by their actions but must wait for feed delivery, feeding at 2 fixed times would be preferred. Animals in this treatment group presented lower resting heart rates at the end of the experiment than animals in the other 2 groups (P < 0.01). Therefore, merely announcing a positive stimulus without giving control to its access is apparently not suitable for increasing welfare.

Social deprivation is a severe stressor affecting a number of behavioral and physiological functions of gregarious species. It is assumed that, dependent upon the level of familiarity, social support given by a conspecific may attenuate the adverse consequences of stress. We investigated the effects of a 4h maternal and littermate deprivation on behavioral reactions, stress hormone responses and brain corticosteroid receptor expression in 7-, 21- and 35-day-old domestic piglets (Sus scrofa) that were left alone or in the presence either of a familiar or unfamiliar age-matched piglet. Compared to control animals, all of the socially deprived piglets showed significant stress responses, such as impaired habituation in repeated open-field/novel-object tests, enhanced ACTH and cortisol release, and altered corticosteroid receptor expression in the hypothalamus. In addition, our results demonstrated that younger piglets had more difficulty coping with stress. The presence of an age-matched conspecific had a direct calming effect on the deprived piglet during the deprivation procedure, which was revealed by diminished stress-induced HPA activity and altered reactions in the behavioral test situations (e.g., activity, escape, and vocalization). Furthermore, because the presence of a familiar piglet causes a more pronounced buffering effect, we have shown for the first time that the degree of familiarity between the piglets may influence the effectiveness of social support. Our study emphasizes the benefits of social partners on positive welfare and the ability for pigs to cope with stress; therefore, our results should be taken into account during handling practices such as weaning and mixing., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Tumour necrosis factor (TNF)-alpha is known to be involved in anxiety and the regulation of the hypothalamic-pituitary-adrenal axis. To examine the role of its receptors in neuroendocrine immunomodulation, we studied behaviour, corticosterone production and T-cell activation in mice with a C57BL/6J background and deficient for one or both TNF receptors (TNFR1-/-, TNFR2-/-, and TNFR1+2-/-) compared to wildtype C57BL/6J mice with and without psychological stress. Stress was induced by social disruption (SDR), and anxiety-like behaviour was examined using the elevated plus maze (EPM). Anxiety of unstressed TNFR1+2-/- mice was increased compared to C57BL/6J mice as shown by reduced ratios of entries into open arms relatively to total entries. SDR-stressed TNFR1+2-/- mice showed reduced ratios of entries into open arms relatively to total entries, reduced ratios of distances walked in open relatively to distances walked in both arms and reduced time in open arms compared to C57BL/6J mice. Locomotor activity of unstressed and SDR-stressed TNFR1-/- and TNFR2-/- mice was reduced. Serum corticosterone concentrations of control mice do not differ between mouse strains. However, TNFR1+2-/- mice had significantly higher corticosterone concentrations than C57BL/6J mice after SDR. EPM testing significantly increased corticosterone concentrations in all strains. Mitogen-induced activation-marker expression was reduced in TNFR1-/- T-helper cells under control and stress conditions, while activation marker expression of TNFR2-/- and TNFR1+2-/- cells was only slightly affected by stress compared to C57BL/6J T cells. Our study suggests that both TNF receptors contribute to anxiety-like behaviour and corticosterone responses, whereas TNFR1 has a larger impact on T-cell activation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Stressful early life events can have short- and long-term effects on neuroendocrine and behavioural mechanisms of adaptation. Here, we investigated the effects of a single social isolation (4 h) of domestic piglets on both behavioural alterations in open-field tests and modifications in the expression of genes regulating glucocorticoid response in stress-related brain regions at 7, 21 or 35 days of age. The mRNAs of glucocorticoid receptor (GR), mineralocorticoid receptor (MR), 11ss-hydroxysteroid dehydrogenase 1 and 2 (11ss-HSD1 and 11ss-HSD2) and c-fos were analysed by real-time RT-PCR in the hypothalamus, hippocampus and amygdala. The social isolation caused both elevated stress hormone concentrations (e.g. cortisol) and open-field reactivity (e.g. locomotion, vocalisation) compared to control piglets. The enhanced behavioural and neuroendocrine activity was associated with distinct changes in gene expression in the limbic system. The hypothalamic GR, MR and 11ss-HSD1 mRNA expressions and the hippocampal 11ss-HSD1 mRNA was significantly higher in isolated piglets, whereas in the amygdala social isolation caused a significant decrease in MR mRNA expression. Isolated piglets also displayed significantly higher c-fos mRNA expression, an estimate of neuronal activation, in hypothalamus and amygdala. The mRNA alterations as well as the behavioural and hormonal pattern show an effect of social isolation on days 7 and 21, but no effect on day 35. In conclusion, a single social isolation in piglets caused age-dependent neuroendocrine and behavioural changes that indicate increased arousal and experienced distress. The present results also suggest that psychosocial stress effects should be considered for the assessment of livestock handling practices with respect to health and welfare.

Psychosocial stress in the form of maternal deprivation and social isolation during early postnatal life induces persistent alterations in behavioral and physiological mechanisms of adaptation. One consequence may be an increased susceptibility to diseases in later life. Therefore, the aim of the present study was to investigate in domestic piglets the effects of a repeated social isolation (2 h daily from day 3 to day 11 of age) on behavioral, endocrine and immune responses to an endotoxin challenge with lipopolysaccharide (LPS) 1 day or 45 days after the isolation period. Peripheral LPS administration caused serious sickness behavior (somnolence, shivering, vomiting) and provoked profound increases in circulating tumor necrosis factor-alpha (TNF-alpha), ACTH and cortisol concentrations. The prior social isolation treatment enhanced signs of sickness and impaired suckling behavior. Early isolated piglets responded to LPS by an increase of shivering on day 12 and by increased vomiting on day 56 compared to controls. Further, there were considerable delays and reductions of time isolated piglets spent suckling on day 12. The repeated isolation stressor diminished TNF-alpha increases after LPS, whereas stress hormone levels were not significantly affected by isolation treatment. Finally, stronger relationships between signs of sickness and physiological measures were revealed in early isolated piglets. The duration of somnolence in isolated piglets was related to changes of cortisol and TNF-alpha concentrations, and the highest impact on duration of shivering was found for changes in cortisol and corticosteroid binding globulin levels. The present results suggest a sustained adaptive sensitization of coping with infection by social stress experience during early development in piglets.

The impact of a 10-h social confrontation on behavior, plasma adrenaline, noradrenaline and cortisol was studied in 14 domestic pigs (eight castrated males and six females) with prior dominance experience. Prior to the experiments, animal groups, each consisting of nine growing pigs (12 weeks old) from different litters, were composed randomly. After 5 days, the pig with the highest rank from each group was removed, provided with a jugular vein catheter and kept in single housing for 2-3 weeks. After this period, each test animal was returned into its familiar group for a 10-h social confrontation. The reintroduction of the test animals into the familiar groups caused frequent agonistic interactions during the first 30 min. Seven animals succeeded to win most of their encounters during the confrontation test and were classified as High Success (HS) animals, whereas seven other animals lost most of their encounters and were classified as Low Success (LS) animals. The reintroduction of the test animals into the groups provoked also marked changes in behavioral and physiological measures. The frequent fighting behavior during the first 30 min was accompanied by a rapid increase of plasma catecholamines and a delayed increase of cortisol. Immediately after introduction, LS pigs tended to show higher plasma adrenaline and noradrenaline concentrations than HS pigs. There was also a tendency for a sustained increase of noradrenaline/adrenaline ratios in HS pigs, whereas the ratios of LS pigs remained nearly unchanged. No significant differences between both groups were found in cortisol levels and in the frequency of agonistic interactions. However, LS animals showed less locomotion, more lying and spent less time exploring the pen or other animals. These results show that during a social confrontation the experience of defeats for formerly high-ranking pigs is accompanied by increased submissive or passive behavior and a higher sympathoneural and adrenomedullary reaction, which may indicate more emotional distress and fear compared to successful animals.

Behavioural patterns and plasma adrenaline, noradrenaline and cortisol responses were studied in domestic pigs with different dominance status during 10-h social confrontation tests with a familiar and an unfamiliar group. Eight trials were carried out, where in each trial two groups of nine growing pigs (12 weeks old) were randomly formed. The pigs with the highest (HR) and lowest (LR) rank from each group were selected as test animals, provided with surgically implanted catheters and kept in single housing for 2 to 3 weeks. After this period, each test animal was introduced once into the familiar and once into the unfamiliar group for 10 h. Introduction of the test animals into the groups caused frequent agonistic interactions during the first 30 min and significantly more agonistic interactions during the confrontation with the unfamiliar group. The agonistic behaviour was accompanied by a rapid increase of plasma catecholamines and cortisol. HR pigs showed significantly higher plasma catecholamine concentrations and more agonistic interactions during the first 30 min compared with the LR pigs. During confrontation with the unfamiliar group, HR pigs experienced more defeats and showed a higher increase of plasma cortisol levels than during the confrontation with the familiar group. No influences of rank or familiarity were found on the other behavioural patterns examined. The results show that agonistic behaviour and activation of the sympatho-adrenomedullary and the hypothalamic-pituitary-adrenal system in pigs during a social confrontation test are determined by the former dominance rank of the animals and the familiarity of the group.