Validation of a Psychosocial Chronic Stress Model in the Pig Using a Multidisciplinary Approach at the Gut-Brain and Behavior Levels

Abstract

Psychological chronic stress is an important risk factor for major depressive disorder, of which consequences have been widely studied in rodent models. This work aimed at describing a pig model of chronic stress based on social isolation, environmental impoverishment and unpredictability. Three groups of animals of both sexes were constituted. Two were exposed to the psychosocial stressors while receiving (SF, n = 12) or not (SC, n = 22) the antidepressant fluoxetine, and a third group (NSC, n = 22) remained unstressed. Animals were observed in home pens and during dedicated tests to assess resignation and anxiety-like behaviors. Brain structure and function were evaluated via proton MRS and fMRI. Hippocampal molecular biology and immunodetection of cellular proliferation (Ki67 + ) and neuron maturation (DCX + ) in the dentate gyrus were also performed. Salivary cortisol, fecal short-chain fatty acids (SCFAs), and various plasmatic and intestinal biomarkers were analyzed. Compared to NSC, SC animals showed more resignation ( p = 0.019) and had a higher level of salivary cortisol ( p = 0.020). SC brain responses to stimulation by a novel odor were lower, similarly to their hippocampal neuronal density ( p = 0.015), cellular proliferation ( p = 0.030), and hippocampal levels of BDNF and 5-HT 1A R ( p = 0.056 and p = 0.007, respectively). However, the number of DCX + cells was higher in the ventral dentate gyrus in this group ( p = 0.025). In addition, HOMA-IR was also higher ( p < 0.001) and microbiota fermentation activity was lower (SCFAs, SC/NSC: p < 0.01) in SC animals. Fluoxetine partially or totally reversed several of these effects. Exposure to psychosocial stressors in the pig model induced effects consistent with the human and rodent literature, including resignation behavior and alterations of the HPA axis and hippocampus. This model opens the way to innovative translational research exploring the mechanisms of chronic stress and testing intervention strategies with good face validity related to human.

fMRI‐Based Brain Responses to Olfactory Stimulation with Two Putatively Orexigenic Functional Food Ingredients at Two Different Concentrations in the Pig Model

“…We showed here that the two ingredients used modulated differently both these areas via olfaction only. It would be very interesting to assess their effects in a pig model of chronic psychosocial stress and/or anxio‐depressive symptoms for example, as modulations of the aforementioned brain areas were recently described in this model (Menneson et al., ).…”

What are you actually measuring? A review of techniques that integrate the stress response on distinct time‐scales

“…Salivary Cort can also detect longer term disruptions, including repeated stressors and social disruption (e.g. Menneson et al., 2019). The response latency (about 5 min) and stressor duration (minutes‐to‐lifetime) measurable by salivary Cort is represented in Figure 1.…”

Review: Impact of food, gut–brain signals and metabolic status on brain activity in the pig model: 10 years of nutrition research using in vivo brain imaging

“…We also showed that high-concentration olfactory stimuli induced a higher brain activity (Table 1; Coquery et al, in press). More interestingly, pigs with a psychosocial stress had lower brain responses in the right hippocampus compared to unstressed control pigs, as well as lower magnetic resonance spectroscopy-estimated neuronal density in the hippocampus, which suggested an impact of the internal state on cognitive and limbic processes at the brain level (Table 1; Menneson et al, 2019).…”