Neuropeptide S alters anxiety, but not depression-like behaviour in Flinders Sensitive Line rats: a genetic animal model of depression.

Neuropeptide S (NPS) and its receptor (NPSR) have been implicated in the mediation of anxiolytic-like behaviour in rodents. However, little knowledge is available regarding the NPS system in depression-related behaviours, and whether NPS also exerts anxiolytic effects in an animal model of psychopathology. Therefore, the aim of this work was to characterize the effects of NPS on depression- and anxiety-related parameters, using male and female rats in a well-validated animal model of depression: the Flinders Sensitive Line (FSL), their controls, the Flinders Resistant Line (FRL), and Sprague-Dawley (SD) rats. We found that FSL showed greater immobility in the forced swim test (FST) than FRL, confirming their phenotype. However, NPS did not affect depression-related behaviour in any rat line. No significant differences in baseline anxiety levels between the FSL and FRL strains were observed, but FSL and FRL rats displayed less anxiety-like behaviour compared to SD rats. NPS decreased anxiety-like behaviour on the elevated plus-maze in all strains. The expression of the NPSR in the amygdala, periventricular hypothalamic nucleus, and hippocampus was equal in all male strains, although a trend towards reduced expression within the amygdala was observed in FSL rats compared to SD rats. In conclusion, NPS had a marked anxiolytic effect in FSL, FRL and SD rats, but did not modify the depression-related behaviour in any strain, in spite of the significant differences in innate level between the strains. These findings suggest that NPS specifically modifies anxiety behaviour but cannot overcome/reverse a genetically mediated depression phenotype.

Behavioral and systemic consequences of long-term inflammatory challenge.

Inflammatory reactions are involved in a diversity of diseases, including major depressive disorder. Cytokines act as intercellular signaling molecules and mediators of inflammation between the periphery and the brain. Within the brain, evidence from animal studies of acute inflammation has shown that elevated cytokine levels are linked to behavioral responses of sickness and depression-like behavior. Although chronic inflammation is more translational to human depression than acute studies, little is known on central cytokine expression and associated behavioral responses following chronic immune challenges. The present study assessed behavioral changes and a selection of cytokines in the brain and in the blood in rats randomized to receive a single or 8week administration with either lipopolysaccharide (LPS, 600µg/kg, i.p.) or saline. Acute and long-term LPS treatments caused similar sickness and depression-like behavior. Chronic LPS administration did not have an effect on blood cytokine levels, indicating endotoxin tolerance, whereas increased fasting blood glucose was observed, indicating insulin resistance, a metabolic consequence of chronic inflammation. While a single LPS injection produced a generalized cytokine response in the brain, long-term LPS administration produced a specific central cytokine response with increased interleukin (IL)-1ß and interferon (IFN)-γ. These cytokines can explain the behavioral changes observed, and could indicate microglia activation, although future studies are needed to uncover this assumption. Taken together, although the behavioral outcome was similar between acute and chronic LPS administration, the central cytokine response was distinct. As the long-term LPS paradigm also posed a metabolic demand, this setting may reflect a more translational insight into inflammatory reactions in human depression, and could prove useful for assessing cytokine down-stream effects and experimental antidepressant drug products.

Chronic exposure to low doses of lipopolysaccharide and high-fat feeding increases body mass without affecting glucose tolerance in female rats.

Obesity-related inflammation may have a causal role in the development of diabetes and insulin resistance, and studies using animal models of chronic experimental endotoxemia have shown the link. However, many studies use only males, and much less is known about the role of obesity-related inflammation in females. Therefore, we addressed how experimentally induced chronic inflammation affects body mass, energy intake, and glucose metabolism in female rats. Adult female Sprague Dawley rats were instrumented with slow release pellets that delivered a constant daily dose of 53 or 207 µg of lipopolysaccharide (LPS) per rat for 60 days. Control rats were instrumented with vehicle pellets. Due to inflammatory nature of high-fat diet (HFD) half of the rats received HFD (60% of calories from lard), while the other half remained on control diet to detect possible interactions between two modes of induced inflammation. Our results showed that chronic LPS administration increased female rat body mass and calorie intake in a dose-dependent manner, and that HFD further exacerbated these effects. Despite these effects, no effects of LPS and HFD were evident on female rat glucose metabolism. Only LPS elevated expression of inflammatory markers in the hypothalamus. To conclude, female rats respond to experimentally induced chronic inflammation by increasing body mass, but do not develop glucose intolerance in the given period of time.

Isolation-induced behavioural changes in a genetic animal model of depression.

Depression is a heterogeneous disorder displaying a range of symptoms including feelings of despair and social withdrawal. Social isolation may complicate the progression of depression and have effects on both behaviour and physiology. The aim of this study was to investigate the effects of social isolation on behavioural and metabolic parameters in a genetic rat model of depression, the Flinders Sensitive and Resistant Line (FSL/FRL) rats. Rats were housed either individually (social isolation) or pair-housed for 5weeks, and subjected to behavioural testing and metabolic evaluation. We found that social isolation erased the characteristic difference in depressive-like behaviour, measured as immobility in the forced swim test, between the FSL and FRL rats. Social isolation affected both strains equally in impairing object recognition memory, while leading to an increased explorative behaviour in the elevated plus maze test. Surprisingly, single-housed FRL rats showed an increased food intake compared to pair-housed FRL rats, whereas no difference in food intake or body weight was evident in FSL rats. Our results indicate that social isolation for 5weeks causes behavioural alterations, independent of strain. As the changes in appetite were only observed in the FRL rats, this may suggest that this strain responds to the stress of isolation by a change in feeding behaviour.