Altered inflammatory responsiveness in serotonin transporter mutant rats

Macchi, F.; Homberg, Judith R.; Calabrese, Francesca; Zecchillo, C.; Racagni, Giorgio; Riva, Marco A.; Molteni, Raffaella

doi:10.1186/1742-2094-10-116

Cited by 21 publications

(13 citation statements)

References 54 publications

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“…Behavioural signs of helplessness resulting from circulating cytokines have been shown to be prevented by a blockade of SERT [ 68 ]. Furthermore, SERT mutant rats show abnormal behaviour (including decreased sucrose preference, decreased spontaneous activity and increased anxiety [ 69 ]) and CNS cytokine expression profiles in response to LPS [ 70 ]. In humans, however, the reverse appears to be true.…”

Section: Discussionmentioning

confidence: 99%

Low-dose lipopolysaccharide (LPS) inhibits aggressive and augments depressive behaviours in a chronic mild stress model in mice

Couch

Трофимов

Markova

et al. 2016

J Neuroinflammation

102

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BackgroundAggression, hyperactivity, impulsivity, helplessness and anhedonia are all signs of depressive-like disorders in humans and are often reported to be present in animal models of depression induced by stress or by inflammatory challenges. However, chronic mild stress (CMS) and clinically silent inflammation, during the recovery period after an infection, for example, are often coincident, but comparison of the behavioural and molecular changes that underpin CMS vs a mild inflammatory challenge and impact of the combined challenge is largely unexplored. Here, we examined whether stress-induced behavioural and molecular responses are analogous to lipopolysaccharide (LPS)-induced behavioural and molecular effects and whether their combination is adaptive or maladaptive.MethodsChanges in measures of hedonic sensitivity, helplessness, aggression, impulsivity and CNS and systemic cytokine and 5-HT-system-related gene expression were investigated in C57BL/6J male mice exposed to chronic stress alone, low-dose LPS alone or a combination of LPS and stress.ResultsWhen combined with a low dose of LPS, chronic stress resulted in an enhanced depressive-like phenotype but significantly reduced manifestations of aggression and hyperactivity. At the molecular level, LPS was a strong inducer of TNFα, IL-1β and region-specific 5-HT2A mRNA expression in the brain. There was also increased serum corticosterone as well as increased TNFα expression in the liver. Stress did not induce comparable levels of cytokine expression to an LPS challenge, but the combination of stress with LPS reduced the stress-induced changes in 5-HT genes and the LPS-induced elevated IL-1β levels.ConclusionsIt is evident that when administered independently, both stress and LPS challenges induced distinct molecular and behavioural changes. However, at a time when LPS alone does not induce any overt behavioural changes per se, the combination with stress exacerbates depressive and inhibits aggressive behaviours.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0572-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Low-dose lipopolysaccharide (LPS) inhibits aggressive and augments depressive behaviours in a chronic mild stress model in mice

Couch

Трофимов

Markova

et al. 2016

J Neuroinflammation

102

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“…The samples were run in 384-well formats in triplicates as multiplexed reactions with a normalizing internal control (36B4) using protocols established and validated before [ 12 , 39 ]. Probe and primer sequences for cytokine genes were purchased from Applied Biosystems (IL-1β: Mm00434228_m1; IL-4: Mm00445259_m1; IL-6: Mm00446190_m1; TNF-α: Mm00443258_m1) and were validated before [ 46 ]. IL-1β, IL-4, IL-6, and TNF-α were selected to match the quantification of cytokine proteins (see above).…”

Section: Methodsmentioning

confidence: 99%

Late prenatal immune activation causes hippocampal deficits in the absence of persistent inflammation across aging

Giovanoli

Notter

Richetto

et al. 2015

J Neuroinflammation

103

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BackgroundPrenatal exposure to infection and/or inflammation is increasingly recognized to play an important role in neurodevelopmental brain disorders. It has recently been postulated that prenatal immune activation, especially when occurring during late gestational stages, may also induce pathological brain aging via sustained effects on systemic and central inflammation. Here, we tested this hypothesis using an established mouse model of exposure to viral-like immune activation in late pregnancy.MethodsPregnant C57BL6/J mice on gestation day 17 were treated with the viral mimetic polyriboinosinic-polyribocytidilic acid (poly(I:C)) or control vehicle solution. The resulting offspring were first tested using cognitive and behavioral paradigms known to be sensitive to hippocampal damage, after which they were assigned to quantitative analyses of inflammatory cytokines, microglia density and morphology, astrocyte density, presynaptic markers, and neurotrophin expression in the hippocampus throughout aging (1, 5, and 22 months of age).ResultsMaternal poly(I:C) treatment led to a robust increase in inflammatory cytokine levels in late gestation but did not cause persistent systemic or hippocampal inflammation in the offspring. The late prenatal manipulation also failed to cause long-term changes in microglia density, morphology, or activation, and did not induce signs of astrogliosis in pubescent, adult, or aged offspring. Despite the lack of persistent inflammatory or glial anomalies, offspring of poly(I:C)-exposed mothers showed marked and partly age-dependent deficits in hippocampus-regulated cognitive functions as well as impaired hippocampal synaptophysin and brain-derived neurotrophic factor (BDNF) expression.ConclusionsLate prenatal exposure to viral-like immune activation in mice causes hippocampus-related cognitive and synaptic deficits in the absence of chronic inflammation across aging. These findings do not support the hypothesis that this form of prenatal immune activation may induce pathological brain aging via sustained effects on systemic and central inflammation. We further conclude that poly(I:C)-based prenatal immune activation models are reliable in their effectiveness to induce (hippocampal) neuropathology across aging, but they appear unsuited for studying the role of chronic systemic or central inflammation in brain aging.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0437-y) contains supplementary material, which is available to authorized users.

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“…; Segrate, Italy) according to the manufacturer's instructions and quantified by spectrophotometric analysis. The samples were then processed for real-time polymerase chain reaction (PCR) as previously reported [33] to assess mRNA levels of: interleukin-1␤ (IL-1␤); interleukin-6 (IL-6); transforming growth factor-␤ (TGF-␤); integrin alpha M (cluster of differentiation molecule CD11b); chemokine (C-X3-C Motif) ligand 1 (CX3CL1; fractalkine); chemokine receptor 1 (CX3CR1).…”

Section: Rna Preparation and Gene Expression Analysesmentioning

confidence: 99%

Stress-induced anhedonia is associated with the activation of the inflammatory system in the rat brain: Restorative effect of pharmacological intervention

Rossetti

Papp

Gruca

et al. 2016

Pharmacological Research

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Altered inflammatory responsiveness in serotonin transporter mutant rats

Cited by 21 publications

References 54 publications

Low-dose lipopolysaccharide (LPS) inhibits aggressive and augments depressive behaviours in a chronic mild stress model in mice

Low-dose lipopolysaccharide (LPS) inhibits aggressive and augments depressive behaviours in a chronic mild stress model in mice

Late prenatal immune activation causes hippocampal deficits in the absence of persistent inflammation across aging

Stress-induced anhedonia is associated with the activation of the inflammatory system in the rat brain: Restorative effect of pharmacological intervention

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