Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior

Summary 

Proinflammatory cytokines induce both sickness behavior and depression, but their respective neurobiological correlates are still poorly understood. The aim of the present study was therefore to identify in mice the neural substrates of sickness and depressive-like behavior induced by lipopolysaccharide (LPS, 830μg/kg, intraperitoneal). LPS-induced depressive-like behavior was dissociated from LPS-induced sickness by testing mice either at 6h (at which time sickness was expected to be maximal) or at 24h post-LPS (at which time sickness was expected to be minimal and not to bias the measurement of depressive-like behavior). Concurrently, the expression of acute and chronic cellular reactivity markers (c-Fos and FosB/ΔFosB, respectively) was mapped by immunohistochemistry at these two time points. In comparison to saline, LPS decreased motor activity in a new cage at 6h but not at 24h. In contrast, the duration of immobility in the tail suspension test was increased at both 6 and 24h. This dissociation between decreased motor activity and depressive-like behavior was confirmed at 24h post-LPS in the forced swim test. LPS also decreased sucrose consumption at 24 and 48h, despite normal food and water consumption by that time. At 24h post-LPS, LPS-induced depressive-like behavior was associated with a delayed cellular activity (as assessed by FosB/ΔFosB immunostaining) in specific brain structures, particularly within the extended amygdala, hippocampus and hypothalamus, whereas c-Fos labeling was markedly decreased by that time in all the brain areas at 6h post-LPS. These results provide the first evidence in favor of a functional dissociation between the brain structures that underlie cytokine-induced sickness behavior and cytokine-induced depressive-like behavior, and provide important cues about the neuroanatomical brain circuits through which cytokines could have an impact on affect.

Keywords: Sickness behavior, Depression, Tail suspension test, Forced swim test, Functional neuroanatomy, C-Fos, FosB/ΔFosB, Mapping, Lipopolysaccharide, Cytokines, Extended amygdala, Hippocampus, Mouse

Abbreviations: FST, forced swim test, IDO, indoleamine 2, 3 dioxygenase, IEGs, immediate-early genes, LPS, lipopolysaccharide, PBS, phosphate buffer saline, PFA, paraformaldehyde