Behavioral and monoamine perturbations in adult male mice with chronic inflammation induced by repeated peripheral lipopolysaccharide administration

Abstract

Considering the limited information on the ability of chronic peripheral inflammation to induce behavioral alterations, including on their persistence after inflammatory stimuli termination and on associated neurochemical perturbations, this study assessed the effects of chronic (0.25 mg/kg; i.p.; twice weekly) lipopolysaccharide (LPS) treatment on selected behavioral, neurochemical and molecular measures at different time points in adult male C57BL/6 mice. Behaviorally, LPS-treated mice were hypoactive after 6 weeks, whereas significant hyperactivity was observed after 12 weeks of LPS and 11 weeks after 13 week LPS treatment termination. Similar biphasic responses, i.e., early decrease followed by a delayed increase were observed in the open field test center time, suggestive of, respectively, increased and decreased anxiety. In a forced swim test, mice exhibited increased immobility (depressive behavior) at all times they were tested. Chronic LPS also produced persistent increase in splenic serotonin (5-HT) and time-dependent, brain region-specific alterations in striatal and prefrontocortical dopamine and 5-HT homeostasis. Microglia, but not astrocytes, were activated by LPS early and late, but their activation did not persist after LPS treatment termination. Above findings demonstrate that chronic peripheral inflammation initially causes hypoactivity and increased anxiety, followed by persistent hyperactivity and decreased anxiety. Notably, chronic LPS-induced depressive behavior appears early, persists long after LPS termination, and is associated with increased splenic 5-HT. Collectively, our data highlight the need for a greater focus on the peripheral/central monoamine alterations and lasting behavioral deficits induced by chronic peripheral inflammation as there are many pathological conditions where inflammation of a chronic nature is a hallmark feature.

Expression of cerebral serotonin related to anxiety-like behaviors in C57BL/6 offspring induced by repeated subcutaneous prenatal exposure to low-dose lipopolysaccharide

“…The cerebral DA levels showed a decreasing trend although the mRNA levels of th (DA synthesizing enzyme) and dard1a (DA receptor) genes were not altered from adolescence to adulthood. Aberrant cerebral striatal and prefrontocortical DA and 5-HT expression associated with anxiety and hypoactivity for the mice repeatedly exposed to LPS [ 56 ]. Thus, 5-HT or DA deficiency in the brain might be an important causative factor of anxiety- and ASD-like behaviors in humans or animal models [ 6 , 9 , 57 , 58 ].…”

What Animal Models Can Tell Us About Long-Term Psychiatric Symptoms in Sepsis Survivors: a Systematic Review

“…Usually, adult animals more frequently developed protracted anxiety or depressive symptoms when compared to controls. Additionally, some studies injected repeated LPS doses [163][164][165][166][167][168][169][170][171][172][173][174].…”

Nurr1Cd11bcreconditional knockout mice display inflammatory injury to nigrostriatal dopaminergic neurons

“…A number of studies have demonstrated that systemic LPS stimulation can cause a loss of DAergic neurons and other PD-related pathological abnormalities (Biesmans et al, 2013;Krishna, Dodd, & Filipov, 2016). A single intraperitoneal injection of LPS at 5 mg/kg leads to significant DAergic neuron damage in C57BL/6 mice 7 months after LPS treatment (Qin et al, 2007).…”