Therefore, behavior was determined at 48 and 72 h
Therefore, behavior was determined at 48 and 72 h. to determine significant main effects and interactions. == Results == LPS injection caused a prolonged duration of social withdrawal in CX3CR1-/-mice compared to control mice. This extended social withdrawal was associated with enhanced mRNA expression of IL-1, indolamine 2,3-dioxygenase (IDO) and kynurenine monooxygenase (KMO) in microglia 4 h after LPS. Moreover, elevated expression of IL-1 and CD14 was still detected in microglia of CX3CR1-/-mice 24 h after LPS. There was also increased turnover of tryptophan, serotonin, and dopamine in the brain 24 h after LPS, but these increases were independent of CX3CR1 expression. When submitted to the tail suspension test 48 and 72 h after LPS, an increased duration of immobility was evident only in CX3CR1-/-mice. This depression-like behavior in CX3CR1-/-mice was associated with a persistent activated microglial phenotype in the hippocampus and prefrontal cortex. == Conclusions == Taken together, these data indicate that a deficiency of CX3CR1 is permissive to protracted microglial activation and prolonged behavioral alterations in response to transient activation of the innate immune system. == Background == Microglia are myeloid derived cells that play a key role in immune surveillance of the central nervous system (CNS) [1,2]. Together with brain macrophages these cells interpret and propagate inflammatory signals in response to activation of the peripheral immune system [3]. Activated microglia produce pro-inflammatory cytokines and secondary messengers which elicit a sickness behavior syndrome [4]. While this sickness response is normally adaptive, amplified or Rabbit Polyclonal to Collagen V alpha3 prolonged microglial activation is associated with a myriad of behavioral and cognitive complications [5]. Therefore, tight regulation of microglial activation is necessary to limit cytokine production and maintain a transient neuroinflammatory response. One mechanism of microglial regulation involves interactions between fractalkine (CX3CL1) and fractalkine receptors (CX3CR1) [6,7]. Complementary expression of CX3CL1 on neurons and CX3CR1 on microglia [6-9] establishes a unique communication system whereby neurons constitutively express and release CX3CL1 to regulate activation of microglia [10]. For example, pretreatment with neutralizing anti-CX3CL1 antibody exaggerates TNF and 8-isoprostane production after intracerebroventricular (i.c.v.) injection of lipopolysaccharide (LPS) [11]. In cultured microglia or mixed glial cultures, soluble CX3CL1 attenuates LPS-induced production of TNF, IL-6, and IL-1 [12,13]. Moreover, CX3CR1-deficiency amplifies microglial IL-1 expression and neurotoxicity in CX3CR1-/-mice compared to CX3CR1+/-mice after repeated i.p. injections of lipopolysaccharide (LPS) [10]. Recent work using rodent models of aging also support the premise that impaired CX3CL1/CX3CR1 interactions cause increased microglial activation. For example, CX3CL1 mRNA and protein are decreased in the brain of aged rats [14, 15] and mice [5]. This age-associated increase in activated (e.g., MHC II+) microglia was attenuated following a single i.c.v. injection of CX3CL1 [15]. In a related experiment, infusion of a neutralizing antibody to CX3CR1 increased the Fanapanel hydrate number of MHC II+microglia in young rats [14]. Along with reductions in brain levels of Fanapanel hydrate CX3CL1, regulation of CX3CR1 expression on the surface of microglia may also be impaired in the aged brain. In comparisons between adult and aged mice, CX3CR1 surface expression was decreased on microglia after peripheral injection of LPS. In aged mice, however, the LPS-induced downregulation of CX3CR1 on microglia was protracted and corresponded with amplified IL-1 levels in microglia and impaired recovery from sickness behavior [5]. Collectively, these data indicate that CX3CL1-CX3CR1 interactions are important in normal regulation of microglia and become dysregulated with age. Clinical and experimental data indicate that there is a cause/effect relationship between inflammation and depression [16,17]. In animal models, proinflammatory cytokine production (e.g., IL-1, IL-6, or TNF) following systemic LPS challenge [18-20], chronic infection with Bacillus Calmette-Guerin (BCG) [21,22], stroke [23], or psychological Fanapanel hydrate stress [24-26] cause depression-like behavior. One potential mechanism by which inflammatory cytokines promote depression-like behavior is through the activation of the tryptophan degrading enzyme indoleamine 2,3-dioxygenase (IDO) [21,27]. Active IDO converts tryptophan (TRP) into kynurenine (KYN). In microglia [28], KYN is processed by kynurenine monooxygenase (KMO), which produces two highly neuroactive mediators, 3-hydroxykynurenine (3HK) and quinolinic acid (QUIN) [29]. IDO activity and downstream processing of KYN have been shown to cause inflammatory-associated depression in rodent models [20,22]. It is hypothesized that IDO activation is a key mechanism underlying mood and depressive complications because it alters serotonergic, dopaminergic, and noradrenergic neurotransmission [4,17,30,31]. Because CX3CL1 and CX3CR1 interactions are impaired in the brain of aged rodents [5], we hypothesize that a loss of CX3CR1 may be permissive to exaggerated microglial activation and the promotion of a maladaptive sickness response after an innate immune challenge. Therefore, the purpose of this study was to determine the extent to which an.