Neonatal lipopolysaccharide treatment alters hippocampal neuroinflammation, microglia morphology and anxiety-like behavior in rats selectively bred for an infantile trait

Claypoole, Lauren D.; Zimmerberg, Betty; Williamson, Lillie D.

doi:10.1016/j.bbi.2016.08.017

Cited by 36 publications

(15 citation statements)

References 48 publications

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“…Data by others have demonstrated that LPS injection induces microglial activation in neonatal brains (Claypoole et al, 2016; Du et al, 2011). Considering that in neonatal brain TLR2 expression is already high under physiological conditions, we asked whether LPS further upregulates TLR2.…”

Section: Resultsmentioning

confidence: 99%

Live imaging of the innate immune response in neonates reveals differential TLR2 dependent activation patterns in sterile inflammation and infection

Lalancette–Hébert

Faustino

Thammisetty

et al. 2017

Brain, Behavior, and Immunity

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Activation of microglial cells in response to brain injury and/or immune stimuli is associated with a marked induction of Toll-like receptors (TLRs). While in adult brain, the contribution of individual TLRs, including TLR2, in pathophysiological cascades has been well established, their role and spatial and temporal induction patterns in immature brain are far less understood. To examine whether infectious stimuli and sterile inflammatory stimuli trigger distinct TLR2-mediated innate immune responses, we used three models in postnatal day 9 (P9) mice, a model of infection induced by systemic endotoxin injection and two models of sterile inflammation, intra-cortical IL-1β injection and transient middle cerebral artery occlusion (tMCAO). We took advantage of a transgenic mouse model bearing the dual reporter system luciferase/GFP under transcriptional control of a murine TLR2 promoter (TLR2-luc-GFP) to visualize the TLR2 response in the living neonatal brain and then determined neuroinflammation, microglial activation and leukocyte infiltration. We show that in physiological postnatal brain development the in vivo TLR2-luc signal undergoes a marked ~30 fold decline and temporal-spatial changes during the second and third postnatal weeks. We then show that while endotoxin robustly induces the in vivo TLR2-luc signal in the living brain and increases levels of several inflammatory cytokines and chemokines, the in vivo TLR2-luc signal is reduced after both IL-1β and tMCAO and the inflammatory response is muted. Immunofluorescence revealed that microglial cells are the predominant source of TLR2 production during postnatal brain development and in all three neonatal models studied. Flow cytometry revealed developmental changes in CD11b+/CD45+ and CD11b+/Ly6C+ cell populations, involvement of cells of the monocyte lineage, but lack of Ly6G+ neutrophils or CD3+ cells in acutely injured neonatal brains. Cumulatively, our results suggest distinct TLR2 induction patterns following PAMP and DAMP - mediated inflammation in immature brain.

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Section: Resultsmentioning

confidence: 99%

Live imaging of the innate immune response in neonates reveals differential TLR2 dependent activation patterns in sterile inflammation and infection

Lalancette–Hébert

Faustino

Thammisetty

et al. 2017

Brain, Behavior, and Immunity

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“…Bacterial infection is one of the most common immune challenges occurring in early life. Exposure to LPS in the first postnatal week produces a rise in microglial cell density that lasts for a few days after the injection [97][98][99]. Pang and colleagues (2016) reported an acute LPS-induced increase in the number of microglial cells, which mostly colocalized with markers of an anti-inflammatory profile (TGF-β, CD206), except for few pro-inflammatory-profiled cells (expressing CD68, major histocompatibility complex-II, iNOS) [99].…”

Section: Postnatal Environmental Agents and Infectionmentioning

confidence: 99%

“…Pang and colleagues (2016) reported an acute LPS-induced increase in the number of microglial cells, which mostly colocalized with markers of an anti-inflammatory profile (TGF-β, CD206), except for few pro-inflammatory-profiled cells (expressing CD68, major histocompatibility complex-II, iNOS) [99]. Claypoole et al (2017) found sex differences in this response, with increase found only in female HIP [97]. Notably, the timing of LPS exposure is determinant for microglial responses, given that injection at P2, but not at P21, results in an immediate increase in microglial activation markers (CD11a, F4/80, CD172a, SLAM family member 7) [100].…”

Section: Postnatal Environmental Agents and Infectionmentioning

confidence: 99%

Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

Catale

Gironda

Iacono

et al. 2020

JCM

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The putative effects of early-life stress (ELS) on later behavior and neurobiology have been widely investigated. Recently, microglia have been implicated in mediating some of the effects of ELS on behavior. In this review, findings from preclinical and clinical literature with a specific focus on microglial alterations induced by the exposure to ELS (i.e., exposure to behavioral stressors or environmental agents and infection) are summarized. These studies were utilized to interpret changes in developmental trajectories based on the time at which the stress occurred, as well as the paradigm used. ELS and microglial alterations were found to be associated with a wide array of deficits including cognitive performance, memory, reward processing, and processing of social stimuli. Four general conclusions emerged: (1) ELS interferes with microglial developmental programs, including their proliferation and death and their phagocytic activity; (2) this can affect neuronal and non-neuronal developmental processes, which are dynamic during development and for which microglial activity is instrumental; (3) the effects are extremely dependent on the time point at which the investigation is carried out; and (4) both pre- and postnatal ELS can prime microglial reactivity, indicating a long-lasting alteration, which has been implicated in behavioral abnormalities later in life.

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“…A variety of interventions, including neonatal exposure to systemic LPS, intracerebral ventricular infusion of Poly I:C and maternal separation cause transient elevation of proinflammatory brain cytokines; even maternal immune activation elevates cytokine messenger RNA (mRNA) in the fetal brain, and some of the changes persist in offspring well into adulthood . Because both microglia and the cytokines they elaborate play important roles in development, it is likely that a CNS milieu with elevated cytokine levels may undergo aberrant development that could lead to ASD in offspring.…”

Section: Epilepsy and Autismmentioning

confidence: 99%

Neurobehavioral comorbidities of epilepsy: Role of inflammation

2017

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Epilepsy is associated with a high incidence of comorbid neurologic and psychiatric disorders. This review focuses on the association of epilepsy with autism spectrum disorder (ASD) and depression. There is high concordance of these behavioral pathologies with epilepsy. We review data that unambiguously reveal that epilepsy, ASD, and depression are associated with elevated brain inflammatory markers and that these may interact with serotoninergic pathways. Interference with inflammatory pathways or actions can reduce the severity of seizures, depression, and ASD-like behavior. Inflammation in the brain can be induced by seizure activity as well as by behavioral, environmental, and physiologic stressors. Furthermore, induction of inflammation at an early time point during gestation and in early neonatal life can precipitate both an ASD-like phenotype as well as a more excitable brain. It appears likely that priming of the brain due to early inflammation could provide a means by which subsequent inflammatory processes associated with epilepsy, ASD, and depression may lead to comorbidity.

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Neonatal lipopolysaccharide treatment alters hippocampal neuroinflammation, microglia morphology and anxiety-like behavior in rats selectively bred for an infantile trait

Cited by 36 publications

References 48 publications

Live imaging of the innate immune response in neonates reveals differential TLR2 dependent activation patterns in sterile inflammation and infection

Live imaging of the innate immune response in neonates reveals differential TLR2 dependent activation patterns in sterile inflammation and infection

Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

Neurobehavioral comorbidities of epilepsy: Role of inflammation

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