Fangfang Qi

Influenza vaccination during early pregnancy contributes to neurogenesis and behavioral function in offspring

Prenatal influenza virus infection has been associated with an increased risk of schizophrenia. Thus, inactivated flu vaccines are widely recommended for pregnant women. In a mouse model of pregnancy, immune activation via exposure to viruses or lipopolysaccharide (LPS) impaired brain development and behavioral function in offspring. The objective of our study was to determine if flu vaccination as an immune activation could affect postnatal neurogenesis and behavior. Female C57BL/6J mice were administered A(H1N1) influenza vaccine (AIV) or seasonal influenza vaccine (SIV) early in pregnancy. We found that the offspring of vaccinated mice, especially AIV group, presented superior performance in terms of exploratory behavior and spatial ability compared with controls at postnatal day 28 (P28), but at P56, there was no significance differences among these pups. Quantification of BrdU(+)/DCX(+) and BrdU(+)/NeuN(+) cells in the dentate gyrus (DG) indicated an increase in the hippocampal neurogenesis of the pups born to both vaccinated mothers. The cytokine levels in both the serum and hippocampus changed to varying degrees. Furthermore, administration of the A(H1N1) vaccine blocked LPS-induced cognitive impairment in the progeny. Altogether, the results suggest that maternal influenza vaccination promotes neurogenesis and behavioral function, as well as protection from LPS insults in the developing offspring.

Influenza A(H1N1) vaccination during early pregnancy transiently promotes hippocampal neurogenesis and working memory. Involvement of Th1/Th2 balance.

The 2009 influenza A(H1N1) pandemic led to a particularly high risk of morbidity and mortality among pregnant women. Therefore, inactivated influenza vaccines have been widely recommended for women in any period of gestation. Recent studies have shown that the peripheral adaptive immune system plays an important role in the function of the central nervous system (CNS). The present study was conducted to explore if influenza vaccination, aiming to induce protective immune activation, affects maternal neurogenesis and cognitive ability. The results showed that A(H1N1) pregnant mice (AIV+Pre) had superior spatial working memory performance compared with pregnant controls (Pre). At the cellular level, a transient increase in both cell proliferation and neuronal differentiation in the dentate gyrus (DG) was found in the AIV+Pre group compared with the Pre group when BrdU was injected on gestational day 14 (G14). However, there were no obvious differences between A(H1N1) virgin mice (AIV+Vir) and virgin controls (Vir) in both hippocampal neurogenesis and working memory. Our findings further indicated that prolactin (PRL) concentrations were not overtly different between the AIV+Pre group and the Pre group at any time. Interestingly, IL-4 and IFN-γ levels were obviously increased both in the serum and hippocampus of the AIV+Pre group (with a T helper-1 like response; Th1) compared with the Pre group (with a T helper-2 like response; Th2) at G14, whereas the expression of IL-6 and TNF-α, the proinflammatory factors, was significantly reduced. Altogether, the results suggest that A(H1N1) vaccination during early pregnancy may contribute to adult hippocampal neurogenesis and spatial working memory and that the improvements were, at least in part, associated with Th1/Th2 balance.

Neonatal BCG vaccination of mice improves neurogenesis and behavior in early life.

Bacillus Calmette-Guérin (BCG) is administered to neonates worldwide, but it is still unknown whether this neonatal vaccination affects brain development during early postnatal life, despite the close association of the immune system with the brain. Newborn C57BL/6 mice were injected subcutaneously with BCG or phosphate-buffered saline (PBS) and their mood status and spatial cognition were observed at four and eight weeks (w) old. The mice were also subjected to tests at 2 and 6 w to examine BCGs effects on neurogenesis, the hippocampal microglia phenotype and number, and the expression of hippocampal neuroimmune molecules and peripheral cytokines. The BCG-injected mice showed better behavioral performances at 4 w. We observed elevated neurogenesis, M2 microglial activation and a neurotrophic profile of neuroimmune molecules [more interferon (IFN)-γ, interleukin (IL)-4, transforming growth factor (TGF)-β, brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF)-1 and less tumor necrosis factor (TNF)-α and IL-1β] in the hippocampus of the 2-w-old BCG-mice. In the periphery, BCG induced a T helper (Th)-1 serum response. At the individual level, there were positive correlations between the serum IFN-γ/IL-4 ratio and the levels of neurotrophins and neurogenesis in the hippocampus. These findings suggest that neonatal BCG vaccination improved neurogenesis and mouse behavior in early life by affecting the neuroimmune milieu in the brain, which may be associated with a systemic Th1 bias.

Combined effect of BCG vaccination and enriched environment promote neurogenesis and spatial cognition via a shift in meningeal macrophage M2 polarization

BackgroundThe spatial learning abilities of developing mice benefit from extrinsic cues, such as an enriched environment, with concomitant enhancement in cognitive functions. Interestingly, such enhancements can be further increased through intrinsic Bacillus Calmette-Guérin (BCG) vaccination.ResultsHere, we first report that combined neonatal BCG vaccination and exposure to an enriched environment (Enr) induced combined neurobeneficial effects, including hippocampal long-term potentiation, and increased neurogenesis and spatial learning and memory, in mice exposed to the Enr and vaccinated with BCG relative to those in the Enr that did not receive BCG vaccination. Neonatal BCG vaccination markedly induced anti-inflammatory meningeal macrophage polarization both in regular and Enr breeding mice. The meninges are composed of the pia mater, dura mater, and choroid plexus. Alternatively, this anti-inflammatory activity of the meninges occurred simultaneously with increased expression of the neurotrophic factors BDNF/IGF-1 and the M2 microglial phenotype in the hippocampus. Our results reveal a critical role for BCG vaccination in the regulation of neurogenesis and spatial cognition through meningeal macrophage M2 polarization and neurotrophic factor expression; these effects were completely or partially prevented by minocycline or anti-IL-10 antibody treatment, respectively.ConclusionsTogether, we first claim that immunological factor and environmental factor induce a combined effect on neurogenesis and cognition via a common pathway-meningeal macrophage M2 polarization. We also present a novel functional association between peripheral T lymphocytes and meningeal macrophages after evoking adaptive immune responses in the periphery whereby T lymphocytes are recruited to the meninges in response to systemic IFN-γ signaling. This leads to meningeal macrophage M2 polarization, subsequent to microglial M2 activation and neurotrophic factor expression, and eventually promotes a positive behavior.

A(H1N1) vaccination recruits T lymphocytes to the choroid plexus for the promotion of hippocampal neurogenesis and working memory in pregnant mice.

We previously demonstrated that A(H1N1) influenza vaccine (AIV) promoted hippocampal neurogenesis and working memory in pregnant mice. However, the underlying mechanism of flu vaccination in neurogenesis and memory has remained unclear. In this study, we found that T lymphocytes were recruited from the periphery to the choroid plexus (CP) of the lateral and third (3rd) ventricles in pregnant mice vaccinated with AIV (Pre+AIV). Intracerebroventricular delivery of anti-TCR antibodies markedly decreased neurogenesis and the working memory of the Pre+AIV mice. Similarly, intravenous delivery of anti-CD4 antibodies to the periphery also down-regulated neurogenesis. Furthermore, AIV vaccination caused microglia to skew toward an M2-like phenotype (increased Arginase-1 and Ym1 mRNA levels), and elevated levels of brain-derived growth factor (BDNF) and insulin-like growth factor-1 (IGF-1) were found in the hippocampus, whereas these effects were offset by anti-TCR antibody treatment. Additionally, in the CP, the expression level of adhesion molecules and chemokines, which assist leukocytes in permeating into the brain, were also elevated after AIV vaccination of pregnant mice. Collectively, the results suggested that the infiltrative T lymphocytes in the CP contribute to the increase in hippocampal neurogenesis and working memory caused by flu vaccination, involving activation of the brains CP, M2 microglial polarization and neurotrophic factor expression.

Neonatal vaccination with bacillus Calmette-Guérin and hepatitis B vaccines modulates hippocampal synaptic plasticity in rats

Immune activation can exert multiple effects on synaptic transmission. Our study demonstrates the influence of neonatal vaccination on hippocampal synaptic plasticity in rats under normal physiological conditions. The results revealed that neonatal BCG vaccination enhanced synaptic plasticity. In contrast, HBV hampered it. Furthermore, we found that the cytokine balance shifted in favour of the T helper type 1/T helper type 2 immune response in BCG/HBV-vaccinated rats in the periphery. The peripheral IFN-γ:IL-4 ratio was positively correlated with BDNF and IGF-1 in the hippocampus. BCG raised IFN-γ, IL-4, BDNF and IGF-1 and reduced IL-1β, IL-6, and TNF-α in the hippocampus, whereas, HBV triggered the opposite effects.

Immune-Based Modulation of Adult Hippocampal Neurogenesis, Link to Systemic Th1/Th2 Balance

The interaction between adaptive immune system and the Central Nervous System (CNS) has been extensively studied for decades. A series of researches have indicated that systemic T cells, particularly CD4+ T cells are involved in supporting fundamental processes of brain functional integrity, such as in the maintenance of brain plasticity including spatial learning and memory, and neurogenesis. Moreover, recent data from our laboratory indicate alteration of systemic T helper cell type 1 (Th1)/Th2 balance is tightly linked to hippocampal neurogenesis and working memory. In this review, we summarize current knowledge of the systemic Th1/Th2 balance, describe how this skewing appears to operate in hippocampal neurogenesis, and reinforce the theory of interaction mechanism of these two vital systems.

Neonatal vaccination with bacille Calmette-Guérin promotes the dendritic development of hippocampal neurons.

Dendritic structure is sensitive to changes in the environment during brain development. Accumulating evidence has demonstrated that early immune activation can significantly affect neuronal development. Our study concentrated on the morphological study of neural dendrites and spines in the hippocampal CA1 area using Diolistic labeling with Sholl analysis and fractal analysis. The results revealed that Bacille Calmette-Guérin (BCG) vaccination enhanced dendritic complexity, as reflected by the increased number of intersections, number of branch points and fractal dimension, and promoted neurite outgrowth. In addition, BCG increased the density and promoted the maturation of dendritic spines. The alterations in dendritic structure and spine morphology were observed at 2 and 4 w, but the differences were more apparent at 4 w than at 2 w. However, no significant difference was observed at 8 w. Furthermore, we observed that BCG increased the expression of hippocampal brain derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1). Hippocampal BDNF/IGF-1 was positively correlated with apical dendritic length, fractal dimension, and spine density. Taken together, we show in this study that neonatal BCG vaccination promotes dendritic development in developing hippocampal CA1 neurons, most likely by increasing the expression of BDNF and IGF-1 in the hippocampus.

Neonatal hepatitis B vaccination impaired the behavior and neurogenesis of mice transiently in early adulthood

The immune system plays a vital role in brain development. The hepatitis B vaccine (HBV) is administered to more than 70% of neonates worldwide. Whether this neonatal vaccination affects brain development is unknown. Newborn C57BL/6 mice were injected intraperitoneally with HBV or phosphate-buffered saline. HBV induced impaired behavioral performances and hippocampal long-term potentiation at 8 weeks (w) of age without influence at 4 or 12w. At 6w, there was decreased neurogenesis, M1 microglial activation and a neurotoxic profile of neuroimmune molecule expression [increased tumor necrosis factor-α and reduced interferon (IFN)-γ, brain-derived neurotrophic factor and insulin-like growth factor-1] in the hippocampus of the HBV-vaccinated mice. In the serum, HBV induced significantly higher levels of interleukin (IL)-4, indicating a T helper (Th)-2 bias. Moreover, the serum IFN-γ/IL-4 ratio was positively correlated with the levels of neurotrophins and neurogenesis in the hippocampus at the individual level. These findings suggest that neonatal HBV vaccination of mice results in neurobehavioral impairments in early adulthood by inducing a proinflammatory and low neurotrophic milieu in the hippocampus, which follows the HBV-induced systemic Th2 bias.

Neonatal Bacillus Calmette-Guérin vaccination alleviates lipopolysaccharide-induced neurobehavioral impairments and neuroinflammation in adult mice

The Bacillus Calmette-Guérin (BCG) vaccine is routinely administered to human neonates worldwide. BCG has recently been identified as a neuroprotective immune mediator in several neuropathological conditions, exerting neuroprotection in a mouse model of Parkinsons disease and slowing the progression of clinically isolated syndrome in patients with multiple sclerosis. The immune system is significantly involved in brain development, and several types of neonatal immune activations exert influences on the brain and behavior following a secondary immune challenge in adulthood. However, whether the neonatal BCG vaccination affects the brain in adulthood remains to be elucidated. In the present study, newborn C57BL/6 mice were injected subcutaneously with BCG (105 colony forming units) or phosphate-buffered saline (PBS). A total of 12 weeks later, the mice were injected intraperitoneally with 330 µg/kg lipopolysaccharide (LPS) or PBS. The present study reported that the neonatal BCG vaccination alleviated sickness, anxiety and depression-like behavior, lessened the impairments in hippocampal cell proliferation and downregulated the proinflammatory responses in the serum and brain that were induced by the adult LPS challenge. However, BCG vaccination alone had no evident influence on the brain and behavior in adulthood. In conclusion, the neonatal BCG vaccination alleviated the neurobehavioral impairments and neuroinflammation induced by LPS exposure in adult mice, suggesting a potential neuroprotective role of the neonatal BCG vaccination in adulthood.