nNOS in Erbb4-positive neurons regulates GABAergic transmission in mouse hippocampus.

Neuronal nitric oxide synthase (nNOS, gene name Nos1) orchestrates the synthesis of nitric oxide (NO) within neurons, pivotal for diverse neural processes encompassing synaptic transmission, plasticity, neuronal excitability, learning, memory, and neurogenesis. Despite its significance, the precise regulation of nNOS activity across distinct neuronal types remains incompletely understood. Erb-b2 receptor tyrosine kinase 4 (ErbB4), selectively expressed in GABAergic interneurons and activated by its ligand neuregulin 1 (NRG1), modulates GABA release in the brain. Our investigation reveals the presence of nNOS in a subset of GABAergic interneurons expressing ErbB4. Notably, NRG1 activates nNOS via ErbB4 and its downstream phosphatidylinositol 3-kinase (PI3K), critical for NRG1-induced GABA release. Genetic removal of nNos from Erbb4-positive neurons impairs GABAergic transmission, partially rescued by the NO donor sodium nitroprusside (SNP). Intriguingly, the genetic deletion of nNos from Erbb4-positive neurons induces schizophrenia-relevant behavioral deficits, including hyperactivity, impaired sensorimotor gating, and deficient working memory and social interaction. These deficits are ameliorated by the atypical antipsychotic clozapine. This study underscores the role and regulation of nNOS within a specific subset of GABAergic interneurons, offering insights into the pathophysiological mechanisms of schizophrenia, given the association of Nrg1, Erbb4, Pi3k, and Nos1 genes with this mental disorder.

Electroacupuncture-modulated extracellular ATP levels in prefrontal cortex ameliorated depressive-like behavior of maternal separation rats.

Maternal separation (MS) is a type of early-life stress that has been linked to neuropsychiatric disorders, especially depression. Increasing evidence indicates that the adenosine triphosphate (ATP) level in the prefrontal cortex (PFC) is involved in the pathophysiology of depression. To investigate the potential relationship between ATP in PFC and antidepressant effects of electroacupuncture (EA) treatment, we assessed genes involved in ATP biosynthesis as well as the extracellular ATP levels in a rat model exposed to neonatal MS. Our results demonstrated that reduced expression of ABCG2 (an ATP-binding cassette protein) and ATP levels in the PFC of depressive-like rats exposed to MS can be attenuated by EA stimulus at the Baihui (GV20) and Yintang (GV29) acupoints. Moreover, the antidepressant effect of EA treatment was blocked by administration of suramin, a broad purinergic P2 receptor antagonist. Together, these results suggested that electroacupuncture may be able to modulate extracellular ATP levels in the PFC of depressive-like MS rats, potentially contributing to its antidepressant effects.

Neural function of Bmal1: an overview.

Bmal1 (Brain and muscle arnt-like, or Arntl) is a bHLH/PAS domain transcription factor central to the transcription/translation feedback loop of the biologic clock. Although Bmal1 is well-established as a major regulator of circadian rhythm, a growing number of studies in recent years have shown that dysfunction of Bmal1 underlies a variety of psychiatric, neurodegenerative-like, and endocrine metabolism-related disorders, as well as potential oncogenic roles. In this review, we systematically summarized Bmal1 expression in different brain regions, its neurological functions related or not to circadian rhythm and biological clock, and pathological phenotypes arising from Bmal1 knockout. This review also discusses oscillation and rhythmicity, especially in the suprachiasmatic nucleus, and provides perspective on future progress in Bmal1 research.

[Current situation and outlook of acupuncture-moxibustion translational medicine under the background of multi-disciplinary intersection innovation].

The common development of multi-disciplinary intersection is a hot spot in the research of acupuncture- moxibustion translational medicine. This article analyzes the current situation and reasons for slow development of acupuncture-moxibustion translational medicine, takes acupuncture-moxibustion for depressive disorder as an example, takes acupuncture and moxibustion literature, clinical evidence-based, biological mechanism and medical equipment research and development as the main line, expounds potential strategies to promote the development of acupuncture-moxibustion translational medicine under the background of multi-disciplinary intersection innovation, and discusses the future research direction of acupuncture-moxibustion translational medicine.

Restoring the Autonomic Balance in an Atrial Fibrillation Rat Model by Electroacupuncture at the Neiguan Point.

OBJECTIVES: Autonomic nervous activity imbalance plays an important role in atrial fibrillation (AF). AF can be treated by acupuncture at the Neiguan point (PC6), but the mechanism remains elusive. Here, we investigated autonomic nervous system activity in electroacupuncture (EA) at PC6 in a rat AF model. MATERIAL AND METHODS: In this study, we established a rat AF model via tail vein injection with ACh-CaCl2 for ten consecutive days with or without EA at PC6. AF inducibility and heart rate variability (HRV) were assessed by electrocardiogram. Next, we completed in vivo recording of the activity of cervical sympathetic and vagal nerves, respectively. Finally, the activities of brain regions related to autonomic nerve regulation were assessed by c-Fos immunofluorescence and multichannel recording. RESULTS: EA at PC6 decreased AF inducibility and prevented changes in HRV caused by ACh-CaCl2 injection. Meanwhile, EA at PC6 reversed the increased sympathetic and decreased vagal nerve activity in AF rats. Furthermore, EA treatment downregulated increased c-Fos expression in brain regions, including paraventricular nucleus, rostral ventrolateral medulla, and dorsal motor nucleus of the vagus in AF, while c-Fos expression in nucleus ambiguus was upregulated with EA. CONCLUSION: The protective effect of EA at PC6 on AF is associated with balance between sympathetic and vagal nerve activities.

Loss of SST and PV positive interneurons in the ventral hippocampus results in anxiety-like behavior in 5xFAD mice.

Neuropsychiatric symptoms, such as anxiety and depression often appear early in patients with Alzheimer's disease (AD), and a comorbid, anxiety-like phenotype is also found in rodents with AD. However, the underlying mechanisms behind these conditions and potential therapeutic targets to treat them remain unclear. In this study, we used 5 familial AD mutations (5xFAD) mice that developed early amyloid ß-amyloid deposition and related synaptic loss and memory deficits to identify a potential mechanism behind abnormally high anxiety levels observed in these subjects. We observed anxiety-like behavior in mice that had an excitatory/inhibitory (E/I) imbalance in the ventral hippocampus (vHPC) of 5xFAD mice. Both the number of parvalbumin-positive (PV+) and somatostatin-positive (SST+) cells decreased in the ventral hippocampus of the subject 5xFAD mice, however, no reductions were observed in calretinin-positive cells. We found that selectively inhibiting vHPC pyramidal cells via hM4Di expression normalized anxiety-like behaviors and E/I balance in 5xFAD mice. Finally, we found that the ventral hippocampus SST+ or PV+ neurons were activated through selectively expressed hM3Dq, which ameliorated anxiety-like behaviors and the synaptic E/I imbalance of vCA1 in 5xFAD mice. These results determined that anxiety-like behaviors accompanied by hippocampal synaptic E/I imbalance in 5xFAD mice are due to the loss of SST+ and PV+ interneurons in the vHPC. This provides a better understanding of high anxiety levels observed in patients with early-stage AD.

Investigating the efficiency and tolerability of traditional Chinese formulas combined with antiarrhythmic agents for paroxysmal atrial fibrillation: A systematic review and Bayesian network meta-analysis.

BACKGROUND: The combination of antiarrhythmic drugs with traditional Chinese formulas are used treatments for the management of paroxysmal atrial fibrillation (PAF). However, the most effective treatment for PAF has yet to be been determined. A Bayesian network meta-analysis study was thus performed for comparing the relative efficacy and tolerability of different treatment alternatives. METHODS: A comprehensive literature review of randomized controlled trials (RCTs) is performed from eight database. Maintenance rate of sinus rhythm (MRSR), p-wave dispersion (Pd), left atrium diameter (LAD), left ventricular ejection fraction (LVEF), and adverse events (AEs) were used as outcomes. We also estimated treatment rank based on the surface under the cumulative ranking curve (SUCRA). This study was performed using a Bayesian network meta-analysis with a random-effects model. FINDINGS: After screening, 59 RCTs involving 5,543 patients and 16 treatments were included. The results showed that Shensong-Yangxin capsule (SSYX) plus amiodarone (81%) was the most effective treatment for MRSR according to the value of SUCRA, followed by Wenxin-Keli granules (WXKL) plus amiodarone (73%). Meanwhile, SSYX plus amiodarone (7%) was most likely to reduce Pd, followed by SSYX plus metoprolol (23%), WXKL plus amiodarone (26%), WXKL plus bisoprolol (27%). Furthermore, SSYX plus amiodarone (4%) was more effective in improving LAD. WXKL plus amiodarone was preferred because it had the lowest toxicity. For benefit-risk ratio, amiodarone combined with WXKL or SSYX appeared to be the best option. CONCLUSION: Antiarrhythmic agents combined with traditional Chinese formulas had higher efficacy and lower toxicity than other treatment alternatives. This study might provide reference to help find the better treatment options for PAF.

Microbial Profiles of Patients With Antipsychotic-Related Constipation Treated With Electroacupuncture.

Antipsychotic-related constipation (APRC) is one of the most common side effects of taking antipsychotic medication. APRC can seriously impact patient quality of life and is potentially fatal, though the efficacy of current APRC treatments is low for most patients. In this study, we conducted a controlled, pilot randomized, sham-electroacupuncture (SEA) study to assess the efficacy of electroacupuncture (EA) in patients with APRC. We used 16S rRNA gene sequencing to assess the microbial profiles of these patients and analyze how EA treatments affected their bacteria. Methods: We treated 133 APRC patients with randomly assigned EA treatments or SEA treatments for 4 consecutive weeks, fully evaluating the patients 8 weeks after treatment. The participants, outcome assessors, and statistics were all blind to the EA and SEA treatments. Outcomes assessed included changes in spontaneous bowel movements (SBMs) and the frequency of rescue measures. We detected assessed the microbial diversity of stool specimens both before and after EA treatment using 16S rRNA gene sequencing. Results: Both EA and SEA treatments reduced the need for constipation rescue measures and did not have serious side effects. EA treatments were better than SEA treatments at increasing SBMs and reducing rescue measures. The diversity of gut microbiota changed after EA treatment. LEfSe analysis indicated changes in the genus (belonging to phylum Proteobacteria) of gut microbiota in patients following EA treatment. Conclusions: This study found that EA treatment is effective and safe for patients with APRC, and could be associated with changes in their microbial profiles. Further study, with larger sample sizes, is needed to explore the efficacy of EA intervention as a clinical treatment for APRC. Trial Registration: ChiCTR, ChiCTR-ONC-17010842, http://www.chictr.org.cn/showproj.aspx?proj=18420.

Comparative Efficacy of Multiple Therapies for the Treatment of Patients With Subthreshold Depression: A Systematic Review and Network Meta-Analysis.

Background: Subthreshold depression (SD) is considered to be the precursor stage of major depression, which is correlated with functional impairment and increased suicide rate. Although there are multiple therapies for the treatment of SD, the comparison and efficacy of various methods has yet to be evaluated. This study aimed to evaluate the efficacy of different therapies by performing a Bayesian network meta-analysis. Methods: We searched eight databases on April 3, 2021. Center for Epidemiologic Studies Depression Scale (CES-D), Beck Depression Inventory scale (BDI), the Patient Health Questionnaire-9 (PHQ-9), and the Kessler Screening Scale for Psychological Distress (K-6) were used as efficacy outcomes. This Bayesian network meta-analysis used a fixed-effects model. Findings: Twenty-one randomized controlled trials involving 5,048 participants were included in this study. The results suggested that electroacupuncture (MD -12.00, 95% CrI -15.00, -10.00), conventional acupuncture plus wheat-grain moxibustion (MD -9.70, 95% CrI -14.00, -5.30), and the Chinese traditional peripateticism pill plus group counseling (MD -9.00, 95% CrI -11.00, -6.70) had better efficacy than the control group (CG) in improving CES-D. For BDI outcome, bright light therapy (MD -9.70, 95% CrI -13.00, -6.00), behavioral activation program (MD -5.70, 95% CrI -6.10, -5.40), and dim light therapy (MD -6.30, 95% CrI -10.00, -2.20) were better than the CG. Tai chi (MD -3.00, 95% CrI -4.00, -2.00) was better than CG for PHQ-9 outcomes. Telephone-based cognitive behavioral treatment (MD -2.50 95% CrI -2.70, -2.30) was better than the CG for K-6 scores. Conclusion: Our results suggest that electroacupuncture or bright light therapy appear to be the better choices in the treatment of SD. This study provide new insights into clinical treatment selection and may aid the development of guidelines for the management of SD.

Neuregulin1-ErbB4 Signaling in Spinal Cord Participates in Electroacupuncture Analgesia in Inflammatory Pain.

Chronic inflammatory pain is a severe clinical symptom that aggravates the life quality of patients and places a huge economic burden on individuals and society. As one complementary and alternative therapy, electroacupuncture (EA) is widely used in clinical practice to treat chronic inflammatory pain based on its safety and efficacy. Previous studies have revealed the potential role of adenosine, neuropeptides, and inflammatory factors in EA analgesia in various pain models, but the identity of some of the signaling pathways involved remain unknown. In the present study, we explored whether neuregulin1 (NRG1)-ErbB4 signaling is involved in EA analgesia in inflammatory pain. Repeated EA treatment at the acupoints Zusanli (ST36) and Sanyinjiao (SP6) for 3 consecutive days remarkably attenuated mechanical allodynia and thermal hyperalgesia in complete Freund's adjuvant (CFA)-treated mice, with an increased expression of NRG1 in spinal cord (SC). We found that ErbB4 kinase participated in both the EA and NRG1 mediated analgesic effects on inflammatory pain by pharmacological inhibition or genetic ablation ErbB4 in vivo. Intriguingly, the mice with conditional knockout of ErbB4 from PV+ interneurons in SC showed abnormal basal mechanical threshold. Meanwhile, NRG1 treatment could not relieve tactile allodynia in PV-Erbb4-/- mice or AAV-PV-Erbb4-/- mice after CFA injection. These experimental results suggest that regulating NRG1-ErbB4 signaling in SC could reduce pain hypersensitivity and contribute to EA analgesia in inflammatory pain.

Early Life Stress Induces Different Behaviors in Adolescence and Adulthood May Related With Abnormal Medial Prefrontal Cortex Excitation/Inhibition Balance.

Early life stress is thought to be a risk factor for emotional disorders, particularly depression and anxiety. Although the excitation/inhibition (E/I) imbalance has been implicated in neuropsychiatric disorders, whether early life stress affects the E/I balance in the medial prefrontal cortex at various developmental stages is unclear. In this study, rats exposed to maternal separation (MS) that exhibited a well-established early life stress paradigm were used to evaluate the E/I balance in adolescence (postnatal day P43-60) and adulthood (P82-100) by behavior tests, whole-cell recordings, and microdialysis coupled with high performance liquid chromatography-mass spectrometry (HPLC-MS) analysis. First, the behavioral tests revealed that MS induced both anxiety- and depressive-like behaviors in adolescent rats but only depressive-like behavior in adult rats. Second, MS increased the action potential frequency and E/I balance of synaptic transmission onto L5 pyramidal neurons in the prelimbic (PrL) brain region of adolescent rats while decreasing the action potential frequency and E/I balance in adult rats. Finally, MS increases extracellular glutamate levels and decreased the paired-pulse ratio of evoked excitatory postsynaptic currents (EPSCs) of pyramidal neurons in the PrL of adolescent rats. In contrast, MS decreased extracellular glutamate levels and increased the paired-pulse ratio of evoked EPSCs of pyramidal neurons in the PrL of adult rats. The present results reveal a key role of E/I balance in different MS-induced disorders may related to the altered probability of presynaptic glutamate release at different developmental stages.

Modulating microglia activation prevents maternal immune activation induced schizophrenia-relevant behavior phenotypes via arginase 1 in the dentate gyrus.

Prenatal infection during pregnancy increases the risk for developing neuropsychiatric disorders such as schizophrenia. This is linked to an inflammatory microglial phenotype in the offspring induced by maternal immune activation (MIA). Microglia are crucial for brain development and maintenance of neuronal niches, however, whether and how their activation is involved in the regulation of neurodevelopment remains unclear. Here, we used a MIA rodent model in which polyinosinic: polycytidylic acid (poly (I:C)) was injected into pregnant mice. We found fewer parvalbumin positive (PV+) cells and impaired GABAergic transmission in the dentate gyrus (DG), accompanied by schizophrenia-like behavior in the adult offspring. Minocycline, a potent inhibitor of microglia activation, successfully prevented the above-mentioned deficits in the offspring. Furthermore, by using microglia-specific arginase 1 (Arg1) ablation as well as overexpression in DG, we identified a critical role of Arg1 in microglia activation to protect against poly (I:C) imparted neuropathology and altered behavior in offspring. Taken together, our results highlight that Arg1-mediated alternative activation of microglia are potential therapeutic targets for psychiatric disorders induced by MIA.

HuangqiGuizhiWuwu Decoction Prevents Vascular Dysfunction in Diabetes via Inhibition of Endothelial Arginase 1.

Hyperglycemia induces vascular endothelial dysfunction, which contributes to the development of vascular complication of diabetes. A classic prescription of traditional medicine, HuangqiGuizhiWuwu Decoction (HGWWD) has been used for the treatment of various cardiovascular and cerebrovascular diseases, which all are related with vascular pathology. The present study investigated the effect of HGWWD treatment in streptozocin (STZ)-induced vascular dysfunction in mouse models. In vivo studies were performed using wild type mice as well as arginase 1 knockout specific in endothelial cells (EC-A1-/-) of control mice, diabetes mice and diabetes mice treated with HGWWD (60 g crude drugs/kg/d) for 2 weeks. For in vitro studies, aortic tissues were treated with mice serum containing HGWWD with or without adenoviral arginase 1 (Ad-A1) transduction in high glucose (HG) medium. We found that HGWWD treatment restored STZ-induced impaired mean velocity and pulsatility index of mouse left femoral arteries, aortic pulse wave velocity and vascular endothelial relaxation accompanied by elevated NO production in the aorta and plasma, as well as reduced endothelial arginase activity and aortic arginase 1 expression. The protective effect of HGWWD is reversed by an inhibitor of nitric oxide synthesis. Meanwhile, the preventive effect of serum containing HGWWD in endothelial vascular dysfunction is completely blocked by Ad-A1 transduction in HG incubated aortas. HGWWD treatment further improved endothelial vascular dysfunction in STZ induced EC-A1-/- mice. This study demonstrates that HGWWD improved STZ-induced vascular dysfunction through arginase 1 - NO signaling, specifically targeting endothelial arginase 1.

Chronic mild stress induced anxiety-like behaviors can Be attenuated by inhibition of NOX2-derived oxidative stress.

Chronic stress-induced anxiety disorder is a highly-prevalent, modern social disease in which oxidative stress plays an important role. It is necessary to determine the underlying mechanisms governing this disorder to establish an effective treatment target for anxiety disorders. In this study, we examined the behavioral changes in mice subjected to chronic mild stress (CMS). We found that CMS exposure leads to anxiety-like phenotypes and increased levels of oxidative stress in the ventral hippocampus of mice. Furthermore, CMS increased the excitatory synaptic transmission of pyramidal cells in the ventral CA1 (vCA1). Administration of 4-hydroxy-3-methoxy-acetophenone (apocynin), an inhibitor of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, clearly ameliorated the changes induced by CMS exposure. In addition, our results of behavioral tests and analyses of reactive oxygen species (ROS) using NOX2-deficient mice indicate that CMS-induced enhanced oxidative stress level is primarily caused by the increased expression of NOX2. NOX2-derived oxidative stress can serve as a target for anxiety therapy led by chronic stress.

Transcriptome Analysis on Maternal Separation Rats With Depression-Related Manifestations Ameliorated by Electroacupuncture.

Maternal separation (MS), a stressful event in early life, has been linked to neuropsychiatric disorders later in life, especially depression. In this study we investigated whether treatment with electroacupuncture (EA) could ameliorate depression-related manifestations in adult animals that had adverse early life experiences. We demonstrated depression-like behavior deficiencies in a sucrose preference test and a forced swimming test in a rat model with neonatal MS. Repeated EA treatment at the acupoints Baihui (GV20) and Yintang (GV29) during adulthood was shown to be remarkably attenuated above behavioral deficits. Using unbiased genome-wide RNA sequencing to investigate alterations in the transcriptome of the prefrontal cortex (PFC), we explored the altered gene sets involved in circadian rhythm and neurotransmitter transporter activity in MS rats, and their expression tended to be reversed after EA treatment. In addition, we analyzed the interaction network of differentiated lncRNA- or circRNA-miRNA-mRNA by using the principle of competitive endogenous RNA (ceRNA). These results suggest that EA at GV20 and GV29 ameliorates depression-related manifestations by regulating the expression of multiple genes.

An enriched environment restores hepatitis B vaccination-mediated impairments in synaptic function through IFN-γ/Arginase1 signaling.

Activation of the neonatal immune system may contribute to deficits in neuronal plasticity. We have reported that neonatal vaccination with a hepatitis B vaccine (HBV) transiently impairs mood status and spatial memory involving a systemic T helper (Th) 2 bias and M1 microglial activation. Here, an EE induced microglial anti-inflammatory M2 polarization, as evidenced by selectively enhanced expression of the Arginase1 gene (Arg-1) in the hippocampus. Interestingly, knock-down of the Arg-1 gene prevented the effects of EE on restoring the dendritic spine density. Moreover, levels of the Th1-derived cytokine IFN-gamma (IFN-γ) were elevated in the choroid plexus (CP), which is the interface between the brain and the periphery. IFN-γ-blocking antibodies blunted the protective effects of an EE on spine density and LTP. Furthermore, levels of complement proteins C1q and C3 were elevated, and this elevation was associated with synapse loss induced by the HBV, whereas an EE reversed the effects of the HBV. Similarly, blockade of C1q activation clearly prevented synaptic pruning by microglia, LTP inhibition and memory deficits in hepatitis B-vaccinated mice. Together, the EE-induced increase in IFN-γ levels in the CP may disrupt systemic immunosuppression related to HBV via an IFN-γ/Arg-1/complement-dependent pathway.

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 brain's CP, M2 microglial polarization and neurotrophic factor expression.

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.

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.