Brain, Behavior, and Immunity最新文献

Angiotensin II is well known to have an important influence on blood pressure, mediated via the angiotensin II type 1 receptor (AT1R), but more recent studies have shown that angiotensin II may play an important additional role in eliciting pain via a distinct action at the angiotensin II type 2 receptor (AT2R). Signalling pathways that link activation of AT2R to a sensation of pain are, however, incompletely understood. Here we use rodent inflammatory pain models to confirm that selective activation of AT2R triggers aversive responses, and that these are abolished by either antagonism or genetic deletion of AT2R. Pain induced by AT2R activation is abolished by pharmacological block or genetic deletion of the HCN2 ion channel, which other studies have implicated in several distinct pain modalities. We found, however, no evidence for direct activation of isolated nociceptive neurons by AT2R agonists. In agreement, the effect of AT2R agonists was completely abolished by the cyclooxygenase (COX) inhibitor indomethacin or by selective antagonism of the EP4 receptor for PGE₂, showing that PGE₂ is a critical extracellular mediator that transmits the signal from AT2R to nociceptive neurons and causes activation of HCN2 ion channels. When inflammatory pain was induced by injection of carrageenan, pharmacological inhibition or genetic deletion of AT2R gave near-complete pain relief, together with a reduction in chemokine and PGE₂ release. This study shows that angiotensin II is an important pro-inflammatory mediator that causes pain indirectly by activating AT2 receptors on non-neuronal cells, stimulating the release of PGE₂ that mediates activation of HCN2 ion channels in nociceptive neurons.

Background: Perinatal depression and anxiety pose significant risks to maternal health and may lead to suicide. The gut microbiota may play a crucial role in perinatal depression and anxiety. However, the relationship between the alterations in gut microbiota and perinatal depression and anxiety remains unclear. This study aimed to investigate the dynamic changes of gut microbiota over various perinatal stages and their associations with perinatal depression and anxiety symptoms, especially suicide ideation.

Methods: A total of 177 pregnant and 19 postpartum women were recruited in this study, with 48 of them participating longitudinally. Maternal depression and anxiety symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS), 9-item Patient Health Questionnaire (PHQ-9), and 7-item Generalized Anxiety Disorder Scale (GAD-7). Fecal samples collected during the perinatal period were analyzed using 16S rRNA gene sequencing.

Results: Significant changes in microbial diversity and multi-taxonomic levels were observed during pregnancy. The random forest regression model showed significant associations of some gut microbial features with depression and anxiety symptoms. Several genera were significantly associated with gestation age and perinatal depression and anxiety, such as Akkermansia, Bifidobacterium and Streptococcus. In addition, Erysipelotrichaceae_UCG-003 and Eubacterium_hallii_group were positively associated with suicidal ideation. The glycine biosynthesis pathway might act as a mediator between Eubacterium_hallii_group and suicidal ideation (ab = 3.27, p < 0.05).

Conclusion: The gut microbiota undergoes a programmed shift during pregnancy, which may play a critical role in perinatal depression and anxiety. Our findings underscore the impact of certain bacterial genera and metabolic pathways on perinatal mental health, which may help to develop new diagnostic tools and targeted interventions to reduce perinatal mental disorders and improve the outcomes for both mothers and infants.

Essential hypertension (EH) with secondary insomnia is associated with increased risks of neuroinflammation, neuronal damage, and Alzheimer's disease (AD). However, its relationship with specific cerebrospinal fluid (CSF) biomarkers of neuronal damage and neuroinflammation remains unclear. This case-control study compared CSF biomarker levels across three groups: healthy controls (HC, n = 64), hypertension-controlled (HTN-C, n = 54), and hypertension-uncontrolled (HTN-U, n = 107) groups, all EH participants experiencing secondary insomnia. CSF samples from knee replacement patients were analyzed for key biomarkers, and sleep quality was assessed via the Pittsburgh Sleep Quality Index (PSQI). Our findings showed that the HTN-U group had significantly higher CSF levels of proinflammatory cytokines IL-6, TNF-α, and IL-17 than the HC and HTN-C groups (all p < 0.01). These cytokines correlated positively with secondary insomnia measures, with IL-6 (r = 0.285, p = 0.003), IL-17 (r = 0.324, p = 0.001), and TNF-α (r = 0.274, p = 0.005) linked to PSQI scores. In the HTN-U group, elevated IL-6, TNF-α, and IL-17 levels were also positively associated with neurofilament light (NF-L) and negatively with β-amyloid 42 (Aβ42), both key AD markers (all p < 0.05). Additionally, secondary insomnia was negatively correlated with Aβ42 (r = -0.225, p = 0.021) and positively with NF-L (r = 0.261, p = 0.007). Higher CSF palmitic acid (PA) levels observed in the HTN-U group were linked to poorer sleep quality (r = 0.208, p = 0.033). In conclusion, EH with secondary insomnia is associated with CSF biomarkers of neuronal damage, neuroinflammation, and neurodegeneration, suggesting a potential increase in AD risk among this population.

Background: Individuals with posttraumatic stress disorder (PTSD) have high rates of cardiovascular disease (CVD) and increased cardiometabolic CVD risk factors (CVDRFs, e.g., hypertension, hyperlipidemia, or diabetes mellitus). Nevertheless, it remains unknown whether PTSD accelerates CVDRF development and how that impacts the development of major adverse cardiovascular events (MACE) in a broad population. Furthermore, the underlying mechanisms remain incompletely characterized.

Objective: We hypothesized that 1) PTSD accelerates CVDRF development, 2) accelerated CVDRF development mediates the PTSD-MACE relationship, and 3) accelerated CVDRF development is partially explained by alterations in neural, autonomic, and inflammatory intermediaries (e.g., stress-associated neural activity [SNA], ventromedial prefrontal cortex [vmPFC] activity, heart rate variability [HRV], and C-reactive protein [CRP]).

Methods: Subjects (N = 84,343) in the Mass General Brigham Biobank were studied over 10 years. PTSD, CVDRFs, and MACE were identified by diagnostic codes. From participants with available clinical data, neural, autonomic, and inflammatory mediators (e.g., SNA, vmPFC, HRV, and CRP) were assessed.

Results: PTSD independently predicted incident CVDRFs (hazard ratio [95 % confidence interval] = (1.432 [1.287, 1.592], p < 0.001) and associated with the accelerated development of a new CVDRF by ∼ 4 months versus those without PTSD. The development of new CVDRFs predicted incident MACE (1.736 [1.652, 1.823, p < 0.001) and mediated the link between PTSD and MACE (p < 0.05) by up to 36.4 %. Additionally, lower vmPFC activity, lower HRV, and higher CRP were associated with the development of CVDRFs. HRV and CRP significantly mediated the PTSD-CVDRF link.

Conclusions: The PTSD-MACE link was partially explained by the accelerated development of CVDRFs. Alterations in neural, autonomic, and immune intermediaries contributed to this association. These findings suggest that greater clinical attention to CVDRFs in individuals with PTSD may attenuate MACE risk.

Obesity, a pandemic, worldwide afflicts almost one billion people. Obesity and ageing share several pathological pathways leading to neurological disorders. However, due to a lack of suitable animal models, the long-term effects of obesity on age-related disorders- cognitive impairment and dementia have not yet been thoroughly investigated. Therefore, the current investigation focuses on developing a suitable model to explore the effects of obese-ageing. It also aims to determine whether obesity affects cognitive abilities in an age-dependent manner, and to identify a potential biomarker(s) for cognitive decline. Cognitive tests were carried out on 6-months and 1-year-old melanocortin-4 receptor (Mc4r)-deficient-obese and lean (wildtype) mice. Additionally, brains and sera were harvested for molecular, histological and serological analyses from 6, 12, and 24-months-old mice. Finally, RT-PCR was carried out after hippocampal mRNA sequencing. The cognitive tests revealed that 1-year-old obese mice have cognitive impairment along with underlying neurodegenerative changes, such as enlarged lateral ventricles. Serum neurofilament light chain (sNfL) levels were also elevated. Lipid accumulation and neuroinflammation were apparent besides, a compromised blood-brain barrier (BBB) indicated by altered junction protein gene expression. Differentially-expressed genes associated with cognitive decline were identified by mRNA sequencing of hippocampi. One such gene, Secreted Phosphoprotein 1 (Spp1) had markedly increased expression in cognitively-impaired obese mice. Our findings present an obese-aged mouse model of cognitive decline with neuroinflammation, reduced BBB-integrity and predisposing neurodegenerative changes. Obese-ageing accelerates the progression of cognitive impairment. Furthermore, Spp1 appears to be a potential biomarker for early diagnosis of neuropathological disorders.

Glial cell-induced neuroinflammation in the spinal cord is the critical pathology underlying complete Freund's adjuvant (CFA)-induced inflammatory pain. Previously, we showed that spinal glial cells undergo ferroptosis after CFA injection, which may contribute to the development of neuroinflammation and inflammatory pain. However, the mechanism underlying the occurrence of ferroptosis during inflammatory pain remains unclear. The aim of this study was to investigate the molecular factors involved in the occurrence of ferroptosis during the development of inflammatory pain. Bulk and single-cell RNA sequencing were performed to identify the key genes involved in the ferroptosis of spinal astrocytes, microglia, and oligodendrocytes in rats. We identified nuclear receptor 4A1 (NR4A1) as a common ferroptosis-related gene present in all three types of glial cells. Western blotting and immunostaining revealed increased NR4A1 levels in the spinal glial cells of the CFA-treated rats. Moreover, intrathecal injection of DIM-C-pPhOH (an NR4A1 inhibitor) effectively alleviated mechanical and thermal hypersensitivity in the CFA-treated rats by attenuating ferroptosis and neuroinflammation in spinal glial cells. Proteomic analysis revealed that mitogen-activated protein kinase 3 (MAPK3) may be the target protein of NR4A1. In addition, the combined results of chromatin immunoprecipitation and dual-luciferase assays indicated that NR4A1 can bind to the promoter region and promote transcription of MAPK3, ultimately leading to lipid peroxidation. In conclusion, this study demonstrated that increased expression of NR4A1 promotes the progression of CFA-induced inflammatory pain by enhancing ferroptosis through the transcriptional activation of MAPK3 and subsequent lipid peroxidation. Furthermore, inhibition of NR4A1 was found to suppress ferroptosis and reduce the release of pro-inflammatory cytokines in the spinal cord of rats with inflammatory pain. Collectively, these findings outline a novel pathological mechanism and identify potential therapeutic targets for the treatment of inflammatory pain.

Neonatal pain is a significant clinical issue but the mechanisms by which pain is produced early in life are poorly understood. Our recent work has linked the transcription factor serum response factor downstream of local growth hormone (GH) signaling to incision-related hypersensitivity in neonates. However, it remains unclear if similar mechanisms contribute to inflammatory pain in neonates. We found that local GH treatment inhibited neonatal inflammatory myalgia but appeared to do so through a unique signal transducer and activator of transcription (STAT) dependent pathway within sensory neurons. The STAT1 transcription factor appeared to regulate peripheral inflammation itself by modulation of monocyte chemoattractant protein 1/C-C motif chemokine ligand 2 (MCP1/CCL2) release from sensory neurons. Data suggests that STAT1 upregulation, downstream of GH signaling, contributes to neonatal nociception during muscle inflammation through a novel neuroimmune loop involving chemokine release from primary afferents. Results could uncover new ways to treat muscle pain and inflammation in neonates.

Immune dysfunction in autism spectrum disorder (ASD) has been widely reported and is associated with increased impairments in social interactions, communication, repetitive behaviors, anxiety and gastrointestinal problems. Several lines of evidence point towards increased activation of the innate immune system including activation of microglia, increases in innate inflammatory cytokines/chemokines in blood, brain tissue and CSF, activated dendritic cells and macrophages, and abnormal peripheral monocyte cell function. Monocytes are major players in innate immunity and have important functions in the phagocytosis of pathogens or debris, immune defense and cytokine/chemokine production. However, little is known about the frequencies of different circulating monocytes populations in ASD compared with similarly aged typically developing (TD) controls. In this study, the profile of circulating monocytes exhibiting different markers of activation were assessed in 77 children with ASD, and 49 TD controls who were enrolled as part of the Autism Phenome Project and were of a similar age, 2-4 years old. The frequencies of monocytes expressing the activation marker CD137 (4-1BB) were significantly increased in children with ASD and associated with greater behavioral impairments. In addition, although the frequencies of non-classical monocytes (CD14⁺CD16⁺) were not significantly different across groups, they were linked to worse behaviors in both the context of ASD and TD. Conversely classical monocytes were associated with better behavioral outcomes. These data further implicate monocytes and innate immune cells in the complex pathophysiology of ASD. Monocyte cells play key roles in modulating immune responses and differences in the activation profiles of these cells may result in immune dysfunction in children with ASD.

The prevalence of noncommunicable inflammatory disease is increasing in modern urban societies, posing significant challenges to public health. Novel prevention and therapeutic strategies are needed to effectively deal with this issue. One promising approach is leveraging microorganisms such as Mycobacterium vaccae ATCC 15483, known for its anti-inflammatory, immunoregulatory, and stress-resilience properties. This study aimed to assess whether weekly subcutaneous administrations of a whole-cell, heat-killed preparation of M. vaccae ATCC 15483 (eleven injections initiated one week before the onset of the diet intervention), relative to vehicle injections, in adolescent male C57BL/6N mice can mitigate inflammation associated with Western-style diet-induced obesity, which is considered a risk factor for a number of metabolic and inflammatory diseases. Our results show that treatment with M. vaccae ATCC 15483 prevented Western-style diet-induced excessive weight gain, visceral adipose tissue accumulation, and elevated plasma leptin concentrations. The Western-style diet, relative to a control diet condition, decreased alpha diversity and altered the community composition of the gut microbiome, increasing the Bacillota to Bacteroidota ratio (formerly referred to as the Firmicutes to Bacteroidetes ratio). Despite the finding that M. vaccae ATCC 15483 prevented Western-style diet-induced excessive weight gain, visceral adipose tissue accumulation, and elevated plasma leptin concentrations, it had no effect on the diversity or community composition of the gut microbiome, suggesting that it acts downstream of the gut microbiome to alter immunometabolic signaling. M. vaccae ATCC 15483 reduced baseline levels of biomarkers of hippocampal neuroinflammation and microglial priming, such as Nfkbia and Nlrp3, and notably decreased anxiety-like defensive behavioral responses. The current findings provide compelling evidence supporting the potential for M. vaccae ATCC 15483 as a promising intervention for prevention or treatment of adverse immunometabolic outcomes linked to the consumption of a Western-style diet and the associated dysbiosis of the gut microbiome.