ABSTRACT
Emerging evidence suggests that the gut microbiota is closely related to psychiatric disorders. However, little is known about the role of the gut microbiota in the development of obsessive-compulsive disorder (OCD). Here, to investigate the contribution of gut microbiota to the pathogenesis of OCD, we transplanted fecal microbiota from first-episode, drug-naive OCD patients or demographically matched healthy individuals into antibiotic-treated specific pathogen-free (SPF) mice and showed that colonization with OCD microbiota is sufficient to induce core behavioral deficits, including abnormal anxiety-like and compulsive-like behaviors. The fecal microbiota was analyzed using 16 S rRNA full-length sequencing, and the results demonstrated a clear separation of the fecal microbiota of mice colonized with OCD and control microbiota. Notably, microbiota from OCD-colonized mice resulted in injured neuronal morphology and function in the mPFC, with inflammation in the mPFC and colon. Unbiased metabolomic analyses of the serum and mPFC region revealed the accumulation of succinic acid (SA) in OCD-colonized mice. SA impeded neuronal activity and induced an inflammatory response in both the colon and mPFC, impacting intestinal permeability and brain function, which act as vital signal mediators in gut microbiota-brain-immune crosstalk. Manipulations of dimethyl malonate (DM) have been reported to exert neuroprotective effects by suppressing the oxidation of accumulated succinic acid, attenuating the downstream inflammatory response and neuronal damage, and can help to partly improve abnormal behavior and reduce neuroinflammation and intestinal inflammation in OCD-colonized mice. We propose that the gut microbiota likely regulates brain function and behaviors in mice via succinic acid signaling, which contributes to the pathophysiology of OCD through gut-brain crosstalk and may provide new insights into the treatment of this disorder.
Subject(s)
Disease Models, Animal , Fecal Microbiota Transplantation , Gastrointestinal Microbiome , Obsessive-Compulsive Disorder , Succinic Acid , Animals , Obsessive-Compulsive Disorder/metabolism , Obsessive-Compulsive Disorder/microbiology , Gastrointestinal Microbiome/physiology , Mice , Humans , Male , Succinic Acid/metabolism , Fecal Microbiota Transplantation/methods , Female , Neuroinflammatory Diseases/metabolism , Feces/microbiology , Adult , Behavioral Symptoms/metabolism , Inflammation/metabolism , Prefrontal Cortex/metabolism , Anxiety/metabolism , Anxiety/microbiology , Mice, Inbred C57BL , Behavior, Animal , Brain/metabolism , Brain-Gut Axis/physiologyABSTRACT
OBJECTIVES: Neuroinflammation has been suggested that affects the processing of depression. There is renewed interest in berberine owing to its anti-inflammatory effects. Herein, we investigated whether berberine attenuate depressive-like behaviors via inhibiting NLRP3 inflammasome activation in mice model of depression. METHODS: Adult male C57BL/6N mice were administrated corticosterone (CORT, 20 mg/kg/day) for 35 days. Two doses (100 mg/kg/day and 200 mg/kg/day) of berberine were orally administrated from day 7 until day 35. Behavioral tests were performed to measure the depression-like behaviors alterations. Differentially expressed gene analysis was performed for RNA-sequencing data in the prefrontal cortex. NLRP3 inflammasome was measured by quantitative reverse transcription polymerase chain reaction, western blotting, and immunofluorescence labeling. The neuroplasticity and synaptic function were measured by immunofluorescence labeling, Golgi-Cox staining, transmission electron microscope, and whole-cell patch-clamp recordings. RESULTS: The results of behavioral tests demonstrated that berberine attenuated the depression-like behaviors induced by CORT. RNA-sequencing identified that NLRP3 was markedly upregulated after long-term CORT exposure. Berberine reversed the concentrations of peripheral and brain cytokines, NLRP3 inflammasome elicited by CORT in the prefrontal cortex and hippocampus were decreased by berberine. In addition, the lower frequency of neuronal excitation as well as the dendritic spine reduction were reversed by berberine treatment. Together, berberine increases hippocampal adult neurogenesis and synaptic plasticity induced by CORT. CONCLUSION: The anti-depressants effects of berberine were accompanied by reduced the neuroinflammatory response via inhibiting the activation of NLRP3 inflammasome and rescued the neuronal deterioration via suppression of impairments in synaptic plasticity and neurogenesis.
Subject(s)
Berberine , Neuroinflammatory Diseases , Male , Mice , Animals , Mice, Inbred C57BL , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Depression , Neuronal PlasticityABSTRACT
BACKGROUND: Converging evidence suggests that stress alters behavioural responses in a sex-specific manner; however, the underlying molecular mechanisms of stress remain largely unknown. METHODS: We adapted unpredictable maternal separation (UMS) and adult restraint stress (RS) paradigms to mimic stress in rats in early life or adulthood, respectively. The sexual dimorphism of the prefrontal cortex was noted, and we performed RNA sequencing (RNA-Seq) to identify specific genes or pathways responsible for sexually dimorphic responses to stress. We then performed quantitative reverse transcription polymerase chain reaction (qRT-PCR) to verify the results of RNA-Seq. RESULTS: Female rats exposed to either UMS or RS showed no negative effects on anxiety-like behaviours, whereas the emotional functions of the PFC were impaired markedly in stressed male rats. Leveraging differentially expressed genes (DEG) analyses, we identified sex-specific transcriptional profiles associated with stress. There were many overlapping DEGs between UMS and RS transcriptional data sets, where 1406 DEGs were associated with both biological sex and stress, while only 117 DEGs were related to stress. Notably, Uba52 and Rpl34-ps1 were the first-ranked hub gene in 1406 and 117 DEGs respectively, and Uba52 was higher than Rp134-ps1, suggesting that stress may have led to a more pronounced effect on the set of 1406 DEGs. Pathway analysis revealed that 1406 DEGs were primarily enriched in ribosomal pathway. These results were confirmed by qRT-PCR. LIMITATIONS: Sex-specific transcriptional profiles associated with stress were identified in this study, but more in-depth experiments, such as single-cell sequencing and manipulation of male and female gene networks in vivo, are needed to verify our findings. CONCLUSION: Our findings show sex-specific behavioural responses to stress and highlight sexual dimorphism at the transcriptional level, shedding light on developing sex-specific therapeutic strategies for stress-related psychiatric disorders.
Subject(s)
Maternal Deprivation , Prefrontal Cortex , Animals , Female , Male , Rats , Anxiety/genetics , Anxiety Disorders , Gene Expression Profiling , Prefrontal Cortex/metabolism , Sex Characteristics , Transcription, GeneticABSTRACT
Early-life stress is normally thought of as a major risk for psychiatric disorders, but many researchers have revealed that adversity early in life may enhance stress resilience later in life. Few studies have been performed in rodents to address the possibility that exposure to early-life stress may enhance stress resilience, and the underlying neural mechanisms are far from being understood. Here, we established a "two-hit" stress model in rats by applying two different early-life stress paradigms: predictable and unpredictable maternal separation (MS). Predictable MS during the postnatal period promotes resilience to adult restraint stress, while unpredictable MS increases stress susceptibility. We demonstrate that structural and functional impairments occur in glutamatergic synapses in pyramidal neurons of the medial prefrontal cortex (mPFC) in rats with unpredictable MS but not in rats with predictable MS. Then, we used differentially expressed gene (DEG) analysis of RNA sequencing data from the adult male PFC to identify a hub gene that is responsible for stress resilience. Oxytocin, a peptide hormone, was the highest ranked differentially expressed gene of these altered genes. Predictable MS increases the expression of oxytocin in the mPFC compared to normal raised and unpredictable MS rats. Conditional knockout of the oxytocin receptor in the mPFC was sufficient to generate excitatory synaptic dysfunction and anxiety behavior in rats with predictable MS, whereas restoration of oxytocin receptor expression in the mPFC modified excitatory synaptic function and anxiety behavior in rats subjected to unpredictable MS. These findings were further supported by the demonstration that blocking oxytocinergic projections from the paraventricular nucleus of the hypothalamus (PVN) to the mPFC was sufficient to exacerbate anxiety behavior in rats exposed to predictable MS. Our findings provide direct evidence for the notion that predictable MS promotes stress resilience, while unpredictable MS increases stress susceptibility via mPFC oxytocin signaling in rats.
Subject(s)
Maternal Deprivation , Oxytocin , Animals , Anxiety/metabolism , Male , Oxytocin/metabolism , Prefrontal Cortex/metabolism , Rats , Signal Transduction , Stress, PsychologicalABSTRACT
Nitric oxide (NO), the highly reactive radical gas, provides an attractive strategy in the control of microbial infections. NO not only exhibits bactericidal effect at high concentrations but also prevents bacterial attachment and disperses biofilms at low, nontoxic concentrations, rendering bacteria less tolerant to antibiotic treatment. The endogenously generated NO by airway epithelium in healthy populations significantly contributes to the eradication of invading pathogens. However, this pathway is often compromised in patients suffering from chronic lung infections where biofilms dominate. Thus, exogenous supplementation of NO is suggested to improve the therapeutic outcomes of these infectious diseases. Compared to previous reviews focusing on the mechanism of NO-mediated biofilm inhibition, this review explores the applications of NO for inhibiting biofilms in chronic lung infections. It discusses how abnormal levels of NO in the airways contribute to chronic infections in cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and primary ciliary dyskinesia (PCD) patients and why exogenous NO can be a promising antibiofilm strategy in clinical settings, as well as current and potential in vivo NO delivery methods. KEY POINTS : ⢠The relationship between abnormal NO levels and biofilm development in lungs ⢠The antibiofilm property of NO and current applications in lungs ⢠Potential NO delivery methods and research directions in the future.
Subject(s)
Nitric Oxide , Pseudomonas Infections , Anti-Bacterial Agents/therapeutic use , Biofilms , Humans , Lung , Nitric Oxide Donors , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosaABSTRACT
Obsessive-compulsive disorder (OCD) is a chronic, severe psychiatric disorder that has been ranked by the World Health Organization as one of the leading causes of illness-related disability, and first-line interventions are limited in efficacy and have side-effect issues. However, the exact pathophysiology underlying this complex, heterogeneous disorder remains unknown. This scenario is now rapidly changing due to the advancement of powerful technologies that can be used to verify the function of the specific gene and dissect the neural circuits underlying the neurobiology of OCD in rodents. Genetic and circuit-specific manipulation in rodents has provided important insights into the neurobiology of OCD by identifying the molecular, cellular, and circuit events that induce OCD-like behaviors. This review will highlight recent progress specifically toward classic genetic animal models and advanced neural circuit findings, which provide theoretical evidence for targeted intervention on specific molecular, cellular, and neural circuit events.
ABSTRACT
Oxytocin (OXT), produced and secreted in the paraventricular nucleus and supraoptic nucleus of magnocellular and parvocellular neurons. The diverse presence and activity of oxytocin suggests a potential for this neuropeptide in the pathogenesis and treatment of stress-related neuropsychiatric disorders (anxiety, depression and post-traumatic stress disorder (PTSD)). For a more comprehensive understanding of the mechanism of OXT's anti-stress action, the signaling cascade of OXT binding to targeting stress were summarized. Then the advance of OXT treatment in depression, anxiety, PTSD and the major projection region of OXT neuron were discussed. Further, the efficacy of endogenous and exogenous OXT in stress responses were highlighted in this review. To augment the level of OXT in stress-related neuropsychiatric disorders, current biological strategies were summarized to shed a light on the treatment of stress-induced psychiatric disorders. We also conclude some of the major puzzles in the therapeutic uses of OXT in stress-related neuropsychiatric disorders. Although some questions remain to be resolved, OXT has an enormous potential therapeutic use as a hormone that regulates stress responses.
ABSTRACT
Previous studies have speculated that brain activity directly controls immune responses in lymphoid organs. However, the upstream brain regions that control lymphoid organs and how they interface with lymphoid organs to produce stress-induced anxiety-like behavior remain elusive. Using stressed human participants and rat models, we show that CCL5 levels are increased in stressed individuals compared to controls. Stress-inducible CCL5 is mainly produced from cervical lymph nodes (CLN). Retrograde tracing from CLN identifies glutamatergic neurons in the red nucleus (RN), the activities of which are tightly correlated with CCL5 levels and anxiety-like behavior in male rats. Ablation or chemogenetic inhibition of RN glutamatergic neurons increases anxiety levels and CCL5 expression in the serum and CLNs, whereas pharmacogenetic activation of these neurons reduces anxiety levels and CCL5 synthesis after restraint stress exposure. Chemogenetic inhibition of the projection from primary motor cortex to RN elicits anxiety-like behavior and CCL5 synthesis. This brain-lymph node axis provides insights into lymph node tissue as a stress-responsive endocrine organ.
Subject(s)
Red Nucleus , Stress, Psychological , Rats , Humans , Male , Animals , Stress, Psychological/metabolism , Anxiety/metabolism , Lymph Nodes/metabolism , Brain/metabolism , Chemokine CCL5/metabolismABSTRACT
Anisotropic functional patterned surfaces have shown significant applications in microfluidics, biomedicine and optoelectronics. However, surface patterning relies heavily on high-end apparatuses and expensive moulds/masks and photoresists. Decomposition behaviors of polymers have been widely studied in material science, but as-created chemical and physical structural changes have been rarely considered as an opportunity for wettability manipulation. Here, a facile mask-free confined-etching strategy is reported for intrinsic wettable surface patterning. With printing technology, the surface wetting state is regulated, enabling the chemical etching of setting locations and efficient fabrication of complex patterns. Notably, the created anisotropic patterns can be used for realizing water-responsive information storage and encryption as well as fabricating flexible electrodes. Featuring advantages of simple operation and economic friendliness, this patterning approach brings a bright prospect in developing functional materials with versatile applications.