Search Results (193)

Neuropathic pain is a significant global clinical issue that poses substantial challenges to both public health and the economy due to its complex underlying mechanisms. It has emerged as a serious health concern worldwide. Recent studies involving dorsal root ganglion (DRG) stimulation have provided strong evidence supporting its effectiveness in alleviating chronic pain and its potential for sustaining long-term pain relief. In addition to that, there has been ongoing research with clinical evidence relating to the role of small non-coding ribonucleic acids known as microRNAs in regulating gene expressions affecting pain signals. The signal pathway involves alterations in neuronal excitation, synaptic transmission, dysregulated signaling, and subsequent pro-inflammatory response activation and pain development. When microRNAs are dysregulated in the dorsal root ganglia neurons, they polarize macrophages from anti-inflammatory M2 to inflammatory M1 macrophages causing pain signal generation. By reversing this polarization, a therapeutic activity can be induced. However, the direct delivery of these nucleotides has been challenging due to limitations such as rapid clearance, degradation, and reduction in half-life. Therefore, safe and efficient carrier vehicles are fundamental for microRNA delivery. Here, we present a comprehensive analysis of miRNA-based nano-systems for chronic neuropathic pain, focusing on their impact in dorsal root ganglia. This review provides a critical evaluation of various delivery platforms, including viral, polymeric, lipid-based, and inorganic nanocarriers, emphasizing their therapeutic potential as well as their limitations in the treatment of chronic neuropathic pain. Innovative strategies such as hybrid nanocarriers and stimulus-responsive systems are also proposed to enhance the prospects for clinical translation. Serving as a roadmap for future research, this review aims to guide the development and optimization of miRNA-based therapies for effective and sustained neuropathic pain management. Full article

Glutamate is an excitatory neurotransmitter in the central nervous system (CNS) that mediates synaptic transmission. However, glutamate homeostasis among neural cells is broken in cerebral ischemia. Excessive glutamate triggers N-methyl-d-aspartate receptors (NMDARs) in postsynaptic neurons, leading to intracellular calcium (Ca²⁺) overload and excitoneurotoxicity. At this moment, L-lactate may affect NMDARs and play a protective role in cerebral ischemia. This work proposes that L-lactate regulates glutamate signaling among neural cells. But, dysregulation of L-lactate in glutamate signaling cascades contributes to glutamate excitotoxicity in cerebral ischemia. In detail, L-lactate regulates the glutamine(Gln)-glutamate cycle between astrocytes and presynaptic neurons, which triggers the astroglial L-lactate-sensitive receptor (LLR)-cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway, coordinating astroglial glutamate uptake and neuronal glutamate transmission. L-lactate mediates glutamate signaling and synaptic transmission among neural cells. In addition, L-lactate promotes the function of mitochondrial calcium uniporter complex (MCUC), which quickly depletes intracellular Ca²⁺ in postsynaptic neurons. In addition, L-lactate can promote the conversion of microglia from the pro-inflammatory (M1) to anti-inflammatory (M2) phenotype. Therefore, regulation of L-lactate in glutamate signaling in the CNS might become a preventive target for cerebral ischemia. Full article

Background: The development of cerebral organoids created from human pluripotent stem cells in 3D culture may greatly improve the discovery of neuropsychiatric medicines. Methods: In the current study we differentiated neural organoids from a human pluripotent stem cell line in vitro, recorded the development of neurophysiological activity using multielectrode arrays (MEAs) and characterized the neuropharmacology of synaptic signaling over 8 months in vitro. In addition, we investigated the ability of these organoids to display epileptiform activity in response to a convulsant agent and the effects of antiseizure medicines to inhibit this abnormal activity. Results: Single and bursts of action potentials from individual neurons and network bursts were recorded on the MEA plates and significantly increased and became more complex from week 7 to week 30, consistent with neural network formation. Neural spiking was reduced by the Na channel blocker tetrodotoxin but increased by the inhibitor of K_V7 potassium channels XE991, confirming the involvement of voltage-gated sodium and potassium channels in action potential activity. The GABA antagonists bicuculline and picrotoxin each increased the spike rate, consistent with inhibitory synaptic signaling. In contrast, the glutamate receptor antagonist kynurenic acid inhibited the spike rate, consistent with excitatory synaptic transmission in the organoids. The convulsant 4-aminopyridine increased spiking, bursts and synchronized firing, consistent with epileptiform activity in vitro. The anticonvulsants carbamazepine, ethosuximide and diazepam each inhibited this epileptiform neural activity. Conclusions: Together, our data demonstrate that neural organoids form inhibitory and excitatory synaptic circuits, generate epileptiform activity in response to a convulsant agent and detect the antiseizure properties of diverse antiepileptic drugs, supporting their value in drug discovery. Full article

The development of artificial intelligence has resulted in significant challenges to conventional von Neumann architectures, including the separation of storage and computation, and power consumption bottlenecks. The new generation of brain-like devices is accelerating its evolution in the direction of high-density integration and integrated sensing, storage, and computing. The structural and information transmission similarity between memristors and biological synapses signifies their unique potential in sensing and memory. Therefore, memristors have become potential candidates for neural devices. In this paper, we have designed an optoelectronic memristor based on a ZnO/Cu₂O structure to achieve synaptic behavior through the modulation of electrical signals, demonstrating the recognition of a dataset by a neural network. Furthermore, the optical synaptic functions, such as short-term/long-term potentiation and learn-forget-relearn behavior, and advanced synaptic behavior of optoelectronic modulation, are successfully simulated. The mechanism of light-induced conductance enhancement is explained by the barrier change at the interface. This work explores a new pathway for constructing next-generation optoelectronic synaptic devices, which lays the foundation for future brain-like visual chips and intelligent perceptual devices. Full article

To determine candidate key proteins involved in synaptic transmission in the thalamus in tinnitus, we used bioinformatic methods by analyzing protein–protein interaction networks under different conditions of acoustic activity. The motor system was used to analyze the specificity of the response reaction in the auditory system. The databases GeneCard, STRING-, DAVID-, and Cytoscape version 3.9.1 were applied to identify the top three high-degree proteins, their high-score interaction proteins and the gene ontology—biological processes (GO-BPs) associated in the thalamus with synaptic transmission in tinnitus. Under normal hearing conditions, a balanced state of functional connectivity was observed for both systems, the auditory system and the motor system of the thalamus. Under conditions of acoustic stimulation, the GO-BP-enrichment analyses suggest that in the auditory system, tinnitus-related proteins may be involved in responses typically associated with “xenobiotic stimuli”; in the motor system, the activation of the dopaminergic system was observed. Under conditions of tinnitus in the auditory system, key proteins and the GO-BPs indicate the regulation of different developmental processes and regulation by microRNA transcription; in the motor system, tinnitus is also identified as “xenobiotic” but responded with GO-BPs, corresponding to various signaling systems, e.g., tachykinin. Key proteins and their interactions with neurotransmitter receptors may be useful indicators for tinnitus-associated changes in synaptic transmission in the thalamic auditory system. Full article

Objective:Burning mouth syndrome (BMS) is a chronic, intractable orofacial pain condition characterized by a burning sensation in the oral mucosa without discernible lesions. The syndrome predominantly affects menopausal and postmenopausal women and is considered a form of nociplastic pain, where the processing of pain stimuli is altered. Given the significant sex disparity, it is crucial to consider underlying neurobiological differences that may inform treatment. This review explores potential pharmacological targets by examining the pathological mechanisms of BMS. Method of Research: A narrative review approach was utilized to systematically explore and synthesize literature regarding the pathophysiology of BMS and to identify receptors implicated in the enhancement of sensory transmission and the altered processing of pain stimuli. Results: The mechanism of enhanced sensory transmission points to receptors such as TRPV1, P2X3, and CB2 as potential targets. However, considering the nociplastic nature of BMS and its prevalence in women, mechanisms involving altered central pain processing are paramount. Research indicates significant sex differences in glutamate transmission and plasticity within reward-related brain regions. This suggests that the N-methyl-D-aspartate (NMDA) receptor, a cornerstone of glutamate signaling and synaptic plasticity, is a primary therapeutic target. Furthermore, the altered processing of pain and reward, which is a key feature of chronic pain, implicates the brain’s dopaminergic system. A decrease in dopamine D2 receptor function within this system is believed to contribute to the pathology of BMS. Estrogen receptors are also considered relevant due to the menopausal onset. Conclusions: Based on the evidence, the most promising targets for pharmacotherapy in BMS are likely the NMDA receptor and the dopamine D2 receptor. The high prevalence of BMS in women, coupled with known sex differences in the glutamate and dopamine pathways of the reward system, provides a strong rationale for this focus. Effective treatment strategies should therefore aim to modulate these specific systems, directly or indirectly controlling NMDE receptor hyperactivity and addressing the decreased D2 receptor function. Further research into therapies that specifically target this sex-linked neurobiology is essential for developing effective pharmacotherapy for BMS. Full article

Synbiotics can be used to reduce intestinal inflammation and mitigate dysbiosis in dogs with chronic inflammatory enteropathy (CIE). Prior research has not assessed the colonic mucosal ultrastructure of dogs with active CIE treated with synbiotics, nor has it determined a possible association between morphologic injury and signaling pathways. Twenty client-owned dogs diagnosed with CIE were randomized to receive either a hydrolyzed diet (placebo; PL) or a hydrolyzed diet supplemented with synbiotic-IgY (SYN) for 6 weeks. Endoscopic biopsies of the colon were obtained for histopathologic, ultrastructural, and molecular analyses and were compared before and after treatment. Using transmission electron microscopy (TEM), an analysis of the ultrastructural alterations in microvilli length (MVL), mitochondria (MITO), and rough endoplasmic reticulum (ER) was compared between treatment groups. To explore potential signaling pathways that might modulate MITO and ER stress, a transcriptomic analysis was also performed. The degree of mucosal ultrastructural pathology differed among individual dogs before and after treatment. Morphologic alterations in enterocytes, MVL, MITO, and ER were detected without significant differences between PL and SYN dogs prior to treatment. Notable changes in ultrastructural alterations were identified post-treatment, with SYN-treated dogs exhibiting significant improvement in MVL, MITO, and ER injury scores compared to PL-treated dogs. Transcriptomic profiling showed many pathways and key genes to be associated with MITO and ER injury. Multiple signaling pathways and their associated genes with protective effects, including fibroblast growth factor 2 (FGF2), fibroblast growth factor 7 (FGF7), fibroblast growth factor 10 (FGF10), synaptic Ras GTPase activating protein 1 (SynGAP1), RAS guanyl releasing protein 2 (RASGRP2), RAS guanyl releasing protein 3 (RASGRP3), thrombospondin 1 (THBS1), colony stimulating factor 1 (CSF1), colony stimulating factor 3 (CSF3), interleukin 21 receptor (IL21R), collagen type VI alpha 6 chain (COL6A6), ectodysplasin A receptor (EDAR), forkhead box P3 (FoxP3), follistatin (FST), gremlin 1 (GREM1), myocyte enhancer factor 2B (MEF2B), neuregulin 1 (NRG1), collagen type I alpha 1 chain (COL1A1), hepatocyte growth factor (HGF), 5-hydroxytryptamine receptor 7 (HTR7), and platelet derived growth factor receptor beta (PDGFR-β), were upregulated with SYN treatment. Differential gene expression was associated with improved MITO and ER ultrastructural integrity and a reduction in oxidative stress. Conversely, other genes, such as protein kinase cAMP-activated catalytic subunit beta (PRKACB), phospholipase A2 group XIIB (PLA2G12B), calmodulin 1 (CALM1), calmodulin 2 (CALM2), and interleukin-18 (IL18), which have harmful effects, were downregulated following SYN treatment. In dogs treated with PL, genes including PRKACB and CALM2 were upregulated, while other genes, such as FGF2, FGF10, SynGAP1, RASGRP2, RASGRP3, and IL21R, were downregulated. Dogs with CIE have colonic ultrastructural pathology at diagnosis, which improves following synbiotic treatment. Ultrastructural improvement is associated with an upregulation of protective genes and a downregulation of harmful genes that mediate their effects through multiple signaling pathways. Full article

Autism spectrum disorder is a complex and diverse neurobiological condition. Understanding the mechanisms and causes of the disorder requires an in-depth study and modeling of the immune, mitochondrial, and neurological systems. Computational neuroscience enhances psychiatric science by employing machine learning techniques on neural networks, combining data on brain activity with the pathophysiological and biological characteristics of psychiatric–neurobiological disorders. The research explores the integration of neurotransmitter activity into computational models and their potential roles in diagnosing and treating autism using computational methods. This research employs a narrative review that focuses on four neurotransmitter systems directly related to the manifestation of autism, specifically the following neurotransmitters: serotonin, dopamine, glutamate, and gamma-aminobutyric acid (GABA). This study reveals that computational neuroscience advances autism diagnosis and treatment by identifying genetic factors and improving the efficiency of diagnosis. Neurotransmitters play a crucial role in the function of brain cells, enhancing synaptic conduction and signal transmission. However, the interaction of chemical compounds with genetic factors and network alterations influences the pathophysiology of autism. This study integrates the investigation of computational approaches in four neurotransmitter systems associated with ASD. It improves our understanding of the disorder and provides insights that could stimulate further research, thereby contributing to the development of effective treatments. Full article

Mild traumatic brain injury (mTBI), a leading cause of disability in young adults, often results from external forces that damage the brain. Cellularly, mTBI induces oxidative stress, characterized by excessive reactive oxygen species (ROS) and diminished antioxidant capacity. This redox imbalance disrupts hippocampal glutamatergic transmission and synaptic plasticity, where NMDA receptors (NMDARs) are crucial. The exocyst, a vesicle tethering complex, is implicated in glutamate receptor trafficking. We previously showed that Exo70, a key exocyst subunit, redistributes within synapses and increases its interaction with the NMDAR subunit GluN2B following mTBI, suggesting a role in GluN2B distribution from synaptic to extrasynaptic sites. This study investigated whether Exo70 could mitigate mTBI pathology by modulating NMDAR trafficking under elevated oxidative stress. Using a modified Maryland mTBI mouse model, we overexpressed Exo70 in CA1 pyramidal neurons via lentiviral transduction. Exo70 overexpression prevented mTBI-induced cognitive impairment, assessed by the Morris water maze. Moreover, these mice exhibited basal and NMDAR-dependent hippocampal synaptic transmission comparable to sham animals, preventing mTBI-induced deterioration. Preserved long-term potentiation, abundant synaptic GluN2B-containing NMDARs, and downstream signaling indicated that Exo70 overexpression prevented mTBI-related alterations. Our findings highlight Exo70’s crucial role in NMDAR trafficking, potentially counteracting oxidative stress effects. The exocyst complex may be a critical component of the machinery regulating NMDAR distribution in health and disease, particularly in pathologies featuring oxidative stress and NMDAR dysfunction, like mTBI. Full article

Background: Basolateral amygdala (BLA) deep brain stimulation (DBS) has been shown to alleviate the symptoms of post-traumatic stress disorder (PTSD), but the specific mechanisms remain incompletely understood. The hippocampus, a brain region closely connected to the amygdala, plays a key role in the pathological processes of PTSD. The N6-methyladenosine (m⁶A) methylation of RNAs in the hippocampus is known to play a significant role in regulating the brain’s response to stress and emotional disorders. Methods: This study aimed to comprehensively analyze the roles of transcriptome-wide m⁶A modifications of the hippocampus in the BLA DBS treatment of a PTSD mouse model using m⁶A sequencing. Results: Significant alterations in functional connectivity between the ventral hippocampus (vHPC) and BLA were observed in foot shock (FS) mice through functional magnetic resonance imaging (fMRI) analysis. Furthermore, we observed that the expression of the key m⁶A methyltransferase enzyme, METTL3, in the FS and BLA DBS groups was higher than that in the control group. At the same time, both FS and BLA DBS induced the widespread m⁶A methylation of RNAs in the vHPC. Gene ontology (GO) enrichment analysis revealed that FS altered methylation in metabolic, developmental, and cytoskeletal pathways, while BLA DBS targeted metabolic, cell cycle, and neuroplasticity-related genes. Additionally, BLA DBS reversed the aberrant methylation of genes associated with multiple functional pathways induced by FS, including those related to cholinergic transmission, sodium and calcium ion homeostasis, and stress hormone responsiveness. We identified a set of RNAs with methylation changes that were reversed by BLA DBS in the FS vs. Ctrl (control) comparison, including those associated with cholinergic transmission, sodium and calcium ion balance, and stress hormone response. Additionally, we detected several specific BLA DBS-related genes through MeRIP-qPCR, indicating that DBS influences crucial genes linked to calcium signaling and synaptic plasticity. Conclusions: We draw two conclusions from these findings: BLA DBS may alleviate PTSD-like symptoms by reversing FS-induced methylation changes and by altering the methylation levels of crucial genes. These findings indicate that epigenetic m⁶A modifications in the vHPC may play an important role in the amelioration of PTSD using BLA DBS. Full article

The adrenergic system plays an active role in modulating synaptic transmission in hypothalamic neurocircuitry. While α2-adrenergic receptors are widely distributed in various organs and are involved in various physiological functions, their specific role in the regulation of energy metabolism in the brain remains incompletely understood. Herein, we investigated the functions of α2-adrenergic receptors in the hypothalamus on energy metabolism in mice. Our study confirmed the expression of α2-adrenergic receptors in hypothalamic dopaminergic neurons and assessed metabolic phenotypes, including food intake and energy expenditure, after treatment with guanabenz, an α2-adrenergic receptor agonist. Guanabenz treatment significantly increased food intake (0.25 ± 0.03 g vs. 0.98 ± 0.05 g, p < 0.001) and body weight (−0.1 ± 0.04 g vs. 0.33 ± 0.03 g, p < 0.001) within 6 h post-treatment. Furthermore, guanabenz markedly elevated energy expenditure parameters, including respiratory exchange ratio (RER, 1.017 ± 0.007 vs. 1.113 ± 0.03, p < 0.01) and carbon dioxide production (1.512 ± 0.018 mL/min vs. 1.635 ± 0.036 mL/min, p < 0.05), compared to vehicle-treated controls. Furthermore, using chemogenetic techniques, we demonstrated that the altered metabolic phenotypes induced by guanabenz treatment were effectively reversed by inhibiting the activity of dopaminergic neurons in the hypothalamic arcuate nucleus (ARC) using a chemogenetic technique. Our findings suggest functional connectivity between hypothalamic α2-adrenergic receptor signals and dopaminergic neurons in metabolic controls. Full article

Understanding the distribution of electrical potential within neurons is critical for advancing our comprehension of neuronal signaling and communication. Neurons, the fundamental units of the nervous system, rely on complex electrochemical processes to transmit information. The intricate structure of neurons, especially those with multiple dendrites, plays a crucial role in how these electrical signals are generated, propagated, and integrated. Despite significant progress in neuroscience, accurately modeling the electrical potential within neurons with elaborate dendritic architectures remains a challenge. This article introduces a novel approach to modeling the electrical potential in multi-dendritic neurons using Bessel functions, which offers a more precise and detailed representation of these processes. The proposed method involves solving the electric potential diffusion equation in cylindrical coordinates, a mathematical framework that naturally aligns with the geometry of dendrites. The radial and axial components of the solution are expressed using Bessel functions and sinusoidal functions, respectively. Bessel functions are particularly well-suited for this purpose due to their ability to describe waveforms in cylindrical systems, making them ideal for capturing the spatial variations in electrical potential within the cylindrical shape of dendrites. By leveraging this mathematical approach, we obtain a complete representation of the potential distribution across the neuron, from the soma (cell body) through the dendrites to the synaptic terminals. This model accurately captures the spatial variations of electrical potential in different regions of the neuron, including areas with complex dendritic arborizations, which are branching structures that significantly influence the neuron’s electrical characteristics. Simulation results underscore the effectiveness of this approach in reproducing realistic neuronal behavior. The model successfully mimics the way electrical signals propagate and interact within dendritic structures, providing crucial insights into the underlying mechanisms of signal integration and transmission in neurons. Full article

Sensory signals generated by peripheral nociceptors are transmitted by peptidergic and nonpeptidergic nociceptive primary afferents to the superficial spinal dorsal horn, where their central axon terminals establish synaptic contacts with secondary sensory spinal neurons. In the case of suprathreshold activation, the axon terminals release glutamate into the synaptic cleft and stimulate postsynaptic spinal neurons by activating glutamate receptors located on the postsynaptic membrane. When overexcitation is evoked by peripheral inflammation, neuropathy or pruritogens, peptidergic nociceptive axon terminals may corelease various neuropeptides, neurotrophins and endomorphin, together with glutamate. However, in contrast to glutamate, neuropeptides, neurotrophins and endomorphin are released extrasynaptically. They diffuse from the site of release and modulate the function of spinal neurons via volume transmission, activating specific extrasynaptic receptors. Thus, the released neuropeptides, neurotrophins and endomorphin may evoke excitation, disinhibition or inhibition in various spinal neuronal populations, and together with glutamate, induce overall overexcitation, called central sensitization. In addition, the synaptic and extrasynaptic release of neurotransmitters is subjected to strong retrograde control mediated by various retrogradely acting transmitters, messengers, and their presynaptic receptors. Moreover, the composition of this complex chemical apparatus is heavily dependent on the actual patterns of nociceptive primary afferent activation in the periphery. This review provides an overview of the complexity of this signaling apparatus, how nociceptive primary afferents can activate secondary sensory spinal neurons via synaptic and volume transmission in the superficial spinal dorsal horn, and how these events can be controlled by presynaptic mechanisms. Full article

Aloe vera has garnered significant scientific and commercial attention due to its multifaceted therapeutic and cosmetic potential. This study aimed to investigate the biological effects and molecular mechanisms of Aloe vera phytoplacenta extract (AVPE) on HaCaT cells and skin health. To achieve this, we investigated AVPE, produced using advanced in vitro cell culture techniques, and its effects on HaCaT cells. At 2% concentration, AVPE demonstrated remarkable biological effects, increasing AQP3 protein expression by 120% and healing area fourfold while simultaneously reducing COX-2 messenger RNA (mRNA) by 43% and iNOS mRNA by 48%. An AVPE-containing product notably reduced facial skin temperature to 24.9 °C compared to 32.3 °C for the control product. RNA-sequencing (RNA-seq) analysis of transcriptional changes in HaCaT cells after AVPE treatment revealed 14 upregulated and 58 downregulated RNAs. Upregulated processes included response to hydrogen peroxide and muscle cell migration, while downregulated processes involved cell–cell adhesion and synaptic transmission. Pathway analysis further highlighted significant metabolic changes, including upregulation of pentose phosphate and galactose metabolism pathways and downregulation of the leishmaniasis and GABAergic synapse pathways. In addition, gene expression data indicated subtle changes in epidermal differentiation genes, modulation of inflammatory markers, and alterations in genes related to cell signaling and skin-specific functions. Our comprehensive findings underscore AVPE’s potential in enhancing skin healing, regulating temperature, and modulating cellular processes. Full article

Royal jelly (RJ) has long been considered a crucial dietary component in dictating caste differentiation in honeybees. As a nutritional additive, royal jelly imparts a broad range of benefits to mammals and humans; however, its precise impact on the social hierarchy of these advanced animals is not yet fully understood. This study aims to determine whether the benefits of royal jelly can be transferred to rats to alter their social ranks and uncover the underlying mechanisms. A submissive model was established by inducing dysbiosis in rats, via the persistent exposure of vancomycin. Royal jelly at a dose of 2.5 g/kg was daily administered to the subject rats during postnatal weeks (PNW) 6 and 7. At the end of the intervention, animals were subjected to agonistic, water and tube competition tests, in order to assess their dominance status. As revealed by the results, the RJ treatment significantly improved the social rank of the dysbiotic rats, demonstrating that RJ can elicit positive effect on the social behaviors (caused by dysbiosis) of rats. All behavioral paradigms yielded consistent results, with no notable differences in body weight or anxiety levels. Regarding gut microbiome, vancomycin exposure caused the dysbiosis of the subject rats, which was partially reversed by treatment with royal jelly. Specifically, the intestinal presence of Proteobacteria was profoundly attenuated by the RJ supplementation, resulting in a comparable level with the intact/dominant rats. At the genus level, both Escherichia and Clostridium displayed similar dynamics in relation to Proteobacteria, implying their involvement with the RJ-mediated dominance switching. Transcriptomic analysis in the medial prefrontal context showed that the expression of a broad range of genes was influenced by RJ intake, embodying various pathways related to neuronal transmission such as neuroactive ligan–receptor interaction, the synaptic vesicle cycle, etc. By virtue of correlation analysis, Escherichia, Akkermansia and Clostridium were strongly associated with a set of gene modules around gastrin releasing peptide (Grp) and signaling pathways around Rps6ka3, establishing an intrinsic gut–brain communication. Furthermore, the infection trials of Escherichia significantly degraded the social ranks of the RJ-remedied rats in tube tests, while a series of cerebral genes like Grpr and Grpel1, as well as prefrontal spine density, were concordantly altered, underscoring the critical role of the gut–brain link in deciding the outcomes of the dyadic contests. In summary, this is an intriguing example of how royal jelly can influence the social ranks of mammals, emphasizing the importance of microbe–host interaction in mediating this species-spanning function of royal jelly in shaping social hierarchy. Full article