Lipid droplets are highly dynamic organelles in nerve cells and are essential for the function of the central nervous system. The abnormal accumulation of lipid droplets in dopaminergic neurons, found in Parkinson's disease (PD) cells and animal models, presents as a promising target for PD diagnosis. However, previously reported fluorescent probes are unsuitable for in vivo long-term tracking of lipid droplets, limiting their applications in animal models of PD. Here, we developed three lipid droplet-targeted probes, named s-CBTA, b-CBTA, and LD-b-PBTA, which share similar chemical structures but exhibit distinct staining properties in cells. Both s-CBTA and b-CBTA stained lipid droplets as well as other membrane structures, but the majority of these molecules were largely excluded by live cells within 24 h. In contrast, LD-b-PBTA exclusively targeted lipid droplets and was retained well in live cells for 72 h. LD-b-PBTA was successfully used for long-term monitoring of the abnormal accumulation of lipid droplets in cultured dopaminergic neurons following rotenone treatment. Furthermore, LD-b-PBTA detected lipid droplet accumulation in dopaminergic neurons both in fresh substantia nigra tissue and in fixed tissue sections from PD animal models. Most importantly, abnormal lipid droplet accumulation in the substantia nigra of living PD animals was successfully revealed using LD-b-PBTA. Together, these results suggest that the LD-b-PBTA probe has great potential for application in the clinical diagnosis of PD.

Linalool, a major bioactive compound of lavender essential oil, has been reported to produce analgesic and anxiolytic effects when delivered through olfactory pathways. However, the molecular and structural mechanisms remain unclear. In this study, we investigated behavioral, transcriptomic, and morphological changes in the piriform cortex (Piri) following linalool odor exposure in a CFA-induced inflammatory pain model. Behavioral assessments showed that daily 10-min linalool exposure for 8 consecutive days produced progressive and sustained analgesic effects, as indicated by increased mechanical withdrawal thresholds and prolonged thermal withdrawal latencies. Linalool exposure also reduced anxiety-like behaviors in the open field test and elevated zero maze without affecting locomotor activity. Transcriptomic analysis of Piri tissues revealed 496 differentially expressed genes between linalool-exposed and control mice. Functional enrichment analysis indicated that these genes were primarily involved in neural signal transduction, neurotransmitter release, synaptic function, and behavioral regulation. Several genes associated with vesicle trafficking and neuronal communication, including Hap1, Baiap3, and Sytl4, were significantly upregulated. Golgi staining revealed increased dendritic branching complexity and spine density in pyramidal neurons of the Piri, particularly a selective increase in stubby spines, indicating enhanced synaptic structural plasticity. Collectively, these findings demonstrate that repeated linalool odor exposure produces sustained analgesic and anxiolytic effects accompanied by transcriptional remodeling and synaptic structural plasticity in the Piri. These results provide molecular and structural evidence supporting a potential role for olfactory cortical plasticity in odor-induced modulation of pain.

INTRODUCTION:Preserving adult hippocampal neurogenesis alleviates cognitive deficits in Alzheimer's disease (AD), yet how biophysical alterations in such as stiffness in the neurogenic niche regulate neurogenesis remains unclear. METHODS:Stiffness in the hippocampal dentate gyrus subgranular cell zone (SGZ) of 5×FAD mice was measured using atomic force microscopy. Extracellular matrix (ECM) components in mice and AD patients were profiled through proteomics. Hydrogels were supplemented in the SGZ to upregulate local stiffness in wildtype mice, while glycosaminoglycanases was injected to downregulated stiffness in 5×FAD mice. Gene expression in the neurogenic lineage was analyzed through single nucleus sequencing. Conditional knockdown or overexpression of mechanosensors and/or Yes-associated protein 1 (YAP1) were achieved using viral vectors. RESULTS:We found SGZ stiffening occured early in 3-month 5×FAD mice, associating with ECM remodeling and neurogenesis impairment. Upregulation of tissue stiffness in the SGZ of wild-type mice via supplementing high-density hydrogel suppressed neurogenesis, whereas downregulaion of the niche stiffness in AD mice using hyaluronidase-1 (HAase1) and other glycosaminoglycanases preserved neurogenesis. Single-nucleus transcriptomics reveals that the HAase1 treatment reshaped transcriptome of the neural stem cells (NSCs) lineage. Specifically, we found that the integrin-YAP1 mechanotransduction axis played important roles in the stiffness-induced neurogenesis deficits. Conditional knockdown of both integrin β1 and YAP in the NSC lineage mitigated stiffness-induced deficits. Consistently, the association of ECM remodeling and neurogenesis impairments were also observed in post mortem AD patients. DISCUSSION:ECM stiffness plays as a critical regulator of hippocampal neurogenesis, providing potential targets for pro-neurogenic therapeutics of AD.

Olfactory dysfunction has emerged as a promising target for the early diagnosis and treatment of Alzheimer’s disease (AD). However, the mechanisms underlying neural circuit disruption associated with olfactory dysfunction in AD remain poorly understood. We conducted single-cell RNA sequencing (RNA-seq) and ex vivo electrophysiological studies to determine the link between olfactory memory in AD and dynamic synaptic transmission disorders in PCx-IL engram cell circuits. Clinical functional magnetic resonance imaging (fMRI) data revealed that connectivity between the piriform cortex (PCx) and the infralimbic cortex (IL) was impaired during the early mild cognitive impairment (MCI) stage of AD. Optogenetic stimulation of IL-projecting PCx engram neurons successfully improved olfactory memory retrieval in 5xFAD mice. In addition, single-cell RNA sequencing was employed to investigate the mechanisms of damage in IL engram cells, which revealed increased glutamate expression and impaired synaptic function as key alterations. Guided by single-cell sequencing data, we analyzed glutamatergic synaptic transmission in the PCx-IL engram cell circuit in 5xFAD mice. These results indicated dynamic impairments in AMPA receptor-associated synaptic transmission within this circuit. Optical long-term potentiation (LTP) of synaptic transmission restored directional engram synaptic transmission and prevented olfactory memory decline. Therefore, dynamic impairment of synaptic transmission in the PCx-IL engram cell circuit underlies the early decline in olfactory memory in AD. Impairment of PCx-IL functional connectivity may represent a new target for the diagnosis and treatment of early-stage AD.

Background Oral numbing (Má, Chinese) sensation is a distinctive form of food-related chemesthesis mediated by the trigeminal nervous system and plays a critical role in shaping flavor perception, eating experience, and consumer preference. Although widely present in spices and botanical foods, the material basis, sensory characteristics, and physiological mechanisms underlying numbing perception remain incompletely understood, limiting its rational application in food science and functional foods. Scope and approach This review systematically summarizes recent advances in oral numbing research, covering the chemical classes of numbing-active compounds, analytical and isolation techniques, sensory evaluation methodologies, and emerging sensor and biosensor technologies. Particular emphasis is placed on the molecular and neurophysiological mechanisms of numbing perception, focusing on the roles of TRP channels and KCNK channels in peripheral signal transduction. Key findings and conclusions Current evidence indicates that oral numbing sensation is a complex multimodal process involving the coordinated regulation of TRPA1, TRPV1, and KCNK channels and trigeminal neural pathways. Advances in electronic tongues, biosensors, and neuroimaging techniques have improved the objective characterization of numbing perception. Beyond their sensory functions, numbing compounds exhibit diverse biological activities, including anti-inflammatory, neuroprotective, metabolic regulatory, and anticancer effects, highlighting their potential applications in functional foods and flavor modulation. This review provides an integrated framework linking chemical composition, sensory perception, neural mechanisms, and physiological functions, and outlines future opportunities for objective evaluation and health-oriented food development.

Autism spectrum disorder (ASD) is a neurodevelopmental condition clinically defined by persistent social deficits and restricted, repetitive behavior. Several other neurodevelopmental disorders exhibit these core clinical features of ASD and are therefore classified as "syndromic ASD". Although neurons have been the primary research focus on ASD and associated syndromes, accumulating evidence highlights astrocytes as critical contributors to disease mechanisms. Astrocytes are essential for regulating synapse development, neurotransmitter balance, and neuroinflammation in the brain. In this review, we integrate evidence from studies in human tissues, patient-derived induced pluripotent stem cells and organoids, and animal models to establish a robust link between astrocytic dysfunction and ASD and associated syndromes. By systematically examining key astrocytic functions, we elucidate mechanistic pathways through which astrocytic dysregulation contributes to aberrant synaptogenesis, disrupted ion and neurotransmitter homeostasis, maladaptive neuroinflammatory signaling, and impaired metabolic coupling in ASD and associated syndromes. Finally, we discuss the potential of various astrocyte-targeted interventions, which hold promise for advancing precision medicine approaches to these devastating disorders.

Dietary capsaicin intake appears to affect the pathogenesis of Alzheimer's disease (AD), while the underlying mechanisms remain unclear. Here, we found in human cohorts that moderate-to-high level of dietary capsaicin intake was associated with improved cognitive performance. Similarly, long-term oral capsaicin administration in male 5×FAD mice ameliorated AD-like pathologies and reshaped gut microbial composition. Gut microbiota transfer from capsaicin-treated mice produced similar effects of capsaicin intake. Moreover, capsaicin elevated the level of host 24(S)-hydroxycholesterol (24-HC), relating to the increase of gut Oscillibacter genus abundance. The 24-HC elevation enhanced microglial phagocytic activity in the brain, and inhibited proinflammatory factors production via liver x receptor β (LXRβ)-mediated transcriptional regulation. Finally, we observed elevation of 24-HC in plasma in AD patients with higher level of dietary capsaicin intake, which correlated with cognitive scores and plasma Aβ and p-tau biomarkers. These findings suggest the potential of capsaicin or capsaicin-rich diets in the prevention or treatment of AD and related diseases.

Pain perception is a multidimensional process encompassing sensory, affective, and cognitive components. In recent years, accumulating evidence suggests that olfactory stimulation can modulate pain perception through neurophysiological and emotional mechanisms. However, systematic understanding of how olfactory processing contributes to analgesia across different experimental and clinical contexts remains limited. This review aims to provide an integrative overview of current evidence regarding the role of olfactory pathways in pain modulation, summarizing findings from human and animal studies that investigated the analgesic potential of volatile compounds. A systematic literature search was conducted across PubMed, Web of Science, OVID, Cochrane Reviews, Embase, CNKI, and WanFang databases. A total of 4360 records were retrieved, screened for relevance, and refined to 147 studies, including 138 human-based and 9 animal-based investigations. Lavender, peppermint, chamomile, bergamot, and citrus-derived oils were most frequently associated with analgesic outcomes. Olfactory stimulation was found to modulate pain via central integrative circuits involving affective, autonomic, and sensory processing, engaging conserved pathways that support descending pain inhibition. Olfactory stimulation by specific flavor and fragrance compounds holds translational potential for non-pharmacological pain management. Nevertheless, methodological standardization and mechanistic validation are necessary to advance this emerging field.

Background Human Olfactory receptors (ORs) play a central role in odor perception and food flavor recognition, directly influencing consumer preferences and dietary behavior. However, the majority of human ORs remain orphaned, limiting our understanding of olfactory mechanisms and their practical applications in food science and health. Scope and approach This review summarizes recent developments in OR deorphanization. It covers OR structure and classification, available data resources, and advances in machine learning techniques and modern bioanalytical tools for identifying OR-ligand pairs. Key findings and conclusions Machine learning-based prediction models and structural biology have significantly improved the accuracy and interpretability of OR-ligand identification. Meanwhile, improved OR expression systems and functional assays have enhanced ligand validation. OR-based biosensors offer promising applications in rapid food quality assessment. These combined approaches contribute to a deeper understanding of odor perception and support practical applications in food quality evaluation, sensory enhancement, and the development of functional ingredients.

Tobacco biomass constitutes a substantial yet underexploited lignocellulosic resource with considerable potential for bioconversion. However, its efficient enzymatic utilization is constrained by pronounced structural heterogeneity and the presence of diverse non-structural inhibitory components. This review provides a comprehensive overview of tobacco lignocellulose, emphasizing how tissue-specific variations in cellulose, hemicellulose, lignin, and other cell wall components influence enzyme accessibility and catalytic efficiency. Particular attention is given to tobacco-derived inhibitory compounds, including alkaloids, polyphenols, and pigments, which impair enzymatic hydrolysis through multiple mechanisms. Unlike previous reviews on lignocellulose hydrolysis, this review further summarizes recent advances in inhibitor transformation, enzyme engineering to enhance inhibitor tolerance and degradation activity, and enzymatic system optimization. Looking forward, the integration of advanced metagenomic screening and artificial intelligence-driven design is expected to accelerate the development of more robust lignocellulolytic enzymes with enhanced resistance to inhibitory compounds. Collectively, these insights provide a mechanistic basis for efficient and sustainable utilization of tobacco biomass.

Pain is a complex sensory and affective experience regulated by distributed neural circuits that integrate internal physiological states with external stimuli. Orexinergic neurons, a widely projecting neuronal population within the lateral hypothalamus (LH), play a central role in this process. This review synthesizes current evidence on the involvement of LH orexinergic neurons in nociceptive regulation and highlights their role as a key integrative substrate for non-pharmacological analgesia. Orexin peptides (orexin A and orexin B) modulate both the sensory-discriminative and affective-motivational components of pain via their receptors (OX1R and OX2R) in a context-dependent manner, producing antinociceptive or pro-nociceptive effects depending on peptide subtype, receptor distribution, circuit architecture, and pain modality. In parallel, emerging evidence indicates that orexinergic neurons are critically engaged in diverse non-pharmacological analgesic paradigms, including stress-induced analgesia, olfactory modulation, electroacupuncture, and exercise-induced hypoalgesia. In addition, other neuronal populations within the LH, such as glutamatergic, GABAergic, and neurotensinergic neurons, also contribute to pain regulation in a circuit-specific manner and partially overlap anatomically and functionally with orexinergic neurons. Collectively, these findings position LH orexinergic neurons as a central node linking neural circuit dynamics with the behavioral and physiological modulation of pain. Targeting orexin-related pathways may therefore provide novel avenues for the development of non-pharmacological and integrative pain management strategies.

Nicotinic acetylcholine receptors (nAChRs) are a family of pentameric ligand-gated ion channels with diverse subunit compositions and subtype-specific functional profiles, such as in neurotransmission and inflammatory modulation. The central involvement of nAChRs in neurological and psychiatric disorders has these receptors as compelling therapeutic targets, especially for nicotine addiction, Alzheimer's disease, schizophrenia, attention-deficit/hyperactivity disorder, and pain disorders. Recent advances in nAChRs structural biology have revealed detailed mechanisms of ligand binding at orthosteric and allosteric sites, and rational drug design leveraging natural toxin-derived peptides and small molecules have yielded many nAChR subtype-selective agonists, antagonists, and allosteric modulators. Despite clinical success with some candidate drugs like nicotine patch and varenicline for smoking cessation, broader therapeutic application has been limited by challenges in receptor selectivity, desensitization, and off-target effects. Here, we provide a concise overview of nAChR structural biology, outline the physiological and pathological significance of distinct receptor subtypes, and offer a comprehensive review of the progress in the discovery of nAChR-targeting ligands, either of natural toxins or small molecules, in preclinical conditions and their advances in clinical trials. We also discuss the prevailing challenges while underscoring emerging opportunities for future therapeutic innovation.

Sensory peptides are short-chain peptides with flavor characteristics or affecting flavor effects.Beyond their advantages of diverse sources,high bioavailability,and safety,certain peptides exhibit physiological regulatory functions.Firstly,the four stages of research on sensory peptides were summarized.The initial stage was the 1950s to the 1970s,when sensory peptides were isolated from natural food materials and their artificial synthesis was achieved.The rapid development stage was the 1980s to the 1990s,when analytical techniques and taste receptor research were used to systematically explore the structure-activity relationship and sensory evaluation methods.The process and application stage took place in the first decade of the 21st century,when the focus was placed on the optimization of enzymatic hydrolysis processes and the development of compound condiments to promote industrialization.And the multi-functional and precision stage has continued from 2010 to the present,when artificial intelligence and green manufacturing were combined to expand the high-throughput screening of sensory peptides and their nutritional and health functions.Secondly,by integrating multi-source databases and conducting systematic literature mining,a standardized dataset covering 781 sensory peptides was constructed from dimensions including screening strategies and information,inclusion principles of sensory peptides,standardized database category information,taste types,chain lengths,molecular weights,sources,and processing technologies.Their taste-type distribution,sequence characteristics,and source discovery were comprehensively analyzed to map current research landscapes.Furthermore,182 sensory peptides with clear bioactivity reports were screened through high-throughput sequence alignment,and their sensory types,bioactivities,and"sensory-bioactivity"distribution characteristics were summarized.The research paradigms for three high-frequency bioactivities,ACE inhibition,DPP-Ⅳ inhibition,and antioxidant effects,were systematically summarized.This study aimed to provide multi-dimensional database support for the sensory peptide industry and offer a reference for the synergistic study of"flavor-function"dual attributes of sensory peptides.

Dopamine (DA) is a key neurotransmitter that regulates neuropsychological behaviors, including movement, emotion, motivation, and cognition. Dysregulation of dopaminergic signaling is linked to psychiatric and neurodegenerative disorders, including Parkinson's disease, depression, and schizophrenia. The dopamine transporter (DAT) controls DA levels by facilitating its reuptake from the synaptic cleft, terminating dopaminergic signaling. Here, we report structures of full-length human DAT (hDAT) in its apo state and in complexes with substrates and antidepressant compounds. The antidepressant compounds bupropion and vanoxerine bind to the central site of hDAT and inhibit substrate transport. Integration of structural analysis with functional assays and molecular dynamics simulations further suggests a role for potassium ions in regulating hDAT conformational transitions. Our findings reveal the molecular mechanisms governing DA reuptake and the specific ways in which hDAT interacts with antidepressant compounds. These insights provide a structural basis for the design of therapeutic agents targeting hDAT.

How the chemical structures of odorant molecules determine biologically oriented behaviors remains a central challenge at the intersection of food informatics and biology. To identify structural features of odorant molecules that are associated with mouse first-encounter approach-avoidance responses, this study used a published human flavor semantic descriptor database only as a stratification tool to select a semantically diverse set of odorants; the behavioral labels came from the mice's own first-encounter approach-avoidance responses. By integrating multidimensional molecular representations with machine learning algorithms, we established a predictive method for odor-driven behavioral preference. The results showed that, among the prespecified model-representation pipelines evaluated in this study, the Logistic Regression model based on structural keys and physicochemical descriptors achieved the highest mean F1-score (0.812 ± 0.016). Model interpretability analysis indicated that ester groups, aromatic rings, ethers, and branched carbon motifs were more likely to be associated with approach behavior, whereas thioethers, sulfur-containing heterocycles, disulfides, and certain carbonyl/heteroatom environments were more likely to be associated with avoidance behavior. Behavioral experiments using structural analogs provided supporting evidence for an association between local structural modification and shifts in first-encounter approach-avoidance behavior in mice. This study establishes an interpretable olfactory prediction methodology. This methodology provides an interpretable computational framework to support the screening and prioritization of candidate odorant molecules and may inform subsequent human sensory evaluation and product-level validation.

Taste perception governs dietary selection, with alkaline sensation playing a pivotal role in food avoidance. In Drosophila, a chloride channel named alkaliphile (Alka) is both necessary and sufficient for aversive taste responses to alkaline food. In this study, we resolved the high-resolution structure of Alka. Alka forms a homopentameric complex, with each subunit comprising four transmembrane helices. Residues P276, T280, and T284 were indicated as key regulators of channel gating. Guided by the structure, we performed molecular docking screening followed by surface plasmon resonance (SPR) validation, identifying three representative ligands that specifically interact with Alka. SPR analysis of Alka mutants confirmed that P276 is essential for ligand recognition, whereas T280 and T284 selectively affect ligand interactions. We also explored the binding dynamics between Alka and ligands. This study elucidates the molecular mechanisms underlying ligand binding and channel gating, providing a theoretical foundation for future studies on alkaline taste perception.

AIMS:Aromatherapy-mediated analgesia is widely applied, but the underlying neural mechanisms remain poorly understood. This study aimed to investigate the neurobiological basis underlying linalool-induced attenuation of inflammatory pain. METHODS:A complete Freund's adjuvant (CFA)-induced hind-paw inflammatory pain model was used to evaluate the antinociceptive effects of linalool odor exposure through mechanical and thermal nociceptive threshold tests, together with conditioned place preference. Viral tracing, in vivo fiber photometry, electrophysiological recordings, and chemogenetic or optogenetic manipulations were employed to identify and functionally characterize the neural circuits underlying linalool-induced analgesia. RESULTS:Linalool odor exposure increased mechanical and thermal nociceptive thresholds and induced pain relief-associated place preference in CFA mice. Linalool exposure activated orexin A-expressing neurons in the lateral hypothalamus (LHorexin A) and LH-projecting glutamatergic neurons in the piriform cortex (PiriGlu-LH). Electrophysiological recordings demonstrated functional excitatory monosynaptic connectivity from the Piri to the LH. Activation of LH-projecting PiriGlu neurons produced analgesic effects in CFA mice, whereas inhibition of this pathway attenuated linalool-induced analgesia. CONCLUSION:Our study identified an olfactory cortex-hypothalamic circuit contributing to linalool-induced antinociceptive effects, providing mechanistic insight into olfactory modulation of inflammatory pain.

Nicotine withdrawal-induced anxiety is a key contributor to the return to cigarette smoking. Cordycepin, an adenosine analogue, is hypothesized to counteract the withdrawal-induced decline in hippocampal AMP/ATP ratios and consequent AMP-activated protein kinase (AMPK) dephosphorylation, as its monophosphate derivative structurally mimics AMP and directly activates AMPK. In this study, a mouse model of chronic nicotine exposure followed by withdrawal was used to investigate whether cordycepin mitigates nicotine withdrawal-induced anxiety and its underlying mechanisms. Our results revealed that chronic nicotine exposure significantly elevated hippocampal AMPK phosphorylation, whereas nicotine withdrawal led to a sharp decline in p-AMPK levels (p-AMPK/t-AMPK: F = 23.11, P < 0.001), concomitant with pronounced anxiety-like behaviors in the elevated plus maze (open-arm time: F = 16.18, P < 0.01) and open field tests (center time: F = 6.63, P < 0.01). Pretreatment with cordycepin (10 mg/kg) effectively alleviated nicotine withdrawal-induced anxiety-like behaviors (open-arm time: F = 11.74, P < 0.01; center time: F = 5.79, P < 0.01), an effect that was counteracted by the AMPK inhibitor Compound C. Further mechanistic studies via Western blot and immunohistochemical analyses demonstrated that cordycepin activated the hippocampal AMPK/CREB/BDNF signaling pathway, restoring withdrawal-induced reductions in p-AMPK, p-CREB, and BDNF expression. This effect was further validated in PC12 cell experiments. In conclusion, cordycepin alleviates nicotine withdrawal-induced anxiety by activating the AMPK/CREB/BDNF pathway, offering preliminary experimental evidence for its potential as an adjunctive therapy for smoking cessation.