Fear memory (FM) is a neurophysiological process regulated by diverse neural cell populations and closely linked to general memory function. However, the precise cellular and molecular mechanisms underlying FM remain insufficiently understood. In this study, spatial transcriptomic data from four sagittal mouse brain sections obtained from 10xGenomics were systematically analyzed. Cell2location deconvolution was applied to characterize cellular composition and identify key cell populations associated with FM. CellChat and Monocle analyses were used to investigate intercellular communication and cellular activation trajectories during FM progression. Signaling pathways identified utilizing CellChat, together with pathways enriched from hypervariable genes identified by MFUZZ and DESeq2, were analyzed to clarify the molecular basis of FM. To further explore the mechanisms through which FM influences general memory function, key ligands, receptors, transcription factors (TFs), and downstream targets were identified using scMLnet. Spatial transcriptomic analysis revealed extensive interactions among M2 macrophages, astrocytes, oligodendrocytes, and cholinergic neurons during FM, while M1 macrophages and dopaminergic neurons exhibited supportive roles in cellular co-occurrence networks. These interactions mediated autocrine and paracrine transmission through JAM, EPHB, NCAM, NRXN, and AMPK signaling pathways. Among the identified genes, Opalin, Thbs4, and Cyp2j12 emerged as potential biomarkers associated with dominant cellular interactions and were upregulated in FM-related regions. FM-associated molecular alterations may impair memory function through EPH/Ephrin-mediated ligand-receptor interactions that activate TFs, including CREB, E1A-binding proteins, and estrogen receptors, subsequently regulating Ras-related proteins and epidermal growth factor receptors. These findings suggest that estrogen signaling may represent a potential strategy for FM modulation. Astrocytes, cholinergic neurons, M1/M2 macrophages, and oligodendrocytes appear to play central roles in FM regulation. Notably, M1 macrophages may promote the transcriptional transition toward M2 macrophages, thereby contributing to neuroinflammatory resolution. EPHB and NRXN signaling pathways demonstrated prominent regulatory associations with FM, whereas the functional significance of pathways such as JAM requires further investigation. In addition, competitive interactions between FM and general memory processes were closely linked to EPH/Ephrin signaling. Estrogen-mediated regulation may therefore provide a therapeutic avenue for suppressing maladaptive FM, although the underlying mechanisms remain incompletely defined. This study provides a spatially resolved characterization of cellular composition, intercellular communication, and molecular regulation associated with FM. The findings generate new hypotheses regarding the relationship between emotional regulation and memory function, particularly the possibility that FM formation and consolidation compromise general memory processes. Collectively, these results offer new insights into the cellular and molecular neurobiology of FM.

Ketamine and its structural analog, 2-Fluorodeschloroketamine, both potent stimulants, can induce euphoria but also cause neurotoxicity, cognitive decline, and neurodevelopmental deficits in the fetus. However, the molecular mechanisms responsible for these neurodevelopmental abnormalities are not yet fully elucidated, particularly concerning effects that are specific to certain cell types. Human cerebral organoids were used as a model, and single-cell transcriptomics was conducted to evaluate the effects of prenatal exposure to KET or 2-FDCK (30 μM) on fetal brain development. A total of 83,436 cells from both control and treated organoids were analyzed. Key findings were corroborated through the assessment of mitochondrial dysfunction and bioenergetic deficiencies following KET or 2-FDCK exposure in primary cortical neurons isolated from fetal mice. The analysis revealed that the cerebral organoids contained a diverse range of glial and neuronal cell types. Importantly, the findings demonstrated that both substances induced corticalspecific gene expression networks involved in the regulation of mitochondrial oxidative phosphorylation. The results indicated that KET and 2-FDCK exposure can augment mitochondrial fragmentation and oxidative stress, accompanied by a significant decrease in ATP production capacity, thereby increasing the risk of the fetus to neurological diseases through neurodevelopmental damage. Disruptions in energy production during rapid developmental periods can make the offspring more vulnerable to neurological issues. The research highlights how cerebral organoids serve as a valuable tool for studying how substance exposures affect brain development, thereby enhancing the understanding of these important effects. In conclusion, the results offer direct evidence of the neurodevelopmental toxicity associated with KET and 2-FDCK following prenatal exposure, utilizing cerebral organoids as an invaluable translational model. It was recognized that mitochondrial oxidative phosphorylation disruption was a probable primary molecular mechanism. These findings highlight the substantial risks these substances pose to fetal brain development.

This multi-source bibliometric and translational mapping study provides a panoramic synthesis of how research on microglia-mediated spinal pain signaling has evolved from foundational mechanistic studies to clinically oriented innovations. The aim is to identify developmental trajectories, mechanistic hotspots, and translational opportunities, thereby offering strategic insight into guiding the future direction of neuropathic pain research. We analyzed 1313 original research papers from the Web of Science Core Collection (WoSCC; 2005-2024) using CiteSpace and VOSviewer to construct collaboration networks, journal co-citation graphs, and keyword-driven mechanism clustering. To add a translational medicine dimension, we conducted a targeted PubMed search ("microglia AND spinal cord AND (translational OR therapeutic OR drug targets)"), retrieving 692 additional records, enabling cross-database overlay to link mechanistic themes with specific therapeutic targets. The scientometric model indicates that spinal pain research has shifted from primarily descriptive work to more detailed regulatory models. Key themes include glial cell activation, oxidative stress, mitochondrial dysfunction, and changes in microglia state. Research on heat shock protein pathways and sex-related microglial responses is also increasing. Some core terms have remained frequent over the years, such as "neuroinflammation" and "activated protein kinases". In contrast, the explosive emergence of brain-derived neurotrophic factor (BDNF) and spinal cord stimulation (2020-2021; burst intensity = 2.56) indicates a growing interest in synaptic and circuit control and neuromodulation-based approaches. In the PubMed subset, 33.6% of studies directly focused on treatment development, with gene therapy, intrathecal administration, and microenvironment remediation also appearing more frequently. When we combine data from WoSCC and PubMed over the past 20 years, we can see a significant shift in the explanation of spinal pain in this field. Early research often described the problem as "glial cell activation-cytokine release." Recent research, however, focuses on specific pathways, particularly microglial state regulation, oxidative stress-autophagy connections, and kinase signaling. This shift in treatment approaches is also reflected in translational studies. Many studies no longer rely primarily on systemic drugs but instead focus on targeted strategies such as intrathecal administration, gene or cell therapy, extracellular vesicles, and neuromodulation. These trends make polarization-related molecular nodes ideal candidate targets for precision analgesia. However, bibliometric results are dependent on database coverage, keyword processing, and clustering settings. Some "hotspots" may reflect changes in terminology or citation habits rather than true mechanistic importance. The rise of neuromodulation keywords may also reflect broader clinical applications; microglial mechanisms are plausible, but contributions from other circuit-level mechanisms may also play a role. These results indicate that the field is moving beyond a purely inflammatory perspective toward systemic intervention models. Currently, there is a greater focus on microglial homeostasis and M2-like anti-inflammatory/immune repair processes, as well as sex and metabolic factors that may influence responses. This research direction supports immune repair and more personalized analgesia. Simultaneously, stronger mechanistic arguments require cell state-specific measurements rather than broad phenotypic labels.

Cocaine Use Disorder (CUD) poses a major public health challenge, with no Food and Drug Administration-approved pharmacotherapies currently available. A deeper understanding of Morphometric Similarity Network (MSN) alterations and their associations with neurotransmitter systems in CUD may facilitate the development of targeted therapeutic strategies. We aimed to investigate the aberrant MSN patterns and their relationships with neurotransmitter distributions in CUD. This case-control study enrolled 70 patients with CUD and 57 age- and sex-matched healthy controls (HCs). Individual-level MSNs were constructed for each participant, and regional morphometric similarity (MS) strength was computed. Group differences in MSN connectivity and regional MS strength were compared between the CUD and HC groups. The JuSpace toolbox was employed to assess spatial correlations between regional MS alterations and specific neurotransmitter maps. Network-based statistic analysis revealed disrupted MSN connectivity in patients with CUD, primarily involving the prefrontal cortex, striatum, thalamus, frontoparietal control network, and insula. Regional MS strength abnormalities demonstrated significant spatial correlations with the neurotransmitter density distributions of the serotonergic, dopaminergic, glutamatergic, GA-BAergic, and cholinergic systems. These spatial correlations were further associated with CUD severity and weekly cocaine dose. These findings provide novel insights into the neuropathological mechanisms of CUD from the perspectives of gray matter morphometric covariance patterns and neurotransmitter systems. The consistency with existing findings further supports the clinical translational value of the neurotransmitter targets we have identified. Our findings revealed co-altered patterns of gray matter morphometric covariance and neurotransmitter interactions in CUD, providing novel insights into the neuropathological mechanisms of CUD and identifying potential therapeutic targets.

Bipolar Disorder (BD) presents with heterogeneous longitudinal cycling patterns, including Manic-Depressive-free Interval (MDI), Depressive-Manic-free Interval (DMI), and Irregular (IRR) cycles. Studies investigating how these cycle types affect clinical course remain limited. This study aimed to examine a large, well-characterised sample of patients with BD types I (BD-I) and II (BD-II). Life charts were used to determine the type of cycle, collecting information on first affective episode type, hospitalisations (presence or absence), suicidal ideation/attempts, psychiatric family history, seasonality, agitated depression, predominant polarity, and diagnostic subtype (BD-I vs. BD-II). The impact of cycle type on clinical course was analysed through univariate and multivariate models. Of 378 BD patients, 140 (37.0%) had MDI cycles, 92 (24.3%) had DMI cycles, and 146 (38.6%) had IRR cycles. Multivariate analyses showed MDI patients were more likely to have a manic onset compared to DMI and IRR (p < 0.001). They also showed a higher likelihood of hypomanic onset compared to DMI (p < 0.001). Conversely, DMI was associated with a depressive onset relative to MDI and IRR (p < 0.001). Seasonality was more frequent in patients with regular cycles (MDI and DMI) compared to IRR (p < 0.001). Hospitalisations were more frequent in MDI and DMI cycles compared to IRR, but the association survived only for MDI in multivariate analysis. MDI patients had a higher prevalence of manic predominant polarity and lower rates of depressive predominant polarity compared to both DMI and IRR (p < 0.001). A BD-II diagnosis was significantly more frequent in DMI and IRR (p < 0.001), and a BD-I diagnosis was more prevalent in MDI (p < 0.001). Cycle type affected the BD clinical course, with MDI tending to show more frequent hospitalisations, BD-I diagnosis, and manic predominant polarity, while DMI and IRR patients had more BD-II diagnoses. Findings underscore the importance of classifying BD based on cycle patterns and suggest that taking into account these patterns may support more personalised treatment planning and improve clinical outcomes.

Multiple sclerosis (MS) is an immune-mediated and demyelinating disease affecting oligodendrocytes, leading to neurodegeneration. Immunocompromised individuals may have a reduced antibody response after vaccination, and this insufficient immune response in COVID-19 individuals might contribute to the pathophysiology of MS. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds the angiotensin-converting enzyme 2 (ACE2) to entry into the host's cell and infect human cells. Evaluation of the effects of drugs for the treatment of MS, such as fingolimod, cladribine, dimethyl fumarate, and teriflunomide, on the expression of ACE2 in human lung carcinoma cell lines. We used Calu-3 human lung adenocarcinoma cells, physiologically expressing the ACE2 gene, and A549-hACE2-TMPRSS2 human lung carcinoma cells, overexpressing the human ACE2 gene, and challenged them with the pro-inflammatory interleukin-1β (IL-1β) in the presence or absence of MS drugs, and assessed ACE2 mRNA and protein levels. MS drugs affected ACE2 mRNA and protein levels differently in Calu-3 and A549-hACE2-TMPRSS2 cells. Fingolimod (50 nM) significantly reduced ACE2 protein levels under inflammatory conditions in Calu-3 cells. Cladribine reduced ACE2 protein levels in A549-hACE2-TMPRSS2 cells. Dimethyl fumarate increased ACE2 protein levels in Calu-3 cells under both basal and pro-inflammatory conditions. Teriflunomide increased ACE2 protein levels in Calu-3 cells and ACE2 mRNA levels in A549-hACE2-TMPRSS2 cells, both in basal and pro-inflammatory conditions. We incubated cells with drug concentrations similar to those found in the plasma of relapsing-remitting MS patients treated with disease-modifying drugs (DMD), although they act via different mechanisms. Fingolimod acts on sphingosine-1-phosphate receptors and inhibiting class 1 histone deacetylase could suppress ACE2 expression, independently of its immunosuppressive action, or might act at post-transcriptional levels. Fingolimod also stimulates the secretion of neurotrophic factors in the CNS and exerts neuroprotective effects. Data suggest that drugs used in the treatment of MS can modify ACE2 expression; specifically, fingolimod reduces ACE2 expression and may have a protective role against SARS-CoV-2 infection.

Cerebral Small Vessel Disease (CSVD) is a dynamic whole-brain disease, characterized by pathological cascades that affect the brain's venules, capillaries, small arteries, and arterioles. Neuroimaging features of CSVD typically comprise Recent Small Subcortical Infarcts (RSSI), lacunes of presumed vascular origin, White Matter Hyperintensities (WMH) of presumed vascular origin, enlarged Perivascular Spaces (PVS), Cerebral Microbleeds (CMB), and Brain Atrophy (BA). The main clinical features of CSVD often include stroke, abnormal gait, psychiatric disorders, cognitive decline, and urinary incontinence, imposing a heavy burden on individuals and society. Despite its impact, the pathogenesis of CSVD remains unclear, and current clinical diagnosis relies primarily on neuroimaging, presenting considerable challenges for effective treatment. In recent years, most studies have addressed the pathophysiological and molecular mechanisms of CSVD, including chronic cerebral hypoperfusion, inflammatory cascades, oxidative stress, endothelial dysfunction, and Blood-Brain Barrier (BBB) leakage. In addition, genetic factors have been strongly associated with CSVD, though genetic heterogeneity and the complexity of internal environment homeostasis contribute to the persistent uncertainty surrounding its exact mechanisms. A comprehensive overview of these individual mechanisms is crucial for a holistic understanding of the pathogenesis of CSVD. Currently, there is a relative lack of therapeutic drugs and interventions for the complex pathogenesis of CSVD. The existing treatments, such as antihypertensives, antiplatelet agents, lipid-lowering drugs, and hypoglycemic agents, along with traditional alternative therapies like Chinese herbal medicine and acupuncture, have demonstrated efficacy in modulating the occurrence and progression of CSVD. These therapies provide a new perspective for developing more rational CSVD prevention strategies and treatment plans. This review systematically summarizes the cutting-edge research achievements in the field of pathological and physiological mechanisms of CSVD over the past few years, as well as potential treatment pathways and limitations, to provide a theoretical basis and intervention directions for the diagnosis and treatment of this patient population.

Rare diseases, affecting approximately 8% of the global population, remain among the most underserved areas in modern medicine due to their low prevalence, complex genetic origins, and limited commercial incentives for drug development. Rare neurological disorders, in particular, pose formidable challenges owing to their progressive nature and the difficulty of delivering thera-peutics across the blood-brain barrier. This review explores the emerging role of nanomedicine in transforming rare disease management through precision-targeted drug delivery, enhanced bioavail-ability, and the ability to bypass biological barriers. Nanoparticles (NPs)-including PEGylated NPs, lipid-based NPs, polymeric NPs, and hybrid formulations-are being engineered to deliver therapeu-tic agents for gene therapy, enzyme replacement, and RNA interference. These platforms have shown promise in treating conditions such as Krabbe disease, Niemann-Pick type C1, spinocerebel-lar ataxia type 1, and prion diseases. Additionally, nanotherapeutics are being investigated for pulmonary and congenital lung disorders, including cystic fibrosis and idiopathic pulmonary fibro-sis, with improved tissue penetration and reduced systemic toxicity. The review also highlights the potential of AI-integrated diagnostics and personalized nanomedicine to address disease heterogene-ity and improve patient outcomes. Despite these advances, significant barriers remain, including regulatory complexity, high development costs, and limited clinical models. The manuscript calls for collaborative innovation across academia, industry, and regulatory bodies to accelerate clinical translation and ensure equitable access. By bridging molecular innovation with patient-centric care, nanotherapeutics offer a paradigm shift in the diagnosis and treatment of rare diseases, potentially redefining therapeutic landscapes and improving the quality of life for affected individuals.