Objective: Perineural invasion (PNI) is a critical determinant of poor prognosis in laryngeal squamous cell carcinoma (LSCC), but its underlying mechanisms remain unclear. This study aimed to investigate whether LSCC-derived exosomes induce axonal growth by delivering neuroactive molecules, thereby contributing to tumor perineural invasion. Methods: Clinical data from the laryngeal cancer cohort of The Cancer Genome Atlas Head and Neck Squamous Cell Carcinoma (TCGA-HNSC) dataset were analyzed. Propensity score matching (PSM) and Cox regression were used to evaluate the prognostic value of nerve density, and these findings were validated using 35 pairs of laryngeal cancer and adjacent normal tissue specimens collected at Yantai Yuhuangding Hospital between 2022 and 2026 to assess neural morphological changes. Exosomes were isolated from the human LSCC cell line AMC-HN-8, characterized by quality-control assays, and co-cultured with PC12 cells. A rescue experiment using GW4869, a specific inhibitor of neutral sphingomyelinase, was performed to confirm the exosome-dependent effect. Neurite outgrowth was evaluated by immunofluorescence, and the expression of axonal growth-related genes was measured by RT-qPCR. Targeted metabolomics was employed for the absolute quantification of neuroactive metabolites within the vesicles and for pathway enrichment analysis. Results: After PSM adjustment, high nerve density was identified as an independent poor prognostic factor in LSCC patients (HR=2.10, P=0.035), with particularly pronounced prognostic value in the early-stage node-negative (N0) subgroup (HR=4.07, P=0.001). Pathological sections showed high expression of the neural markers βIII-tubulin and PGP9.5 in LSCC tissues (βIII-tubulin: t=2.234, P<0.05; PGP9.5: t=2.575, P<0.05). Exosomes were successfully isolated from AMC-HN-8 cells and passed quality control. In vitro assays showed that LSCC-derived exosomes significantly promoted neurite extension and branching in PC12 cells (t=4.147, P<0.000 1) and upregulated core axonal growth genes, including GAP-43, NEFL, and NEFM (GAP-43: t=3.698, P<0.05; NEFL: t=5.113, P<0.01; NEFM: t=5.263, P<0.01); this effect was completely reversed by the exosome-release inhibitor GW4869 (t=3.535, P<0.001). Targeted metabolomics revealed a specific enrichment of 12 neurotransmitters and metabolites within LSCC exosomes, centered on glutamine (83.411 μmol/L, FC=1.88) and glutamate (18.461 μmol/L, FC=1.21), which were significantly enriched in signaling pathways such as "central carbon metabolism in cancer" and "glutamatergic synapse". Conclusion: Nerve density is a potential adverse prognostic factor in patients with LSCC. LSCC-derived exosomes can directly induce axonal growth in neuron-like cells, suggesting that tumor cells actively remodel the neural microenvironment and drive axonal growth through exosome-mediated long-range signaling.

In Hopfield-type associative memory models, memories are stored in the connectivity matrix and can be retrieved subsequently thanks to the collective dynamics of the network. In these models, the retrieval of a particular memory can be hampered by overlaps between the network state and other memories, termed "spurious overlaps" since these overlaps collectively introduce noise in the retrieval process. In classic models, spurious overlaps increase the variance of synaptic inputs but do not affect the mean. We show here that, in models equipped with a learning rule inferred from neurobiological data, spurious overlaps collectively reduce the mean synaptic inputs to neurons, and that this mean reduction causes in turn an increase in storage capacity through a sparsening of network activity. Our Letter demonstrates a link between a specific feature of experimentally inferred plasticity rules and network storage capacity.

The biological mechanisms behind aggressive and affiliative behaviors are difficult to pinpoint. In the Farm-Fox Experiment, conventional foxes were selectively bred since 1959 in two different directions, one for tame and another for aggressive response to humans. The distinct differences in social behavior of tame, aggressive, and conventional populations are genetically based and the three populations live in conditions that control for factors that could impact social reactions, such as environment and social experiences. Genomic and transcriptomic studies of genetic differences among the fox populations have highlighted genes involved in synaptic processes in the prefrontal cortex. To investigate how the synaptic mechanisms differ between the three fox populations, synaptosomes were isolated from prefrontal and premotor cortex extracts of sixteen female foxes. Tandem mass tags with liquid chromatography tandem mass spectrometry (LC-MS) were used to identify and quantify the relative abundance of the proteins. The results were sorted into protein groups and compared between populations using a limma analysis to determine proteins with differential expression (DE). In the tame versus aggressive comparison, 174 protein groups were found to be DE, while only five were found in the conventional versus aggressive comparison. Most DE protein groups had lower fold expression in the aggressive population compared to tame and aggressive populations. ADGRB2 was found to be the most DE protein group, with 11-fold higher expression in aggressive foxes than in tame foxes. ADGRB2 was previously shown to affect depression-like behavior in mice and is involved in the vascular endothelial growth factor signaling pathway, that is known to influence neurogenesis. Enrichment analyses on the DE protein groups found gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that were enriched in the tame versus aggressive comparison, including multiple, highly enriched terms involving ribosome and translation. Local translation at synapses plays an important role in synaptic plasticity and, as a result, can profoundly influence behavior. This study highlighted potential mechanisms that could underly the behavioral differences between tame and aggressive foxes.

While obesity induces cardio-metabolic disorders and cognitive deficits, the underlying neural mechanisms remain unexplored. In mice, exposure to an obesogenic high-fat and sugar diet (HFD) resulted in social recognition memory deficits in both males and females, a process that is dependent upon hippocampal area CA2 and oxytocin signaling. HFD-fed mice had stronger inputs onto CA2 pyramidal neurons that led to increased action potential firing, without altering intrinsic properties or inhibitory transmission. Chemogenetic CA2 pyramidal neuron inhibition in HFD-fed mice rescued social novelty discrimination, with novelty preference in males and familiarity preference in females. We also observed that HFD in both males and females impaired the ability of oxytocin receptor activation to be permissive for endocannabinoid-mediated plasticity. Furthermore, chemogenetic inhibition of CA2 pyramidal neurons rescued oxytocin-induced endocannabinoid plasticity in both HFD-fed male and female mice, whereas it prevented endocannabinoid plasticity in control diet-fed mice. In a concentration-dependent manner, oxytocin restored potentiation of excitatory responses, allowed for endocannabinoid plasticity at CA2 inhibitory synapses, and rescued social novelty discrimination in HFD-fed mice. This study uncovers mechanisms linking neuromodulation and endocannabinoid-mediated plasticity in social memory processes and reveals the deleterious consequences of an obesogenic diet on this process.

The nervous system relies on billions of neurons connected through trillions of synapses to support vital functions. Despite the importance of this synaptic network, cellular mechanisms dictating synapse formation during human neurodevelopment remain unclear. Long-distance trafficking by the microtubule motor KIF1A is crucial for synaptogenesis and downstream synapse maintenance. Mutations in KIF1A cause KIF1A-associated neurological disorder (KAND). We employed isogenic gene-edited human-induced pluripotent stem cell -derived neurons to assess the effects of disparate pathogenic mutations in KIF1A on synaptic trafficking and function. Null (p.C92*) and hypoactive (p.P305L) mutations delay neurite outgrowth, mislocalize synaptic cargoes, and decrease synapse density. Conversely, a hyperactive (p.R350G) mutation supports neurite outgrowth but causes aberrant motility of synaptic vesicle precursors and deficits in microtubule-dependent presynaptic patterning. Functional analysis of neuronal activity reveals delayed synaptic maturation in loss-of-function mutations (p.P305L, p.C92*) and precocious activity in the hyperactive p.R350G mutation. These data provide insights into how KIF1A mutations with distinct molecular-level impacts lead to significant downstream synaptic deficits in human neurons.

Optoelectronic synaptic devices serve as promising hardware platforms for neuromorphic computing; however, achieving stable photoelectric dual-modal synaptic modulation and practical intelligent perception remains challenging. Herein, an Au/Au/Ni0.5Zn0.5Fe2O4 (NZFO)/FTO optoelectronic synaptic memristor was fabricated via a facile sol-gel method. The NZFO film exhibits a single-phase spinel structure with abundant intrinsic defect states, which contribute to defect-assisted carrier transport and conductance modulation under electrical and optical stimuli. The device demonstrates photoelectric dual-modal synaptic behavior, enabling short-/long-term plasticity, paired-pulse facilitation, and STM-to-LTM transition with wavelength-dependent optical modulation over 365-650 nm. The device achieves stable learning and relearning behaviors within 16 and 9.3 s, respectively, and demonstrates repeatable optical pulse modulation over multiple consecutive cycles. Integrated with a convolutional neural network, the NZFO synaptic device achieves recognition accuracies of 96.20% and 84.45% on the MNIST and Fashion-MNIST datasets, respectively. Furthermore, the device-assisted neuromorphic perception framework enables dynamic target perception and traffic signal recognition in an intelligent driving demonstration, highlighting its capability for integrated sensing, memory, and processing. This work demonstrates NZFO as a promising material platform for energy-efficient neuromorphic perception and intelligent computing applications.

In humans transcutaneous high-frequency electrical stimulation (HFS) has been reported to increase pain elicited by single electrical stimuli at the HFS-treated site, an effect thought to represent the perceptual correlate of homosynaptic long-term potentiation (LTP) at spinal C fibre synapses. However this finding has not been consistently replicated. In previous studies hyperalgesia has been commonly assessed using rectangular electrical pulses, which may not sufficiently activate C fibre nociceptors. In two preregistered experiments we investigated whether 4 Hz sinusoidal electrical stimulation, which has been shown to reliably activate C fibres, elicits homotopic hyperalgesia after HFS in healthy human volunteers. In both experiments transcutaneous HFS was applied to one of the two forearms, resulting in enhanced pinprick sensitivity in the adjacent skin. In experiment 1 (N = 26) participants received 60 s of 4 Hz sinusoidal stimulation at 0.2 mA before HFS and at 10, 30 and 50 min afterwards on each arm. The repeated-measures ANOVA on the pain ratings before HFS and at 50 min after HFS revealed no significant interaction between time and arm. To address the possibility that the 4 Hz stimulation given before HFS may have prevented the induction of hyperalgesia, and to enhance C fibre recruitment, a second experiment was conducted (experiment 2, N = 28). Participants received 60 s of 4 Hz sinusoidal stimulation at 0.7 mA, 50 min after HFS on each arm. The Bayesian paired t test provided moderate evidence against a difference in pain ratings between the two arms. Taken together we found no evidence for homotopic hyperalgesia to C fibre stimulation after HFS. KEY POINTS: High-frequency electrical stimulation (HFS) of peripheral nociceptors produces homosynaptic long-term potentiation (LTP) at spinal C fibre synapses in animals. 4 Hz sinusoidal electrical stimulation preferentially activates C fibres. We found no evidence for hyperalgesia to the 4 Hz stimulation after HFS in humans.

Most temperate animals exhibit seasonal rhythms in reproductive physiology and behaviour. Gonadotropin-releasing hormone (GnRH) cells in the preoptic area (POA) and kisspeptin (Kiss) cells in the anteroventral periventricular (AvPv) nucleus are critical for timing photoperiod-induced changes in seasonal reproduction. In response to prolonged exposure to photoperiod cues, many rodents exhibit endogenously generated programmed changes in physiology that reflect a circannual timing mechanism. Here we used transcriptome sequencing coupled with measurements of surface body temperature and testes mass across a simulated circannual interval timer to characterize the molecular changes involved in the seasonal control of reproduction and surface body temperature. Adult male Djungarian hamsters were collected after exposure to short photoperiod on 4-week intervals from 4 to 32 weeks. The POA and AvPv transcriptomes from short-photoperiod hamsters were compared to a long photoperiod reference group. Our analyses confirmed robust photoperiodic regulation of Kiss1 mRNA expression in the AvPv. Weighted gene co-expression network analyses (WGCNAs) identified hundreds (POA: 211, AvPv: 415) of transcripts that were associated with testes mass. Gene set enrichment analysis (GSEA) identified 'gonadotropin secretion' and 'glial cell proliferation' as the primary pathways associated with circannual interval timing. Vimentin had a strong negative association with testes mass, indicating AvPv glial morphology may increase during gonadal involution. In the POA, pathways associated with 'regulation at synapse' and 'regulation of synaptic plasticity' were highly enriched and transcripts positively associated with gonadal involution indicated that ribosomal plasticity and intracellular calcium signalling are key mechanisms involved in seasonal reproduction. WGCNAs identified 567 transcripts in the POA that were significantly associated with surface body temperature. GSEA discovered thyrotrophin-releasing hormone was significantly negatively associated with surface body temperature. Overall, the POA and AvPv transcriptome datasets provide the foundation to expand our understanding of the molecular representation of seasonal time in the mammalian hypothalamus.

Synapses, prototypic sites for neuronal communication, are key to brain function. Their organization and properties are instructed by synaptic cell adhesion molecules (sCAMs) that may operate independently or in coordination through yet unknown linker proteins. Here, we used multi-epitope affinity-purifications combined with quantitative mass spectrometry and immuno-EM to comprehensively map synaptic protein networks in the mouse brain. We identify a pre-synaptic core-module assembled from the major sCAMs, Neurexins1-3 and LAR-type receptor protein-tyrosine-phosphatases (PTPRs), and the previously uncharacterized tetraspanins T178A/B. These ternary Neurexin-T178-PTPR complexes form through their trans-membrane domains and assemble during biogenesis in the ER. Loss of T178B leads to module destabilization, accompanied by strong reduction of LAR-PTPRs and re-distribution of synaptic Neurexins. At synapses, the Neurexin-T178-PTPR module recruits stable trans-synaptic protein networks thereby interlinking machineries of the pre-synaptic active zone and establishing stable associations with post-synaptic neurotransmitter receptors. This work uncovers a widely distributed core-module for synaptic adhesion and trans-synaptic signaling in the mammalian brain.

South African women are disproportionately affected by HIV, with increased incidence during pregnancy and postpartum. While oral TDF/FTC pre-exposure prophylaxis (PrEP) is safe, effective, and recommended for pregnant and postpartum women, adherence to a daily pill is challenging, particularly during the postpartum period. Longer-acting injectable (LAI) PrEP products may be more desirable for postpartum women however, limited data on factors influencing uptake are available to inform roll-out of LAI products among postpartum women. Using the Consolidated Framework for Implementation Research (CFIR), we explored LAI PrEP implementation determinants among postpartum women in South Africa. From March-April 2023, 4 focus group discussions (FGDs) were conducted among postpartum women in KwaZulu-Natal. A directed content analysis method was performed. Among 23 women, median age was 27 (range 19-36) years. Two (9%) reported a pregnancy partner living with HIV, 7 (30%) had ever used PrEP, and 21 (91%) had ever breastfed. Factors that may influence LAI PrEP implementation are organized by three CFIR domains. Individuals expressed interest in and potential willingness to use LAI PrEP, but limited knowledge. At the implementation process domain, participants perceived LAI-PrEP users to have high HIV risk perception, and were themselves worried about side-effects, access, and fear of partner conflict. They also identified implementation opportunities including peer PrEP mentors, mobile clinics, and community clinic integration. At the outer setting, cultural beliefs/practices during postpartum were important determinants. Our findings indicate interest and willingness to consider LAI PrEP among postpartum women and highlight implementation opportunities to reduce HIV acquisition and perinatal transmission.

Cancer is increasingly recognized as a systemic disease whose biology is shaped by reciprocal interactions with its microenvironment, including the central and peripheral nervous systems. Recent evidence demonstrates that neural inputs can directly promote tumour growth through synaptic, paracrine, and neuroendocrine mechanisms, and that these inputs intersect with canonical drug-resistance pathways, creating new opportunities and challenges for precision oncology. Primary brain tumours such as gliomas form bona fide functional synapses with neurons, hijacking both excitatory (AMPA/NMDA) and inhibitory (GABA_A) inputs to sustain proliferation. Comparable mechanisms are now described in brain metastases and, remarkably, in small cell lung cancer (SCLC), where cortical and vagal neurons establish synaptic contacts with tumour cells. Beyond synaptic communication, paracrine neurotransmitter signalling, tumour innervation, autonomic balance (β-adrenergic versus vagal tone), and systemic stress responses jointly modulate tumour biology, immune surveillance, and therapeutic response. Convergent evidence further indicates that neural and stress-related signalling cooperates with classical resistance circuits-including p53-EGFR-ERK signalling, P-glycoprotein-mediated drug efflux, reactive oxygen species (ROS)-dependent redox programmes, and adipokine-Hsp90 axes-to attenuate the efficacy of chemotherapy, targeted agents, and immune checkpoint inhibitors. Neuron-tumour interactions represent a novel and clinically actionable dimension of cancer pathogenesis that extends well beyond gliomas. Targeting neuron-tumour synapses, neurotransmitter pathways, autonomic inputs, and the resistance circuits with which they intersect offers new therapeutic opportunities, but translation requires careful attention to specificity, neurological safety, and rational combination with cytotoxic, targeted, and immune therapies. Cancer is not driven solely by genetic mutations; it is also shaped by signals from the nervous system. This review synthesizes how nerves and brain activity directly influence tumour growth across multiple diseases-including gliomas, small cell lung cancer, breast cancer, pancreatic cancer, and prostate cancer-and how these neural signals converge with metabolic and drug-resistance pathways that limit the efficacy of conventional therapy. Recent discoveries show that some cancers form direct synapse-like connections with neurons and exploit neurotransmitters to fuel tumour progression and treatment escape. Understanding these interactions opens new therapeutic opportunities-such as targeting neural signalling, autonomic pathways, or neuro-modulated resistance mechanisms-and positions the nervous system as a previously underappreciated but clinically relevant driver of cancer behaviour.