Neuroscience bulletin最新文献

Parkinson's disease (PD) is characterised by dopaminergic (DA) neuron loss and the formation of Lewy bodies composed of aggregated α-synuclein (α-Syn) in the substantia nigra (SN). Emerging evidence suggests that PD may originate in the gastrointestinal (GI) tract, where α-Syn aggregates in enteroendocrine cells that synapse with vagal afferents, facilitating disease spread to the central nervous system. Using electrophysiological, behavioural, molecular, and immunohistochemical methods, we examined the effects of capsaicin-induced degeneration of vagal afferents on PD progression in models: one was prepared by injecting α-Syn preformed fibrils into the GI tract, and the other was prepared by orally administering rotenone. The results showed that vagal afferents mediate GI sensory signals affecting DA and GABA neurons in the SN. Vagal afferent degeneration reduces α-Syn accumulation in the dorsal motor nucleus of the vagus and SN while improving motor impairments, highlighting their role in α-Syn transmission and PD pathogenesis.

White matter, constituting nearly half of the human brain, is increasingly recognized as a dynamic regulator of neural communication, metabolism, and cognition rather than a passive conduit for signal transmission. Recent advances in neuroimaging, molecular biology, and single-cell transcriptomics have revealed that myelin and oligodendrocytes play essential roles in neural plasticity and disease. Here, we synthesize current understanding of white matter organization and myelin function, emphasizing its contributions to conduction efficiency, metabolic support, and network optimization. We further discuss mechanisms of myelin plasticity and highlight its role in learning, adaptation, and repair. Integrating evidence across developmental, immune-mediated, neurodegenerative, and psychiatric disorders, we propose that white matter pathology constitutes a primary driver of brain dysfunction. Finally, we summarize emerging regenerative strategies-including cell and gene therapies, OPC-targeted interventions, and neuromodulation-highlighting translational opportunities for restoring myelin integrity and circuit function. This review reframes white matter as a promising therapeutic frontier.

Endoplasmic reticulum (ER) stress plays a significant role in chronic pain, but its potential involvement in chronic itch remains largely unexplored and poorly understood. In the current study, we investigated whether ER stress signaling in keratinocytes contributes to the pathogenesis of chronic itch. Our behavioral tests showed that the ER stress inhibitor 4-PBA attenuated itch-related behaviors in both acute and chronic itching mouse models, and reduced compound 48/80 and serotonin-induced activity of dorsal root ganglion (DRG) neurons. qPCR and western blotting revealed that the ER stress-related proteins and Lipocalin-2 (LCN2) were significantly elevated in the affected skin under chronic itch conditions and in cultured keratinocyte HaCaT cells and mice skin keratinocytes. The ELISA test showed that the level of LCN2 increased significantly in plasma but not in DRG tissue, from both acetone-ether-water (AEW) induced dry skin and imiquimod (IMQ) induced psoriasis model mice. Current clamp recording demonstrated that LCN2 induced hyperexcitability in dorsal root ganglia neurons, which could be abolished by HS024, the inhibitor of melanocortin receptor 4 (MC4R). In addition, pharmacological inhibition of transient receptor potential vanilloid 1 (TRPV1) or TRPV1 knockout blocked LCN2-induced hyperexcitability in DRG neurons. In conclusion, this study demonstrated that keratinocyte ER stress is involved in chronic itch genesis by releasing LCN2, which sensitized primary sensory neurons via TRPV1. These findings suggested that inhibition of ER stress in keratinocytes could be a promising therapeutic strategy for treating chronic itch.

While Katz's Ca²⁺ hypothesis has defined that action potentials trigger neurotransmitter release through Ca²⁺-dependent secretion (CDS), recent discoveries of Ca²⁺-independent secretion (CiVDS) have demonstrated that action potentials per se can directly trigger exocytosis independent of Ca²⁺. However, a critical gap remains regarding how CDS and CiVDS coordinate to precisely control neurotransmitter release within a single neuron's soma and axons/terminals. Here, using high-resolution live imaging, we simultaneously visualized single-vesicle release in the somata and axons/terminals of individual dorsal root ganglion (DRG) neurons and show that: (1) CiVDS and CDS co-exist in both somatic and axonal regions; (2) the release probability of CiVDS in axons is ~2-fold higher than in somata; (3) CiVDS accounts for > 60% of total axonal release; (4) CiVDS favors full fusion-like quantal release while CDS favors kiss-and-run sub-quantal release. These findings suggest a more profound contribution of CiVDS than CDS in axonal neurotransmission in sensory DRG neurons.

Specialized cutaneous Schwann cells (scSCs) are a recently identified glial class implicated in cutaneous pain modulation, yet their three-dimensional architecture and role in chronic pain remain unclear. Using tissue optical clearing, we reconstructed the 3D morphology of scSCs, revealing an intricate mesh-like network, with extensive branching penetrating the epidermal layer and establishing close associations with A- and C-fiber primary sensory nerve terminals. Optogenetic activation of scSCs elicited nociceptive reflex behaviors, dependent on concurrent A- and C-fiber activation, but not affective-motivational responses. We further investigated the morphological and functional alterations of scSCs in chronic inflammatory pain and neuropathic pain models. Interestingly, scSCs were found to play a partial role in modulating nociceptive behaviors but not aversions in chronic pain. Together, these findings provide new insights into the functional dynamics of scSCs in nociceptive signal processing and their limited contribution to chronic pain states.

Peripheral nerve injury (PNI) significantly impairs patients' quality of life, with elderly individuals experiencing particularly severe consequences due to aging-related declines in neuronal injury response and repair capabilities. Processes of the generation and transmission of injury signals, axonal disruption, initiation of regeneration, and the elongation of regenerating axons, as well as the subsequent reinnervation by these axons, are all significantly influenced by aging. These alterations are closely associated with changes in mitochondrial function, neuronal transport systems, a persistent inflammatory milieu, and various microenvironmental non-neuronal cells. Therefore, this review synthesized the pivotal role of aging in the multifaceted regulation of the nervous system following PNI and highlighted promising molecular regulatory mechanisms in the signaling pathways. Furthermore, it identified critical areas for future research, including unresolved questions in age-associated injury responses, potential targets for pharmacological intervention, and emerging therapeutic strategies meriting consideration for research and development.

Despite widespread exposure to stress and threats, why some develop anxiety while others do not remains unclear. We hypothesize that this discrepancy links to unconscious fear memory generalization in safe contexts, a poorly understood area. Here, we tested whether such memories unconsciously bias visual processing and if attention-based control suppresses this effect. Visual orientations paired with threat (in a threatening context) were rendered invisible via fast chromatic flicker above critical flicker-fusion frequency (CFF), then presented in a safe context. Experiment 1 (attended orientation discrimination task) and Experiment 2 (attended duration discrimination task vs. unattended central color detection task) were conducted. EEG revealed significant unconscious fear responses (CS+ vs. CS-) in attended conditions, positively correlated with broad-alpha power (replicated across experiments). No significant responses emerged for unattended stimuli, despite elevated alpha. These findings show unconscious fear distorts visual processing during generalization in a safe context, with top-down attention gating this effect via broad alpha oscillations-prioritizing it when attended and suppressing it when unattended.

Kainate receptors (KARs) are members of the ionotropic glutamate receptor family and possess diverse structural and functional properties that play critical roles in synaptic signaling, plasticity, and neural development. Several KAR subunits are strongly expressed in dorsal root ganglion neurons, and while their involvement in pain has been suggested, their precise role remains unclear. This review re-evaluates the roles of KARs in sensory physiology, with a particular focus on pain mechanisms. By combining recent single-cell transcriptomic data from dorsal root ganglia neurons with experimental evidence on KAR diversity, signaling, and function, we highlight how these receptors may shape sensory processing under normal and pathological conditions.

The common marmoset has emerged as an increasingly valuable non-human primate model in neuroscience and biomedical research. Recombinant adeno-associated viruses (AAVs) are powerful tools for gene delivery and gene therapy. However, a systematic comparison of different AAV capsids and delivery routes remains lacking in marmosets. In this study, we constructed a barcoded AAV library comprising 21 capsid variants and administered it to marmosets via intravenous, intraventricular, and intrastriatal injections. To evaluate the AAV tropism, we quantified vector DNA, viral RNA abundance, and tdTomato signals in the marmoset brain and other tissues. Intravenous administration led to limited brain transduction, while intraventricular and intrastriatal administrations demonstrated high transduction efficiency in the marmoset brain. Notably, some AAV capsids exhibited distinct transduction patterns in the marmoset brain. These results offer valuable guidance for optimizing AAV-based gene delivery strategies in marmoset models and support their utility in both basic neuroscience research and potential therapeutic applications.