Neuroscience bulletin最新文献

Noise-induced hearing loss is a prevalent form of sensorineural hearing impairment that negatively impacts quality of life and has no effective clinical treatments. Damage due to oxidative stress in cochlear hair cells is thought to be the typical pathological basis. Oxeiptosis is oxidative stress-induced, caspase-independent modality of cell death. In this study, we found that oxeiptosis plays an important role in noise-induced hearing loss, which has not been previously identified. Using protein quantification, protein-protein interaction studies, and immunofluorescence staining in cellular models, we elucidated the pivotal molecules of oxeiptosis. Building on the in vitro experimental data, we detected characteristic protein alterations along the oxeiptosis pathway in noise-induced hearing loss murine models. Furthermore, the pharmacological suppression effectively attenuated noise-induced oxeiptosis in cochlear hair cells and partially alleviated hair cell death. This study confirms the existence of a new cell death pathway in NIHL and provides a potential treatment alternative.

Central nervous system (CNS) injuries trigger a complex glial response, in which oligodendrocyte precursor cells (OPCs) play a far more dynamic role than previously recognized. Moving beyond their canonical function as a remyelination reservoir, reactive OPCs emerge as plastic signaling hubs whose fate and function are dictated by injury-specific cues. This review synthesizes recent evidence to propose a novel conceptual framework: the "reactive OPC state code." We argue that deciphering this code-the molecular signatures that define pro-regenerative, immunomodulatory, or maladaptive OPC states-is the key to understanding functional heterogeneity in CNS injury. We critically analyze how distinct pathological contexts (trauma, ischemia, neuroinflammation) rewrite this code, leading to diverse outcomes. Finally, we pivot from a generic discussion of OPC-directed therapies to advocate for "state-specific targeting" as the next frontier in translational medicine, offering a roadmap for developing precision interventions that steer reactive OPCs towards repair. This perspective aims to redefine OPC reactivity from a passive response to a central, druggable axis in CNS pathology and repair.

Astrocytes have long been considered passive players in brain function, yet emerging evidence suggests they actively modulate neural activity and signal transmission. This study combines chemogenetics and optogenetics approaches with functional magnetic resonance imaging (fMRI) to investigate the impact of astrocyte activation on local field potentials (LFPs) and downstream BOLD signals. Using a multimodal neuroimaging approach, we explore how astrocyte activation influences electrophysiological responses in different brain regions, particularly focusing on the prefrontal cortex (PFC) and its downstream targets. Our results reveal significant increases in LFP energy within specific frequency bands, such as Theta and Delta, in response to laser stimulation. These changes demonstrate the spatial specificity of astrocyte activity and its capacity to modulate local network dynamics. Furthermore, following chemogenetic inhibition of neuronal activity, optogenetic reactivation of astrocytes continued to evoke BOLD responses, supporting the notion that astrocytes have a pivotal role in the regulation of cerebral blood flow and metabolism. These findings challenge traditional views of BOLD signal origins and emphasize the need for a reevaluation of astrocyte involvement in neurovascular coupling. This study provides novel insights into astrocyte function, offering a new perspective on brain-wide connectivity and its implications for both normal brain function and neuropathological conditions.

Retinal organoids (ROs) are three-dimensional in vitro models that replicate the specific cellular composition and inner structure of the retina. Currently, ROs derived from human pluripotent stem cells (hPSCs) have been shown to mimic both the structure and function of the human retina. Furthermore, ROs function as a powerful model system for researchers, facilitating the investigation of the pathogenesis and treatment strategies of retinal diseases. Despite their development for over a decade, ROs remain limited in terms of complexity and clinical application. This review summarizes recent advances in the development of retinal differentiation methods and underscores their potential applications in disease modeling, gene therapy, cell transplantation, and drug screening. In addition, it proposes research directions that are geared towards advancing RO methodologies to further broaden their applications.

Autism spectrum disorder (ASD) pathophysiology often involves striatal dysfunction, yet the underlying mechanisms remain unclear. Mutations in Forkhead box G1 (FOXG1) cause FOXG1 syndrome, a condition sharing core ASD features. Here, loss of Foxg1 in the indirect pathway spiny projection neurons (iSPNs) in mice recapitulates ASD symptoms, including social, language, and fine movement deficits. Foxg1 deficiency causes dendritic simplification, spine reduction, and impairs excitatory synaptic transmission. Transcriptome reveals that FOXG1 drives gene networks to multidimensionally control synaptic functions from spine morphogenesis, synaptic maturation, ion transmembrane transport, glutamate receptor clustering, to neurotransmitter release and synaptic transmission. Importantly, FOXG1 directly activates the transcription of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits, and pharmacological potentiation of AMPAR activity normalizes synaptic function and rescues behavioral deficits. Our study provides a new perspective on the relationship between FOXG1 and ASD etiology in iSPNs and suggests the potential of AMPAR activation as a therapeutic intervention for ASD and FOXG1 Syndrome.

Epilepsy is one of the most prevalent and severe neurological disorders, and it is inadequately controlled with currently available medications. While cinnabar (mercury(II) sulfide)-a traditional Chinese medicine-has historical application in epilepsy treatment, its therapeutic efficacy and underlying mechanisms are unclear. In this study, we find that cinnabar exerts model-dependent antiseizure efficacy in mice. Specifically, it significantly attenuates acute seizures, enhances the termination of diazepam-resistant status epilepticus, and reduces spontaneous seizures in the kainic acid (KA)-induced seizure model. Conversely, no therapeutic effect was found in the maximal electroshock-, pentylenetetrazole-, or kindling-induced seizure model. Fiber photometry revealed that cinnabar normalizes KA-induced hippocampal neurotransmission imbalances by simultaneously decreasing glutamate hyperactivity and γ-aminobutyric acid hypoactivity. Furthermore, cinnabar has neuroprotective effects and alleviates comorbid anxiety-like behaviors, while showing no alterations in motor function. Our findings suggest cinnabar's potential as a therapeutic agent for seizure management, via a mechanism associated with the reversal of the hippocampal excitatory/inhibitory imbalance.

GABA_A receptors containing α5-subunits (GABA_AR-α5) cluster at both extrasynaptic and synaptic locations, interacting with the scaffold proteins radixin and gephyrin, respectively, and the re-localization of GABA_AR-α5 influences GABAergic transmission. Here, we found that when early spatial memory deficits occurred in aged mice at 24 h after sevoflurane anesthesia, there was a re-localization of GABA_AR-α5 that enhanced tonic inhibition and reduced the decay kinetics of miniature inhibitory postsynaptic currents in the hippocampal CA1 region. Mechanistically, increased phosphorylation of radixin at threonine 564 (Thr564) mediates the re-localization of GABA_AR-α5. Acute treatment with the selective extrasynaptic GABA_AR-α5 antagonist S44819 restored the GABA_AR-α5-mediated inhibitory currents by reversing radixin phosphorylation-dependent GABA_AR-α5 re-localization, then improved the sevoflurane-induced spatial memory impairment in aged mice. Our results suggest that the localization of GABA_AR-α5 altered by sevoflurane is linked to unbalanced GABAergic transmission, which induces early memory impairment in aged mice. Modulating the GABA_AR-α5 localization might be a novel strategy to improve memory after sevoflurane exposure.