Neuroscience bulletin最新文献

Cisplatin is a widely-used chemotherapeutic agent, but its dose-limiting ototoxicity often results in irreversible hearing loss. The pathogenesis involves oxidative stress, apoptosis, DNA damage, and inflammatory responses, yet effective preventive strategies remain limited. Here, we demonstrate that magnesium hydride (MgH₂), a hydrogen-releasing compound, provides robust protection against cisplatin-induced hearing loss. Our results showed that MgH₂ protected auditory function and preserved cochlear hair cells in vivo. Furthermore, it significantly attenuated cisplatin-induced oxidative stress and apoptosis in cultured HEI-OC1 (House Ear Institute-Organ of Corti 1) cells and cochlear explants. Notably, MgH₂ suppressed NOD-like receptor family pyrin domain containing 3 (NLRP3)-mediated inflammatory cascades, thereby limiting downstream inflammatory damage. These findings revealed that MgH₂ alleviated cisplatin-induced hearing loss through integrated antioxidant, anti-inflammatory, and anti-apoptotic pathways, with NLRP3 identified as a critical regulatory molecule. Collectively, our study provides compelling evidence for MgH₂ as a potential therapeutic candidate for the prevention of cisplatin-induced hearing loss.

Circadian sensitivity significantly influences the severity of noise-induced hearing loss (NIHL), but the underlying mechanisms remain unclear. Here, we applied single-cell RNA sequencing to 97,043 cochlear cells, identifying macrophages as the primary immune responders to acoustic trauma, with a notable increase in their proportion in the cochlea. Immunofluorescence confirmed significant recruitment and activation of cochlear macrophages following noise exposure, while in vivo macrophage depletion resulted in the recovery of hearing. Furthermore, analyses of differentially-expressed genes and pathways revealed pronounced activation of NLRP3 inflammasome signaling in macrophages during night-time noise exposure. Measurements of elevated IL-1β and IL-18 expression in cochlear macrophages by multiplex immunohistochemistry correlated with heightened inflammation in the night-time exposure group. These findings were further confirmed by the administration of the selective NLRP3 inhibitor CY-09, which mitigated inflammasome activation, preserved synaptic integrity, and protect against hearing loss. In conclusion, our findings underscore the role of macrophage-driven NLRP3 inflammasome activation in mediating circadian variations in cochlear damage, offering a potential therapeutic target for mitigating NIHL.

The locus coeruleus (LC), a norepinephrine nucleus governing arousal states through tonic activity, requires precise regulatory mechanisms to maintain its dynamic activation levels. However, the neural circuitry underlying LC activity maintenance remains unclear. Here, we identify a glutamatergic projection from the ventrolateral periaqueductal gray (vlPAG) to the LC in mice as a critical regulator of arousal dynamics. Fiber photometry recordings revealed stress-induced Ca²⁺ dynamics in vlPAG^CaMKIIα-LC axon terminals across diverse threat paradigms. Slice electrophysiology demonstrated that this pathway mediates LC-norepinephrine (LC-NE) neuronal activity via glutamatergic transmission. Low-frequency pathway activation (1 Hz) mainly induced anxiety-like behaviors, whereas high-frequency stimulation (10 Hz) evoked more panic-like hyperlocomotion, establishing a frequency-dependent continuum of arousal states. Conversely, pathway inhibition reduced pupil size, a reliable biomarker for arousal, concurrently suppressing threat avoidance behaviors and alleviating anxiety-related behaviors without altering environmental preference. These findings reveal that the vlPAG^CaMKIIα-LC pathway maintains baseline arousal while dynamically scaling threat-induced hyperarousal.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons, and its prevalence is increasing, alongside global population aging. Neuroinflammation has been widely recognized as a pivotal contributor to PD pathogenesis, particularly owing to the dual role of microglia in this process. This review systematically identifies the multiple factors regulating microglial function and phenotype, thereby driving PD initiation and progression. Furthermore, aging, a major risk factor for PD, and its profound effects on microglial state and functional dynamics are discussed. Notably, microglial hyperactivation is shown to establish a self-perpetuating cycle of "inflammation-damage-reinflammation" through the excessive release of pro-inflammatory cytokines and chemokines, which exacerbates neuronal degeneration. Lastly, the potential therapeutic strategies targeting microglial dysfunction, including interventions against the senescence-associated secretory phenotype and the modulation of microglial activity, are summarized. By elucidating how multifactorial alterations in microglial states influence PD pathology, this review provides novel insights and directions for advancing therapeutic research in PD.