Neuroscience bulletin最新文献

Hypothermia is widely acknowledged to exert protective effects against cerebral hypoxic-ischemic injury. Despite the neuroprotective effects of hypothermia, the developing brain remains vulnerable to white matter injury (WMI) during hypothermic hypoxia-ischemia, potentially disrupting neurodevelopment and leading to long-term neurological deficits. However, the mechanisms underlying WMI and effective therapeutic strategies following hypothermic hypoxia-ischemia in the developing brain are not well understood. Our study demonstrates that microglia experience pyroptosis following hypothermic hypoxia-ischemia. The release of interleukin 18 (IL-18) derived from pyroptotic microglia induces mature oligodendrocyte death and axonal demyelination, resulting in WMI. Pharmacological inhibition of pyroptosis with disulfiram (DSF) significantly alleviates WMI in vitro and in vivo. These findings highlight microglia pyroptosis as a potential therapeutic target to prevent neurodevelopmental impairment in the developing brain following hypothermic hypoxia-ischemia.

Gouty arthritis is an autoinflammatory joint disease caused by the deposition of monosodium urate crystals, which activate innate immune responses and elicit acute episodes of joint pain and inflammation. Although macrophages are key players in recognizing monosodium urate (MSU) crystals and initiating the inflammatory cascade, the specific contribution of tissue-resident macrophages and their mechanosensory machinery remains unclear. Here, we identify the mechanosensitive ion channel PIEZO1 as a critical mediator of inflammation and pain in MSU-induced acute gout. We show that synovial CX3CR1⁺ tissue-resident macrophages are enriched and activated in both patient samples and a murine model of gout. PIEZO1 is highly expressed in these cells and responds to mechanical stress with calcium influx, which is further amplified in MSU-treated joints. Pharmacological inhibition or genetic ablation of PIEZO1 in CX3CR1⁺ macrophages significantly attenuated joint swelling, inflammatory cytokine expression, mechanical hypersensitivity, and motor dysfunction. In contrast, Piezo1 deletion in CCR2⁺ monocytes, MRP8⁺ neutrophils, or Col1a2⁺ fibroblasts did not affect gout-associated symptoms, indicating a non-redundant role for resident macrophage-expressed PIEZO1. These findings define a PIEZO1-dependent mechanotransduction pathway in tissue-resident macrophages that drives gout-related inflammation and nociception and suggest that targeting PIEZO1 may offer therapeutic benefit in acute gout flares.

Uncovering the underlying process of epileptogenesis is crucial for developing effective treatment strategies for epilepsy. However, the cellular and molecular changes throughout epileptogenesis are not fully understood. In this study, single-nucleus RNA sequencing was performed on the hippocampus, temporal cortex, and thalamus across the acute, latent, and chronic phases in a pilocarpine-induced rat model and controls. We created a comprehensive single-nucleus transcriptomic atlas of rat epileptogenesis, consisting of 311,177 single nuclei. Our analysis revealed distinct transcriptional signatures across the three phases and regions, including significant gene expression changes in the acute phase and critical synaptic and neural network remodeling in the thalamus during the latent phase. Notably, we identified two novel astrocyte clusters during epileptogenesis, with the EX-Astro C3-IN pathway emerging as a potential intervention target. The dataset provides a detailed understanding of the dynamic cellular and molecular landscape of epileptogenesis.

Blood-brain barrier (BBB) dysfunction represents a critical pathological manifestation in exacerbating ischemic stroke, contributing to neuronal death, edema formation, and unfavorable clinical outcomes. GATA zinc finger domain-containing 1 (GATAD1) is recognized as a critical transcription factor in cardiac development and cardiovascular disease. However, the role of GATAD1 in regulating BBB function and ischemic stroke remains elusive. Here, we found that GATAD1 was upregulated in cerebral endothelial cells (ECs) following ischemic stroke in mice. EC-specific Gatad1 deficiency demonstrated remarkable neuroprotection, manifested by reduced infarct volumes, ameliorated BBB dysfunction, and improved neurological outcomes following experimental stroke. Mechanistic investigations revealed that GATAD1 was involved in regulating CD36 expression, thereby modulating caveolae-mediated transcytosis in cerebral ECs. These findings established GATAD1 as a novel regulator of BBB permeability and a potential therapeutic target for ischemic stroke intervention.

Nr4a2 (Nurr1) is well known to be vital for midbrain dopaminergic neurons. Recent single-cell RNA analyses reveal that Nr4a2 is expressed in lateral cerebral regions, within neurons named L4/L5/L6 IT Car3. These neurons have attracted intense attention for the molecular mechanisms underlying their development and functions. We classified Car3 neurons into neocortical (Ncx-Car3), claustral (CLA-Car3), and dorsal endopiriform nucleus (dEn-Car3) subpopulations, focusing on the characterization of Ncx-Car3 neurons. These neurons exhibit distinct birthdates and migratory morphologies compared to CLA- and dEn-Car3 neurons, but share a common transcriptomic profile when Nr4a2 is deleted at the embryonic stage or in adulthood. Notably, Nr4a2 misexpression ectopically induces Car3-enriched genes in vivo. Mice lacking Nr4a2 in Car3 ensembles during the embryonic stage or in adulthood display hyperactivity and reduced anxiety-like behaviors. Therefore, our results demonstrate that Nr4a2 is a key factor in regulating the development and functional maintenance of the forebrain Car3 neurons.

Spatial navigation is one of the brain's most fundamental abilities, enabling us to move through the world with ease. The seemingly effortless act of navigation depends on complex cognitive functions, with the cognitive map playing a central role. In individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI), however, this once intuitive ability becomes disoriented and impaired before the emergence of noticeable memory symptoms. AD pathology disrupts structural and functional disabilities in the brain's navigation system, resulting in cognitive map-based navigational difficulties. These deficits affect not only physical navigation but also extend into abstract, knowledge-based domains. In this review, we explore the role of cognitive map dysfunction in the navigation impairments seen in AD, synthesizing current evidence from studies of both spatial and non-spatial deficits. These insights may deepen our knowledge of how the brain navigates and also offer promising avenues for predictive biomarkers and targeted interventions.

Long-term exposure to monochromatic light during early life has been shown to significantly impact the development of myopia. However, its effect on color processing in the visual cortex remains unclear. In this study, we investigated the effects of different lighting conditions on the functional organization of color representation in the visual cortical areas V1, V2, and V4 of rhesus monkeys raised under long-wave and short-wave monochromatic illumination for four years. Using cytochrome oxidase staining and intrinsic signal optical imaging, we found that the sizes, densities, and response strengths of cortical color domains in V1, V2, and V4 were consistent across illumination conditions. In addition, the cortical distances between specific hue response patches did not significantly differ among the groups. These findings suggested that long-term monochromatic illumination does not alter the spatial organization or functional properties of color domains in the visual cortex of rhesus monkeys. This research provides new insights into the resilience of the visual system's chromatic representation despite altered lighting conditions in early life.

Auditory neuropathy (AN) is a sensorineural hearing loss that impairs speech perception, but its mechanisms and treatments remain limited. Mic60, essential for the mitochondrial contact site and cristae organizing system, is linked to neurological disorders, yet its role in the auditory system remains unclear. We demonstrate that Mic60^+/- mice develop progressive hearing loss from 6 months of age, with reduced auditory brainstem response amplitudes despite preserved outer hair cell function, consistent with AN. Mitochondrial abnormalities in spiral ganglion neurons (SGNs) emerge by 3 months, followed by mitochondrial loss and SGN degeneration, indicating progressive auditory neuron dysfunction. In vitro, Mic60 deficiency disrupts mitochondrial respiration, reversible by N-acetylcysteine (NAC). NAC treatment preserves mitochondrial integrity and rescues hearing by enhancing mitophagy. Our findings establish Mic60^+/- mice as an AN animal model, highlight the role of Mic60 in the mitochondria of primary auditory neurons, and identify NAC as a potential AN treatment.