Neuroscience bulletin最新文献

This study reveals that maternal stress during pregnancy (MSDP) increases anxiety susceptibility in male offspring through Corticotropin-Releasing Factor Receptor 1 (CRFR1)-mediated time-specific hyperactivation of medial habenula (MHb) cholinergic projections to the interpeduncular nucleus (IPN). Male MSDP offspring exhibited heightened anxiety-like behaviors following 30 minutes of acute restraint stress (ARS). In vivo calcium imaging showed excessive activation of MHb ChAT-IPN projections specifically during the late phase (25-30 min) of ARS in MSDP offspring. Chemogenetic and optogenetic manipulations confirmed that this time-specific circuit hyperactivation drives anxiety susceptibility. Mechanistically, MSDP upregulated CRF/CRFR1 in the MHb. Pharmacological experiments demonstrated that CRFR1 activation directly enhances circuit activity. CRFR1 overexpression recapitulated MSDP phenotypes by increasing circuit activity and anxiety, while CRFR1 antagonism reversed both circuit hyperactivation and anxiety behaviors. Chemogenetic circuit inhibition blocked CRFR1 overexpression-induced anxiety, confirming that CRFR1 drives anxiety through this pathway.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by poly-glutamine expansion in the mutant huntingtin (mHTT) protein. While the pathogenesis involves both cell-autonomous and non-cell-autonomous mechanisms, the role of specific intercellular crosstalk in HD remains unclear. The PLP-150Q mouse model, which expresses mHTT selectively in oligodendrocytes, serves as an excellent platform for studying the progression of HD in these cells. RNA sequencing of PLP-150Q mouse brains revealed significant alterations in immune-inflammatory pathways and glial dysfunction, particularly in the corpus callosum and striatum. Notably, we observed an age-dependent upregulation of key inflammatory factors specifically within the corpus callosum. Western blot and immunohistochemical analyses further demonstrated reactive gliosis, characterized by elevated Iba1⁺ and CD68⁺ microglia, as well as GFAP⁺ and S100β⁺ astrocytes, alongside decreased myelin protein levels. Our findings suggest that mHTT in oligodendrocytes triggers age-dependent inflammation, contributing to HD progression and revealing new mechanisms in its pathogenesis.

Polymodal sensory neurons integrate diverse stimuli for environmental perception, but their modality discrimination mechanisms remain unclear. We focused on Caenorhabditis elegans inner labial type 1 (IL1) neurons, key polymodal neurons mediating mechanical and cold responses, and identified a hierarchical channel system supporting their multimodal function. Specifically, DEG-1 sodium channels are dedicated mechanotransduction receptors; GLR-3 glutamate receptors are the main rapid cold sensors, driving cold-induced calcium signals and behaviors; TRPA-1 bidirectionally modulates mechanical adaptation via calcium signaling and promotes cold-related longevity. This framework reveals a polymodal design logic: dedicated channels (DEG-1/GLR-3) process discrete modalities in parallel for specificity, while TRPA-1 regulates both. Our work provides a molecular blueprint for IL1's precise stimulus processing, offering insights into conserved multimodal integration mechanisms across lineages.

The development of a complex nervous system relies on precisely regulated heterogeneity and population stability among multiple types of neural stem cells (NSCs). In Drosophila melanogaster, the larval NSCs consist of type I neuroblasts (I NBs) and type II neuroblasts (II NBs). While the division pattern of II NB lineages is similar to the cortical expansion of primates, the detailed mechanism governing their maintenance is still not completely understood. Here, we demonstrate that the N-myristoyl transferase (NMT) in Drosophila serves as a critical regulator to maintain II NBs identity through N-myristoylation. Mechanistically, NMT myristoylates the proteasome subunit P26s4 that negatively regulates Hairless, an antagonist of Notch, consequently sustaining normal Notch activity. In human brain organoids, the function of NMT is conserved in the maintenance and proliferation of NSCs. Overall, this research not only reveals significant roles of NMT and N-myristoylation in II NB maintenance but also highlights a novel mechanism of how post-translational modification (PTM) regulates the homeostasis among heterogeneous NSCs during neurogenesis.

Interleukin-33 (IL-33) regulates immune responses in central nervous system diseases. This study investigates the effect of IL-33 on astrocyte phenotypic transformation in Parkinson's disease (PD). The associations of IL-33, soluble growth-stimulating expression gene 2 (sST2), with PD severity and clinical symptoms were examined. IL-33 supplementation and knockdown were applied in vivo and in vitro to assess IL-33's impact on neuron loss, astrocyte polarization, and inflammation. Transcriptome sequencing was conducted to identify hub genes and pathways regulated by IL-33 in astrocytes, with validated in primary astrocytes. Plasma sST2 levels were elevated in PD patients and correlated with PD severity, while IL-33 decreased with disease progression. In PD models, IL-33 supplementation improved PD-like symptoms and A2 astrocyte polarization. Conversely, IL-33 knockdown worsened PD-like symptoms and neurotoxic polarization. RNA-seq identified the PENK-ERK/MAPK pathway as the key regulator of IL-33-mediated astrocyte transformation. In conclusion, IL-33 plays a crucial role in regulating astrocytes in PD.

Activation of spinal cord neural stem cells (NSCs) and subsequent neurogenesis holds a promising alternative for spinal cord injury (SCI) repair. Our previous study demonstrated that complement C3a, derived from reactive astrocytes, inhibits NSC proliferation by suppressing protein aggregate clearance through the deubiquitinating enzyme ubiquitin carboxy-terminal hydrolase L1 (UCHL1)-proteasome system post-SCI. However, the potential molecular mechanism by which C3a modulates NSC activation via this pathway remains unclear. Here, we revealed that C3a/C3a receptor (C3aR) signaling activated NF-κB p65, which in turn inhibited Nrf2 activity and UCHL1 expression, resulting in diminished proteasome activity and the accumulation of protein aggregates, and ultimately impaired NSC activation. Both knockdown of NF-κB p65 and Nrf2 upregulation restored UCHL1 expression and proteasome activity in vitro, promoting NSC activation by enhancing protein aggregate clearance. Mechanistically, we found that NF-κB p65 regulated Nrf2 activity through a dual mechanism: (1) promoting Keap1-dependent ubiquitination and proteasome degradation of Nrf2; (2) inhibiting protein kinase C-mediated Nrf2 phosphorylation and nuclear translocation. Using the dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) analysis, we further identified UCHL1 as a direct transcriptional target of Nrf2. Importantly, in vivo experiments using SCI mice confirmed that either C3aR blockade, NF-κB p65 knockdown, or Nrf2 overexpression could rescue SCI-induced UCHL1 downregulation. Together, this study uncovers the C3a-NF-κB p65-Nrf2-UCHL1-proteasome axis as a critical regulator of NSC activation after SCI. This may provide novel molecular targets and intervention strategies for SCI repair.

Butyrate, a short-chain fatty acid (SCFA) produced by gut microbiota, plays crucial roles in maintaining intestinal homeostasis and modulating the gut-brain axis. Dysbiosis and SCFA imbalances are increasingly recognized as contributors to disease pathogenesis. A decrease in butyrate-producing bacteria leads to reduced butyrate levels, which have been linked to increased intestinal permeability, systemic inflammation, and neuroinflammation. Emerging evidence highlights a potential therapeutic role for butyrate in Parkinson's Disease (PD). This review examines butyrate's origins, functions, and mechanisms in the gut, its impact on the gut-brain axis, and its relevance in both "brain-first" and "gut-first" PD models. We also explore the effects of butyrate supplementation in animal models and human clinical studies, highlighting its promise as a therapeutic agent for PD. The understanding of butyrate as a versatile metabolite may pave the way for innovative strategies to prevent or manage PD, stressing the need for integrated approaches targeting both the nervous and gastrointestinal systems.

Cochlear hair cell (HC) damage is a primary cause of sensorineural hearing loss. In this study, we performed metabolomic profiling of cochlear sensory epithelium following neomycin-induced HC injury and identified elevated arginine metabolism as a key metabolic characteristic of damaged HCs. Using a highly sensitive and specific biosensor, we confirmed that injury induced an increase in arginine levels within cochlear HCs. By manipulating the levels of arginine and its downstream metabolites, we discovered that unmetabolized arginine exerts a strong protective effect on cochlear HCs, independent of its downstream metabolites, such as nitric oxide. Furthermore, integrated metabolomic and transcriptomic analyses revealed that arginine plays a critical role in reprogramming phospholipid metabolism. Arginine supplementation enhanced membrane phospholipid saturation through the Lands cycle and de novo lipogenesis, and protected HCs from phospholipid peroxidation-induced membrane damage and subsequent cell death. Notably, arginine supplementation protected hearing from both noise- and aminoglycoside-induced injury in mice. These findings underscore the role of unmetabolized arginine in modulating phospholipid metabolism and preventing membrane damage in cochlear HCs, highlighting that targeting phospholipid metabolism is an effective hearing protection strategy.

A disintegrin and metalloprotease 17 (ADAM17) is a membrane-bound enzyme that cleaves cell-surface proteins. Here, we discovered that neuronal ADAM17-mediated signaling supports the reduction of inhibitory presynaptic inputs to the pre-sympathetic glutamatergic neural hub, located in the paraventricular nucleus of the hypothalamus (PVN), upon stimulation by angiotensin II (Ang-II). For Ang-II-induced disinhibition, targeting microglial migration had an effect similar to ADAM17 knockout in glutamatergic neurons. Ang-II promoted neuron-mediated chemotaxis of microglia via neuronal CX3CL1 and ADAM17. Inhibiting microglial chemotaxis by targeting CX3CR1 abolished the Ang-II-induced microglial displacement of GABAergic presynaptic terminals and significantly blunted Ang-II's pressor response. Using conditional and targeted knockout models of ADAM17, an increase in the contact between pre-sympathetic neurons and reactive microglia in the PVN was demonstrated to be neuronal ADAM17-dependent during the developmental stage of salt-sensitive hypertension. Collectively, this study provides evidence that neuronal ADAM17-mediated microglial chemotaxis facilitates the disinhibition of pre-sympathetic glutamatergic tone upon hormonal stimulation.