Neuroscience bulletin最新文献

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.

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.

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.

Interaction between Müller cells and microglia aggravates neuroinflammation, resulting in retinal ganglion cell (RGC) death in glaucoma. Here, we investigated how tumor necrosis factor-alpha (TNF-α) produced by activated microglia mediates the crosstalk between Müller cells and microglia and impacts RGC injury in a chronic ocular hypertension (COH) glaucoma model. In COH retinas, elevated TNF-α induced the activation of Müller cells and microglia, and recruited microglia to the ganglion cell layer. Co-culture with Müller cells enhanced TNF-α-induced microglial activation, migration, and proliferation. Both in vivo and in vitro experiments confirmed that chemokine C-C motif ligand 2 (CCL2), primarily released from Müller cells, mediated the TNF-α-induced effects on microglia in COH retinas. Knockdown of CCL2 attenuated RGC damage and vision loss. Our results demonstrate that TNF-α released from microglia induces the secretion of CCL2 from Müller cells, thus inducing microglial activation and migration, exacerbating retinal neuroinflammation and RGC injury in glaucoma.

Cortico-thalamic projections (the hyper-direct pathway) are implicated in levodopa-induced dyskinesia (LID), a challenging complication in the advanced stages of Parkinson's disease (PD). Excessive beta and gamma activity in PD and LID has frequently been reported in recent cross-sectional studies. We aimed to investigate the temporal features of beta and gamma activity in the hyper-direct pathway during the development of PD and LID in rats, as well as the regulatory role of the dopamine receptors DI (D1Rs) and DIII (D3Rs) in these disorders. We recorded motor behavior and electrophysiological data during the development of PD and LID, and after interventions with D1R and D3R antagonists and agonists. We demonstrated exaggerated beta-band activity in the PD state and excessive gamma-band activity during on-state dyskinesia. Subsequently, process-dependent increased beta activity correlated with bradykinesia during PD modeling, while process-dependent increased gamma activity correlated with dyskinesia under the cumulative effects of levodopa during on-state dyskinesia. Finally, both D1Rs and D3Rs were found to be involved in regulating dyskinesia and gamma activity. Dynamic oscillations are closely associated with motor behavior, and mapping dynamic oscillations may be associated with optimizing deep brain stimulation parameters and developing personalized neurotherapeutic targeting. Moreover, D1Rs and D3Rs may ameliorate dyskinesia by mediating gamma oscillations.

The temporal pole (TP), one of the most expanded cortical regions in humans relative to other primates, plays a crucial role in human language processing. It is also one of the most structurally and functionally asymmetric regions. However, whether the functional architecture of the TP is shared by humans and macaques is an open question. We used spectral clustering algorithms to define a cross-species fine-grained TP atlas with different anatomical connectivity patterns. We identified three similar subregions, two ventral and one dorsal, within the TP in both humans and macaques. The parcellation scheme for the TP was validated using functional gradient mapping, anatomical connectivity and resting-state functional connectivity pattern analysis, and functional characterization. Furthermore, in conjunction with the Allen Human Brain Atlas, we revealed the molecular basis for the functional connectivity patterns of each human TP subregion. In addition, we compared the hemispheric asymmetry in mean gray matter volume, anatomical connectivity fingerprints, and whole brain functional connectivity patterns to reveal the evolutionary differences in the TP and found different asymmetric patterns between humans and macaques. In conclusion, our findings reveal that the asymmetry in structure and connectivity may underpin the hemispheric functional specialization of the brain and provide a novel insight into understanding the evolutionary origin of the TP.

Sepsis-associated encephalopathy (SAE) is a severe neurological syndrome marked by widespread brain dysfunctions due to sepsis, yet the underlying mechanisms remain elusive. The current study, using a Lipopolysaccharide (LPS)-induced septic rat model, revealed the hyperphosphorylation of tau and cognitive impairments, accompanied by the release of inflammatory cytokines and activation of glial cells in the hippocampal dentate gyrus region of septic rats. Proteomic and bioinformatic analyses identified C-X-C motif chemokine ligand 10(CXCL10) as a central regulator of neuroinflammation. LPS triggered CXCL10 secretion in astrocytes, and astrocyte-conditioned medium from LPS-treated astrocytes induced tau hyperphosphorylation and synaptic deficits. Recombinant CXCL10 recapitulated these effects in vitro and in vivo. Blocking CXCL10-CXCR3 interaction reversed tau phosphorylation, synaptic impairment, and cognitive decline. Mechanistically, CXCL10-CXCR3 interaction activated CaMKII, driving tau hyperphosphorylation, while CaMKII inhibition restored synaptic protein levels. These findings establish CXCL10 as a key driver of tau pathology in SAE and suggest CXCL10-CXCR3 as a therapeutic target for sepsis-induced cognitive impairments.