Molecular Brain最新文献

Alzheimer's disease (AD) originates from both central and peripheral pathways. The gut microbiota is a clear risk factor. In AD, microbiota imbalances drive immune system activation, disrupt protective barriers, and alter neuromodulatory signaling. Additionally, gut microbiota dysbiosis has been identified as a risk factor for AD. Recent research indicates that dysbiosis of the microbiota in AD is linked to immune activation, barrier dysfunction, and neuromodulatory signaling. Studies of AD pathology reveal that short-chain fatty acids, indole derivatives, and bile acids can have both protective and harmful effects. New strategies, such as probiotics, dietary changes, and fecal microbiota transplantation, may influence disease progression in AD. However, conflicting methods, unaccountable motives, and ethical concerns surrounding microbiome interventions pose significant hurdles. To translate findings related to the gut-brain axis into effective solutions, we need standardized multi-omics approaches, personalized therapies, and oversight from regulatory authorities. Ultimately, leveraging insights from the gut microbiome holds great promise for transforming how we diagnose, prevent, and treat AD.

Here, we review recent findings on the development, functions, and alterations of perineuronal nets (PNNs) in relation to neurodevelopmental pathologies. PNNs are dense extracellular matrix structures primarily found in the central nervous system, comprising a heterogeneous array of components surrounding neurons. They play a crucial role in neuronal maturation and function, particularly in synapse formation and stabilization, which impacts higher-order brain connectivity. Emerging evidence underscores the dynamic changes in PNN composition and distribution during neuronal plasticity, with PNN remodeling shown to influence social and cognitive behaviors such as learning and memory. Conversely, disruptions in PNN dynamics have been implicated in developmental brain disorders. This review aims to present recent advancements in PNN neurobiology and to integrate these findings into our understanding of the mechanisms underlying neurodevelopmental pathogenesis.

Stroke is a major cause of morbidity and mortality worldwide. There is an urgent need for effective neuroprotective agents to reduce brain injury. SARM1 (sterile alpha and TIR motif-containing 1) has been identified as a key mediator of axonal degeneration. However, its role in stroke and the underlying mechanisms remain insufficiently understood. In the present study, a mouse model of stroke with focal infarction in the cortex was used to investigate the potential relation between SARM1 and post-stroke brain injury. We found that SARM1 expression increased in neurons of the peri-infarct cortex at an early stage after photothrombotic stroke induction (PTI) and was evenly distributed between excitatory and inhibitory neurons. Deficiency of SARM1 improved neurological performance, reduced the infarct volume and the inflammatory response including reactive gliosis and TNF-α level after PTI. Meanwhile, SARM1 deficiency promoted neuronal preservation in the peri-infarct cortex and mitigated axonal degeneration, possibly because of reduced NAD⁺ consumption of neurons in the peri-infarct cortex. Additionally, we found that SARM1 deficiency inhibited glial scar formation and decreased activated microglia. FK866 and DSRM-3716, two recently reported pharmacological inhibitors of SARM1, failed to alleviate brain injury in mice with stroke. Our findings demonstrate that SARM1 deficiency attenuates ischemic neuronal injury and improves neurological performance post PTI, suggesting that the SARM1 signaling pathway could serve as a potential therapeutic target for stroke in the future.

The Voltage-gated sodium channel NaV1.8 is a critical determinant of nociceptive signaling in primary sensory neurons. Here, we evaluated the analgesic potential of suzetrigine, a potent clinically approved NaV1.8 blocker, using electrophysiological, behavioral, and tolerance paradigms in mice. Whole-cell recordings from dorsal root ganglion neurons revealed that suzetrigine inhibited tetrodotoxin (TTX)-resistant sodium currents in a concentration-dependent manner (IC₅₀ = 0.35 ± 0.17 μM), consistent with high-affinity NaV1.8 inhibition. In vivo, intraperitoneal administration of suzetrigine significantly reduced nocifensive behaviors in the formalin test, attenuated CFA-induced thermal hypersensitivity, and reversed mechanical hyperalgesia in the partial sciatic nerve injury-induced neuropathy model. Importantly, repeated dosing did not produce tolerance in a chronic administration paradigm. Although suzetrigine showed limited efficacy in clinical trials for neuropathic pain, its robust analgesic effects in mouse models underscore the challenges of translating preclinical findings to human neuropathic pain, while still supporting the potential of NaV1.8-targeted therapies.

Schizophrenia is known as a complex and devastating mental disorder due to its profound impact on individuals, families, and society. Emerging evidence proposes that mitochondria play a central role in schizophrenia. Here, we investigated whether cerebrolysin (CBL) can alleviate anxiety-like behaviors and cognitive deficits through a mechanism involving the CREB/PGC-1α pathway. In this study, 30 male BALB/c mice were randomly assigned to three different groups: Control, Ketamine, and Ketamine + CBL. Intraperitoneal injection of ketamine was performed at 20 mg/kg for 14 consecutive days. CBL was delivered intraperitoneally at 2.5 mL/kg once daily for seven days, starting from the 8th day to the 14th day of the experiment. The novel object recognition and elevated plus-maze tests were used to assess episodic-like memory and anxiety, respectively. Hippocampal tissue was examined not only for alterations in mitochondrial activity, encompassing ATP production and levels of reactive oxygen species (ROS), but also for estimating CREB, p-CREB, and PGC-1α protein levels. Behavioral results indicated that treatment with CBL reversed anxiety-like behavior and cognitive dysfunction caused by ketamine. Additionally, ketamine increased the production of ROS and reduced ATP levels in the hippocampus, while CBL treatment restored these changes. Furthermore, CBL therapy upregulated the hippocampal expression of the proteins CREB, p-CREB, and PGC-1α compared with the ketamine-treated animals. It is speculated that treatment with CBL can attenuate ketamine-induced cognitive deficits and anxiety-like behaviors through the upregulation of the CREB/PGC-1α pathway and the improvement of mitochondrial function.

Tau hyperphosphorylation has been considered a major contributor to neurodegeneration in Alzheimer's disease (AD) and frontotemporal dementia, and related tauopathies have gained prominence in the development of therapies for these conditions. Glial responses are key features of AD and frontotemporal dementia, and are associated with neuroinflammation. Numerous transgenic mouse models that recapitulate critical AD-like pathology and cognitive impairment have been developed to examine pathogenic mechanisms and evaluate therapeutic approaches targeting tau and glial reactivity. Glial reactivity and neuroinflammation coincide with tau hyperphosphorylation, which induces behavioral impairment; however, the specific correlation between glial cell activation and abnormal behavior remains unknown. In this study, we investigated changes in glial cell gene expressions related to abnormal behaviors in rTg4510 mice, which phenocopy the tau pathology, neuroinflammation, and neurodegeneration observed in human tauopathies. Both 4- and 6-month-old rTg4510 mice displayed significantly impaired nest-building behavior compared with control mice. Paired association learning was also impaired in 4-month-old rTg4510 mice. Moreover, rTg4510 mice of both age groups exhibited abnormal exploratory behavior, and these mice spent a longer time in the open arms of the plus-maze test than control mice. Using a magnetic-activated cell-sorting technique, we analyzed glial cell gene expressions related to neuroinflammation, phagocytosis, and amyloid synthesis in the prefrontal cortex of rTg4510 mice. Regression analysis of glial gene expressions and behavioral tests revealed that various glial reactivities were associated with behavioral abnormalities. Our findings suggest specific genetic characteristics of glial cells that may lead to abnormal behavior in rTg4510 mice.

Parvalbumin-positive (PV+) interneurons are the most abundant type of interneurons in the cortex. Its characteristic high-frequency non-accommodating firing pattern is critical for cortical inhibition, network activity, and mouse behavior. In the brain, neuromodulation via G protein-coupled receptors (GPCRs) regulates neuronal activities, including the output of neurons. GPCRs are the largest receptor superfamily, and there are GPCRs called "orphan GPCRs" whose endogenous ligands are still not clear. Meanwhile, studies have shown that some of them are constitutively active, but the modulation of these GPCRs on neuronal activity is far from clear. Among orphan GPCRs, Gpr176 is a constitutively active GPCR known for its role in the circadian rhythm in the central nervous system. In the present study, we found that the expression of Gpr176 was mainly expressed in PV + interneurons in the prefrontal cortex, and the knockdown of Gpr176 increased the output of PV + interneurons by increasing the membrane potential change in the repolarizing phase of action potentials in a train. We also found that the synaptic activities of these neurons were not affected. Furthermore, we observed changes in behaviors of mice with the knockdown of Gpr176 in the PV + interneurons of the prefrontal cortex. These data suggest an important role of Gpr176 in the regulation of intrinsic membrane properties of PV + interneurons in the prefrontal cortex.

Substance use disorders, particularly drug addiction, are complex neurophysiological conditions characterized by cycles of compulsive drug use, withdrawal symptoms, and relapses. Methamphetamine (MA) addiction evolves through repeated exposure, altering brain circuits related to reward and neuroplasticity. The need for reliable biomarkers to diagnose and monitor MA addiction has become increasingly critical in clinical practice. In this study, we explored the time-dependent transcriptomic changes in the rat striatum immediately after short-term abstinence following MA self-administration. Using a rat model, we conducted RNA sequencing to analyze the transcriptomic alterations in the striatum immediately after the self-administration and short-term abstinence phases (12- and 24-h post-MA). Through protein-protein interaction (PPI) network analysis and gene expression pattern assessment, we identified key genes that demonstrated significant expression changes. These genes were strongly linked to reward mechanisms, synaptic plasticity, and memory processes, suggesting a role in mediating MA-associated behaviors. Understanding the expression dynamics of these genes provides valuable insights into the molecular mechanisms underlying MA addiction and offers a foundation for developing diagnostic tools and therapeutic strategies targeting addiction-related neural adaptations.

RNA modifications serve as dynamic regulators of neural plasticity through their ability to fine-tune transcript stability and splicing. Pseudouridine (Ψ), an evolutionarily conserved RNA modification catalyzed by pseudouridine synthases, plays established roles in neurodevelopment, yet its functional significance in activity-dependent behavioral adaptation remains poorly defined. Here, we investigate Ψ-mediated epitranscriptomic regulation within the infralimbic prefrontal cortex (ILPFC), a brain region requiring precise synaptic remodeling for the clinically relevant form of fear extinction memory. Combining transcriptome-wide pseudouridylation profiling with behavioral analysis in mice, we identified selective Ψ enrichment at exons of synaptic regulatory genes within ILPFC during fear extinction learning. Fear extinction in the ILPFC drives concomitant exonic Ψ deposition and upregulation of synaptogenic transcripts, processes that involve pseudouridine synthase PUS7. Crucially, PUS7 knockdown in the ILPFC selectively impaired fear extinction memory formation without altering baseline fear expression, establishing a causal link between Ψ-dependent RNA processing and activity-dependent synaptic structural remodeling in this microcircuit. Our findings demonstrate that PUS7-mediated Ψ modification spatiotemporally regulates activity-dependent RNA dynamics in the ILPFC, providing the evidence that epitranscriptomic mechanisms precisely coordinate synaptic gene expression within behaviorally defined brain sub-region. This work bridges molecular RNA biology with systems neuroscience, revealing a novel mechanism for activity-dependent regulation of fear extinction in ILPFC.