Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by the loss of dopaminergic neurons and widespread transcriptomic dysregulation across disease stages. Patients commonly exhibit motor symptoms such as tremors, rigidity, and bradykinesia, alongside non-motor symptoms including depression and cognitive decline. While previous research has largely focused on protein-coding genes, growing attention is being directed toward the regulatory roles of non-coding RNAs in PD pathogenesis-particularly the interplay between circular RNAs (circRNAs) and microRNAs (miRNAs). Emerging evidence indicates that circRNAs can act as competing endogenous RNAs (ceRNAs), modulating gene expression by sequestering miRNAs and thereby mitigating miRNA-mediated repression of target mRNAs. In this study, we performed a dynamic transcriptomic analysis across four PD stages using RNA-seq data to identify differentially expressed circRNA-miRNA-mRNA networks. We constructed stage-specific ceRNA networks by selecting positively co-regulated circRNAs and linear transcripts that were co-expressed exclusively within the same disease stage. Among the upregulated circRNAs with predicted ceRNA activity, circPRDM2 and circHSH2D were identified as uniquely expressed in PD patients. Additionally, we assessed the coding potential of the predicted target genes to further elucidate the regulatory impact of circRNAs on mRNA expression. Our findings provide new insights into the post-transcriptional regulatory mechanisms involved in PD and highlight candidate stage-specific ceRNA axes that may serve as potential biomarkers or therapeutic targets.

Long-lasting synaptic changes enable memory storage and regulate recall in the brain. Our previous work established that generation of multi-innervated dendritic spines (MISs), spines with typically two excitatory presynaptic inputs, underlies hippocampal memory formation in aged, but not young mice. The identification of MIS generation was done by ultrastructural analysis in hippocampal CA1 stratum radiatum 24 h after contextual fear conditioning (CFC). However, our analysis did not consider multi-spine boutons (MSBs), which were recently shown to increase in complexity (complex MSBs are pre-synaptic boutons connecting with more than two post-synapses) at a later time point after CFC in young age. Therefore, we re-analyzed our three-dimensional electron microscopy images and show that, unexpectedly, MSB complexity, decreases in CA1 stratum radiatum 24 h after CFC. The decrease in MSB complexity occurred both in young and aged mice, indicating that aging has no impact on this synaptic change. Considering that complex MSBs link the activity of multiple postsynaptic neurons, we suggest that after CFC a decrease in MSB complexity may be required for specific memory recall.

Astrocytes, the most abundant glial cell type in the central nervous system (CNS), are essential for maintaining neural homeostasis, forming gliovascular unit, and modulating synaptic function. However, commonly used astrocytic markers often display regional variability or lack strict specificity, limiting their reliability for consistently identifying astrocytes across brain regions. To address this limitation, we generated a novel transgenic mouse line (AldoC BAC-GFP) that expresses green fluorescent protein (GFP) under the control of the aldolase C (AldoC) promoter using modified bacterial artificial chromosome (BAC) technology. AldoC is an enzyme abundantly expressed in astrocytes. We confirmed that GFP-expressing cells in these mice co-express endogenous AldoC and are co-labeled with established astrocytic markers, thereby validating their astrocytic identity. Importantly, GFP expression was largely restricted to astrocytes throughout diverse brain regions. Moreover, GFP-positive astrocytes in brain slices exhibited the characteristic linear-shaped passive conductance of mature astrocytes. Collectively, these findings demonstrate that AldoC BAC-GFP transgenic mice represent a reliable and broadly applicable model for functional studies of astrocytes in the CNS.

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.

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.

Septin-3 and Septin-5 are components of the septin cytoskeleton highly expressed in the nervous system, yet the extent of their shared and distinct roles is not fully understood. We recently demonstrated that Septin-3 regulates late-phase long-term potentiation (L-LTP)-dependent invasion of smooth endoplasmic reticulum (sER) into dentate gyrus (DG) spines. mice exhibit normal synaptic ultrastructure in the hippocampal DG, CA3, and CA1, yet the fraction of sER-containing spines is reduced; behaviorally, they show selective deficits in 1-day object recognition and 1-day contextual fear memory, whereas cued fear conditioning and contextual memory tested at 1 month are intact. Here, using adult male mice, we tested whether morphological and behavioral phenotypes identified in mice are shared or subunit-specific. Electron microscopy showed no detectable differences in synapse density, spine volume, and postsynaptic density (PSD) area in the hippocampal DG, CA3, and CA1, with an unchanged fraction of sER-containing spines relative to wild-type littermates. Behaviorally, mice were impaired in recent (1 day) and remote (1 month) contextual fear memory, but were normal in 1-day novel object recognition memory and in recent and remote cued fear memory. The shared and distinct structural and behavioral phenotypes observed in and mice suggest either sER-independent common mechanisms or subunit-specific ones for recent contextual fear memory deficit, and indicate a Septin-5-dependent contribution to remote contextual fear memory.

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 (IC = 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.

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.

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.

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.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and neuroinflammation, primarily mediated by microglia. In this study, we investigate the role of adenylate kinase 5 (AK5) in microglial function and its association with AD-related pathology. Analysis of brain tissues from AD patients and AD model mice revealed a significant reduction in AK5 expression. In vitro knockdown of AK5 in microglial cells attenuated lipopolysaccharide-induced pro-inflammatory responses, including decreased nitric oxide and tumor necrosis factor-alpha production, while enhancing phagocytic activity. Moreover, AK5 silencing induced metabolic reprogramming, evidenced by reduced lipid droplet accumulation and adipose triglyceride lipase mRNA levels, alongside increased farnesoid X receptor mRNA expression. Genome-wide association studies further identified two AK5 single nucleotide polymorphisms (SNPs), rs59556669 and rs75224576, significantly associated with hippocampal and amygdala atrophy as well as increased AD risk. Notably, these SNPs were not in linkage disequilibrium with the apolipoprotein E (APOE) locus, suggesting that AK5 may represent an independent genetic risk factor for AD. Collectively, our findings identify AK5 as a key regulator of microglial immune and metabolic function. The presence of AK5 variants may contribute to AD susceptibility, and AK5 expression or genetic status could serve as a potential biomarker for early risk assessment. Further exploration of AK5-targeted interventions may provide new therapeutic avenues for AD prevention or treatment.

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.

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.

Combining cellular, animal, and MR analyses from three independent cohorts, we identified PDK1 as a consistent risk factor for ALS development, highlighting its potential as a therapeutic target. To further elucidate PDK1's pathogenic mechanisms, we conducted transcriptomic profiling. Samples were stratified into PDK1 high- and low-expression groups. GO and KEGG analyses demonstrated that upregulated DEGs were enriched in pathways involving β-CATENIN, cell adhesion and Ribosome, suggesting a potential role for WNT/β-catenin signaling activation in ALS pathogenesis. To further validate the consistent risk association of PDK1 with ALS across multiple datasets, we utilized 4-month-old SOD1G93A transgenic mice, 4-month-old C9orf72 transgenic mice, and SOD1-overexpressing HEK293T cells. Significant upregulation of PDK1 mRNA was observed in all models, and a significant increase in protein abundance was found in SOD1G93A. This provides strong experimental evidence for the results of the MR study. These results indicate that PDK1 may affect the pathogenesis of amyotrophic lateral sclerosis through genetic variations and transcriptional dysregulation, and may play an important role in the occurrence and development of the disease.

Ischemic stroke, the most prevalent form of stroke, severely impacts human health due to its high incidence, disability, and mortality rates. The complex pathological response to ischemic stroke involves the interplay of various cells and tissues. Among these, astrocytes and microglia, as essential components of nervous system, play significant roles in the pathological processes of ischemic stroke. In addition to their individual functions, an increasing number of studies have revealed that the interaction between astrocytes and microglia is crucial following ischemic stroke. It integrates current research reports to examine and clarify the effects of interaction between the microglia and astrocytes on the nervous system after ischemic stroke, aiming to provide new insights and approaches for future academic research and disease treatment.

Acupuncture has been found to alleviate depressive behaviors caused by chronic unpredictable mild stress (CUMS) in rats. This study explores how acupuncture improves depressive behaviors by modulating synaptic plasticity in the lateral habenula through stimulation of Fengfu and Shangxing acupoints. Male Sprague-Dawley rats were divided into six groups, with the control group excluded. Undergoing a 28-day CUMS protocol, the intervention groups included sham needle stimulation, daily stimulation at the Fengfu (GV16) and Shangxing (GV23) acupoints on alternate days, fluoxetine (2.1 mg/kg, 0.21 mg/mL), or electroacupuncture treatment. All rats were weighed and subjected to behavioral tests. Western blotting was used to examine the expression of the BDNF/ERK/mTOR signaling pathway and associated proteins in the lateral habenula. The monoamine neurotransmitters in serum were measured using ELISA kits. Immunofluorescence staining was used to determine the expression levels of BDNF, TrkB, SYP, and PSD95 in the lateral habenula. Golgi staining was employed to quantify dendritic spine morphology. The study showed that CUMS led to depressive-like behaviors and downregulated the BDNF/ERK/mTOR signaling pathway in the lateral habenula. It also resulted in reduced expression of monoamine neurotransmitters in peripheral blood and changes in dendritic spine length and density. Importantly, both fluoxetine and acupuncture had varying degrees of preventive and restorative effects on these changes. The findings of this study suggest that acupuncture has the potential to activate the BDNF/ERK/mTOR signaling pathway in the lateral habenula of CUMS rats, thereby enhancing synaptic plasticity and exerting an antidepressant effect.

The ErbB4 gene is a schizophrenia (SCZ) risk gene that interacts with PSD-95 via its C-terminus, a connection disrupted in SCZ patients. To investigate the functional significance of this interaction, we generated a zygotic mutant mouse lacking the terminal valine "V" residue from the ErbB4 TVV motif. The homozygous (homo) mice exhibited disrupted ErbB4‒PSD-95 interactions and SCZ-relevant behavioral deficits, including impairments in motor function, sensory processing, and memory performance. Structural computational analysis further revealed that the mutation altered the structural conformation of the ErbB4 C-terminus, which affected its binding affinity for PSD-95. Mechanistically, the mutation led to up-regulated but less activation of ErbB4 and down-regulated but overactivation of PSD-95, possibly representing a failed compensatory response aiming to maintain the ErbB4-PSD-95 interaction. Additionally, homo mice presented NMDAR2A subunit specific hypofunction and reduced GAD67 expression. These findings highlight that the ErbB4-PSD-95 interaction is a critical molecular link in the synaptic dysfunction and behavioral abnormalities associated with SCZ.

Brain-derived neurotrophic factor (BDNF) is a critical blood protein for brain function; however, its genotypic influence on clinical outcomes and brain structure following mild traumatic brain injury (mTBI) remains unclear. This study investigated the relationship between BDNF polymorphisms and cognitive impairment, symptom severity, and cortical structural injury in mTBI patients.

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.

Current treatments for neuropathic pain often provide limited relief and are associated with significant side effects. Transcutaneous auricular vagus nerve stimulation (taVNS) shows promise as a non-pharmacological analgesic approach; however, its optimal therapeutic configuration and underlying brain mechanisms remain incompletely understood. This study investigated the analgesic effects of taVNS on neuropathic pain in a mouse model induced by partial sciatic nerve ligation (PSL), exploring mechanisms and optimizing configurations. PSL-induced neuropathic pain in mice, characterized by mechanical allodynia, was significantly alleviated by taVNS. The most robust analgesic effects were observed with multiple bilateral taVNS sessions, administered once daily for three consecutive days, with effects persisting for at least 48 h post-stimulation. Immunohistochemical analysis of c-Fos expression revealed that taVNS increased neural activity in the dorsal raphe nucleus (DRN), a key source of serotonin, while simultaneously reducing activity in the central amygdala (CeA), a region critical for pain processing and affective responses. Further experiments demonstrated that the analgesic effects of taVNS were abolished by systemic administration of p-chlorophenylalanine, an inhibitor of serotonin synthesis. These findings underscore the critical role of serotonin signaling in mediating taVNS-induced analgesia for neuropathic pain. The study also highlights the importance of stimulation parameters, identifying a multiple bilateral configuration as particularly effective. Our results suggest that taVNS, potentially acting via the DRN-serotonergic system to modulate limbic structures like the CeA, holds significant potential as a non-pharmacological therapeutic option for managing neuropathic pain.

Itch is a common symptom among patients suffering dermatological and systemic diseases, yet effective clinical treatments are currently lacking. Previous research has suggested that vesicular glutamate transporter 3 (VGLUT3)-lineage sensory neurons may play a role in inhibiting itch, but the circuit mechanisms within the spinal cord remain unclear. In this study, we employed optogenetic techniques to activate VGLUT3-lineage sensory afferents in mice and observed a significant reduction in scratching behaviors elicited by both pruritogens and mechanical stimuli. Moreover, aversive component of chemical itch assessed by conditioned place aversion (CPA) was abrogated. Viral tracing combined with electrophysiological recordings revealed synaptic connections between VGLUT3 sensory neurons and spinal dynorphin (SC) /neuropeptide Y-expressing (SC) neurons. Further pharmacological studies indicated that intrathecal injection of antagonists of neuropeptide Y1 receptor and kappa opioid receptor (KOR) separately diminished VGLUT3 neurons-mediated inhibitory effects on mechanical and chemical itch, respectively. In summary, our findings suggest that VGLUT3 sensory neurons participate in itch regulation through interactions with two classes of inhibitory neurons in the spinal cord, shedding light on potential therapeutic targets for distinct forms of itch management.