Molecular Brain最新文献

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.

Objective: 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.

Materials and methods: Sixty-one mTBI patients underwent neuropsychological assessments and MRI scans within one week post-injury, with 46 patients followed up at one month. Fifty-two healthy controls were included for comparison. Patients with mTBI exhibited clinical symptoms, cognitive impairment, and alterations in cortical thickness during in the acute phase.

Results: BDNF Met gene carriers (n = 41) and Val gene carriers (n = 20) demonstrated different cognitive performance in the acute phase and exhibited distinct recovery trajectories. Val carriers showed significantly better cognitive flexibility compared to Met carriers (p = 0.028) during the acute phase and greater improvement in clinical symptoms at one month (p = 0.035). Follow-up MRI scans revealed more extensive and statistically significant alterations in cortical thickness in Met carriers than in Val carriers (p < 0.01), particularly in regions associated with cognitive and emotional regulation.

Conclusion: These findings suggest that BDNF polymorphisms in mTBI patients are associated with brain structural changes and may serve as valuable biomarkers for identifying individuals at risk for long-term clinical symptoms and cognitive impairment.

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.

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.

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.

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^DYN) /neuropeptide Y-expressing (SC^NPY) 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.

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.