CNS Neuroscience & Therapeutics最新文献

{"title":"Brain Alterations Linked to the MPTP Mouse Model of Parkinson's Disease Uncovered by Diffusion Kurtosis Imaging and Magnetic Resonance Spectroscopy.","authors":"Ajay Modi, Sheetal Maria, Jana Ruda-Kucerova, Eva Drazanova, Iveta Harastova-Pavlova, Alzbeta Sejnoha Minsterova, Kristina Kovacovicova, Daniel Havas, Irena Rektorova, Tiago F Outeiro, Amit Khairnar","doi":"10.1002/cns.70846","DOIUrl":"10.1002/cns.70846","url":null,"abstract":"<p><strong>Aims: </strong>This study employed diffusion kurtosis imaging (DKI) and proton magnetic resonance spectroscopy (¹H-MRS) on an MPTP-induced mouse model of Parkinson's disease (PD) to examine microstructural changes linked to neuroinflammation and neurodegeneration.</p><p><strong>Methods: </strong>MPTP (20 mg/kg, i.p.) was given for 4 days, and behavioral assessment, MRI imaging, and immunohistochemistry were performed at 24 h and 72 h after last MPTP treatment.</p><p><strong>Results: </strong>At 24 h, DKI showed higher diffusivity metrics in the hippocampus and thalamus, while ¹H-MRS identified reduced Glu/tCr and Glx/tCr ratios in the striatum of MPTP-treated mice compared to saline-treated mice. Behavioral tests at 72 h revealed motor impairment and DKI showed increased diffusivity in the somatosensory cortex, thalamus, and striatum in MPTP-treated mice. Notably, at 72 h, the hippocampus showed partial recovery in diffusivity, suggesting adaptive changes or partial restoration. Higher diffusivity was observed in the cortex, striatum, and thalamus in MPTP-treated mice. Furthermore, ¹H-MRS detected a higher Tau/tCr in the striatum, while in the hippocampus, lower Gln/tCr and NAA/tCr and higher Cho/NAA were observed at 72 h in MPTP-treated mice, indicating persistent neuronal death and membrane deterioration. Immunofluorescence staining at 72 h confirmed these findings, showing a decrease in NeuN+ neurons and an increase in GFAP+ glial cells in the striatum and hippocampus, indicating neurodegeneration and gliosis. Additionally, MPTP caused a loss of dopaminergic neurons in the substantia nigra and striatum, which likely explains the higher diffusivity shown by DKI.</p><p><strong>Conclusion: </strong>These findings demonstrate DKI and ¹H-MRS are sensitive, non-invasive modalities for detecting and monitoring neurodegenerative microstructural and neurochemical changes, enhancing the understanding of PD-related pathology and progression.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":"e70846"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13093730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147721090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accelerated Magnetic Seizure Therapy for Non-Suicidal Self-Injury in Adolescents With Bipolar Depression.","authors":"Ruiqiu Zhu, Peiyu Cao, Yilin Tang, Yucheng Lin, Yifan Wang, Yantong Li, Ran Tao, Zhuma Jin, Yuxiu Sui","doi":"10.1002/cns.70880","DOIUrl":"https://doi.org/10.1002/cns.70880","url":null,"abstract":"<p><strong>Background: </strong>Adolescents with bipolar depression are typically characterized by a high prevalence of non-suicidal self-injury (NSSI), yet effective therapies remain limited. Accelerated magnetic seizure therapy (aMST) has emerged as a promising neuromodulation technique with potential cognitive advantages. However, evidence regarding its clinical efficacy, cognitive impact, neurostructural and functional alterations in adolescents remains unclear.</p><p><strong>Methods: </strong>Adolescents diagnosed with bipolar depression and comorbid NSSI received once-daily accelerated MST sessions. Clinical symptoms, including depression, anxiety, impulsivity, and emotion regulation, were assessed before and after aMST. Cognitive function was evaluated using the MATRICS Consensus Cognitive Battery (MCCB) and autobiographical memory test (AMT). Structural MRI and diffusion tensor imaging (DTI) were collected to compare the potential neurostructural and functional change induced by aMST.</p><p><strong>Results: </strong>Thirty-two adolescents completed the whole aMST protocol. Following aMST, significant reductions were observed in depressive and anxiety symptoms. Improvements were also found in impulsivity and emotion regulation. Assessment of cognitive function revealed no global impairment. Significant enhancements were found in processing speed, working memory, and visual learning, while verbal learning remained largely unchanged. Autobiographical memory (AM) performance was generally preserved, with a reduction in overgeneral autobiographical memory (OGM) for positive cues. Neuroimaging analyses demonstrated no significant changes in total hippocampal volume or hippocampal subfield volumes. DTI analyses suggested increased fractional anisotropy (FA) in the right uncinate fasciculus and increased mean diffusivity (MD) in the left superior longitudinal fasciculus following aMST.</p><p><strong>Conclusions: </strong>These findings provide preliminary evidence that aMST is associated with clinical improvement and favorable cognitive function in adolescents with comorbid bipolar depression and NSSI. The stably maintained volumes of hippocampal subfield, alongside selective white matter microstructural alterations, suggest that aMST may exert targeted neuroplastic effects while preserving structures which are critical for cognition.</p><p><strong>Trial registration: </strong>Chinese Clinical Trial Registry: ChiCTR2500114164.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":"e70880"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13098537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RFWD2 Mitigates AD-Like Cognitive Impairments via the JNK-SGK1 Signaling Pathway in Mice.","authors":"Mengjiao Ying, Xiaochuan Qi, Ao Wang, Guangshang Zhong, Wenhui Tong, Danting Yu, Gaofeng Liu, Yu Guo","doi":"10.1002/cns.70860","DOIUrl":"10.1002/cns.70860","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer disease (AD) is a degenerative disorder of the central nervous system. Its main pathological feature is the formation of neurofibrillary tangles through abnormal β-amyloid protein (Aβ) aggregation and excessive Tau protein phosphorylation. Ring finger and WD repeating domain 2 (RFWD2) is an E3 ubiquitin ligase that regulates neuronal dendrite complexity through the c-Jun N-terminal kinase (JNK) pathway. This study aimed to investigate the regulatory effect of RFWD2 on the downstream protein, serum/glucocorticoid-regulated kinase 1 (SGK1), through the JNK pathway and explore its influence on AD pathogenesis.</p><p><strong>Methods: </strong>Cognitive-level behavioral detection was performed in RFWD2^+/- mice. Cultured PC12 cells and cortical neurons were also used to analyze the changes in signaling pathways caused by the decreased expression of RFWD2 in vitro and correlations between the expression of related proteins and key signaling pathways of AD at the molecular level.</p><p><strong>Results: </strong>Decreased RFWD2 expression led to cognitive deficits in AD mice, resulting in mitochondrial swelling, fragmentation of hippocampal neurons, abnormally high reactive oxygen species levels, and an imbalance between antiapoptotic and proapoptotic proteins. This effect was significantly improved by inhibiting the JNK pathway and SGK1 protein expression. Furthermore, in vitro experiments showed that in PC12 cells and cortical neurons downregulated by RFWD2, the expression levels of p-JNK, SGK1, and p-Tau increased, and those of LC3B/Beclin-1 decreased; ROS levels increased, and apoptosis was induced; inhibiting JNK or SGK1 expression reversed these changes.</p><p><strong>Conclusion: </strong>RFWD2 regulates SGK1 expression through the JNK pathway, thereby regulating mitochondrial autophagy and apoptosis, altering the expression levels of p-Tau and Aβ proteins, inducing AD-like symptoms in mice, and promoting AD development. The RFWD2-JNK-SGK1 axis provides a valuable basis for studying the mechanisms of AD occurrence and developing early intervention strategies.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":"e70860"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13064414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147637430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-Intensity Alternating Current Stimulation as an Add-On to Multidisciplinary Intensive Rehabilitation for Parkinson's Disease: A Randomized Controlled Trial.","authors":"Ting-Ting Hou, Hong-Yu Zhang, Ke-Ke Chen, Zhao-Hui Jin, Tian Zhang, Lin Qi, Cui-Ping Xue, Qiao-Xia Zhen, Zhen-Zhen Li, Hong-Jiao Yan, Yi Zhen, Xia An, Jia Du, Yuan Su, Cui Liu, Qi-Ping Wen, Xiao-Yan Yan, Bastiaan R Bloem, Bo-Yan Fang","doi":"10.1002/cns.70909","DOIUrl":"https://doi.org/10.1002/cns.70909","url":null,"abstract":"<p><strong>Aims: </strong>In this randomized, double-blind, sham-controlled trial, we explored whether high-intensity transcranial alternating current stimulation (Hi-tACS), as an add-on to multidisciplinary intensive rehabilitation therapy (MIRT), could yield more durable quality of life (QoL) improvements than MIRT alone.</p><p><strong>Methods: </strong>Sixty patients with Parkinson's disease (PwP) (Hoehn and Yahr stages 1-3, aged 45-70) were assigned (1:1) to receive 10 days of MIRT with either twice-daily Hi-tACS (15 mA, 77.5 Hz, 40 min/session) or sham stimulation. The primary outcome was the longitudinal change in the 39-item Parkinson's Disease Questionnaire (PDQ-39) total score from baseline to 4, 12, and 24 weeks after intervention. Secondary outcomes included changes in motor and non-motor symptom scales. Adverse events were monitored throughout the intervention period.</p><p><strong>Results: </strong>Generalized estimating equation analysis revealed a significant group-by-time interaction for PDQ-39 total scores (P_{group × time} = 0.008). The Hi-tACS+MIRT group demonstrated significantly greater reductions in PDQ-39 scores than the sham-Hi-tACS+MIRT group at 4 weeks (T2: effect size = 0.68, 95% CI: 0.14-1.21; P_FDR = 0.009), 12 weeks (T3: effect size = 1.43, 95% CI: 0.80-2.05; P_FDR = 0.003), and 24 weeks (T4: effect size = 1.26, 95% CI: 0.65-1.85; P_FDR < 0.001). In addition, the Hi-tACS+MIRT group exhibited superior improvements in depression and apathy. Adverse events were mild and infrequent, with no serious adverse events reported.</p><p><strong>Conclusions: </strong>This trial demonstrated that the Hi-tACS add-on to MIRT could maintain long-term improvements in QoL and improve non-motor symptoms for PwP, providing a new strategy for PwP rehabilitation.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":"e70909"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13121914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural Representation of Exogenous and Endogenous Temporal Expectations Based on fMRI.","authors":"Zhongtian Guan, Zhixi Zhang, Jingyi Zhao, Hongbin Han, Dehua Chui, Jinglong Wu, Qingyuan He, Yixuan Yuan, Wanyi Fu, Xu Zhang, Chunlin Li","doi":"10.1002/cns.70864","DOIUrl":"https://doi.org/10.1002/cns.70864","url":null,"abstract":"<p><strong>Aims: </strong>Temporal expectations are considered as implicit timing, which is different from explicit timing. Furthermore, temporal expectations could be divided into exogenous and endogenous temporal expectations. However, it is still unclear about the neural activation under temporal expectations.</p><p><strong>Methods: </strong>In the present study, an experimental paradigm was designed for eliciting the related brain activation under exogenous temporal expectations. Three conditions were used for the exogenous temporal expectations task. In order to compare the exogenous temporal expectations related activations to the endogenous', a proper endogenous temporal expectations task was used. Brain activations were obtained by using functional magnetic resonance imaging (fMRI).</p><p><strong>Results: </strong>Exogenous temporal perception-related regions, including TPJ, MTG, thalamus, IFG, caudate, cuneus, SOG, calcarine, FEF, and SPL have a good agreement with previous studies. Furthermore, it shows that the precuneus, PCC, Brodmann area 8 (BA8), ACC, and BA10 were also activated, which overlap with regions of the mesial of the so-called \"default mode network\". Negative correlated activations to exogenous temporal expectations task (use an endogenous temporal expectations task as an analysis baseline) were also evaluated.</p><p><strong>Conclusion: </strong>We found that the sum of exogenous and endogenous temporal expectations related cerebral regions was almost the same when compared to resting-state networks (RSNs). We propose that the cerebrum could activate in two modes for cognition: one is based on endogenous temporal expectations, and another is based on exogenous temporal expectations.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":"e70864"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13104068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GABAergic Neuron Activation in the RMTg-VTA Pathway Modulates Dopaminergic Neuron Excitability and Social Stress Susceptibility in Male Mice","authors":"Guang-Yue Ma,&nbsp;Jin-Zhu Zhuang,&nbsp;Shu-Feng Li,&nbsp;Yu-E Zhang,&nbsp;Di Zhang,&nbsp;Jun Zhao,&nbsp;Zhen Peng,&nbsp;Liu Yang,&nbsp;Zhang Cao,&nbsp;Xin Xie,&nbsp;Rong Jiang,&nbsp;Hui Sun","doi":"10.1002/cns.70855","DOIUrl":"10.1002/cns.70855","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Chronic social stress is a significant risk factor for neuropsychiatric disorders such as anxiety and depression, with the ventral tegmental area (VTA) playing a pivotal role. Although chronic social defeat stress (CSDS) induces adaptations in VTA dopaminergic (DA) neurons, the role of GABAergic modulation in regulating DA neuron excitability and related behaviors remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we investigated the effects of GABA_A receptor activation on VTA DA neuron activity and social stress behaviors in a CSDS model. We employed electrophysiological recordings, immunohistochemistry, and optogenetic manipulations to assess changes in DA neuron excitability and GABAergic input from the rostromedial tegmental nucleus (RMTg).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our results show that susceptible mice exhibit enhanced spontaneous firing of VTA DA neurons and increased GABA_A receptor expression. Pharmacological activation of GABA_A receptors suppressed DA neuron hyperactivity and reversed social avoidance behavior. Moreover, optogenetic stimulation of RMTg GABAergic projections to the VTA significantly reduced DA neuron firing and mitigated social avoidance in susceptible mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings suggest that activation of RMTg GABAergic neurons projecting to VTA effectively reduces DA neuron excitability in the VTA and plays a critical role in the modulation of stress-induced behavioral deficits, offering a potential therapeutic target for neuropsychiatric disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13045366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147588967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of Microglial TRPV1 Ameliorates Brain Injury After Intracerebral Hemorrhage by Suppressing AMPK/PINK1-Mediated Mitophagy.","authors":"Kezhu Chen, Xiangyang Deng, Jun Zeng, Baoye Sun, Jingyu Yu, Tianwen Li, Junjie Zhong, Pengjie Hong, Peng Wang, Fengshi Li, Quan Zhang, Junwei Ren, Qisheng Tang, Tongming Zhu, Jianhong Zhu","doi":"10.1002/cns.70881","DOIUrl":"10.1002/cns.70881","url":null,"abstract":"<p><strong>Background: </strong>The transient receptor potential vanilloid 1 (TRPV1) is a cation channel implicated in neurological disorders. Although TRPV1 activation contributes to intracerebral hemorrhage (ICH) pathology, its microglia-specific role and underlying mechanisms remain poorly defined. This study investigates how microglial TRPV1 influences ICH injury.</p><p><strong>Methods: </strong>We utilized a mouse ICH model alongside microglia-specific TRPV1 knockout mice, BV2 cells, and primary microglial cultures. Interventions included TRPV1 antagonist capsazepine (CPZ), agonist capsaicin (CAP), microglial depletion agent PLX5622, and TRPV1 knockdown. Outcomes were assessed using immunofluorescence, behavioral tests, Western blot, magnetic resonance imaging (MRI), and transmission electron microscopy (TEM).</p><p><strong>Results: </strong>TRPV1 expression was significantly upregulated post-ICH, primarily in microglia. TRPV1 blockade with CPZ treatment reduced hematoma volume, brain edema, neuronal apoptosis, and improved neurological function, whereas CAP exacerbated injury. These benefits were replicated in microglia-specific TRPV1 knockout mice. Mechanistically, CPZ shifted microglia from a pro-inflammatory (iNOS+) to a regulatory (Arg1+) phenotype and suppressed excessive mitophagy via the Ca²⁺-AMPK-PINK1 pathway.</p><p><strong>Conclusion: </strong>TRPV1 activation in microglia exacerbates ICH injury by promoting inflammation and disruptive mitophagy. Targeted inhibition of microglial TRPV1 represents a promising therapeutic strategy for ICH.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":"e70881"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13093729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147721077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acupuncture Modulates Neurotransmitter-Related Molecules in the Amygdala to Ameliorate Generalized Anxiety Disorder.","authors":"Zhao Sun, Yixiang Wang, Xiaona Kang, Binyan Ran, Qiong Wu, Luyu Huang, Jiaxin Li, Lina Kan, Haixia Long, Jiabin Liang, Wei Shen","doi":"10.1002/cns.70847","DOIUrl":"10.1002/cns.70847","url":null,"abstract":"<p><strong>Background: </strong>Neurotransmitter imbalance is a key mechanism contributing to the heightened negative emotions and anhedonia associated with anxiety disorders. However, whether acupuncture exerts its anxiolytic effects by modulating neurotransmitter imbalance remains unclear.</p><p><strong>Methods: </strong>Seventy generalized anxiety disorder (GAD) patients were recruited and randomly assigned to acupuncture or wait-list groups. The Hamilton Anxiety Rating Scale (HAMA) and fMRI scans were used before and after treatment to assess anxiety levels and brain activity. In parallel, male Sprague-Dawley rats were divided into four groups: control, chronic unpredictable stress model (CUS), electroacupuncture (EA), and sham acupuncture (SA). The EA group received stimulation at specific acupuncture points over 21 days, while the CUS group experienced chronic unpredictable stress to induce anxiety. Behavioral assessments and molecular analyses, including qRT-PCR, Western blotting, and immunofluorescence, measured neurotransmitter levels.</p><p><strong>Results: </strong>Clinically, the acupuncture group exhibited a significant reduction in HAMA scores compared to baseline (p < 0.001), unlike the wait-list group. fMRI results indicated decreased ReHo in brain regions such as the amygdala, hippocampus, anterior and posterior cingulate cortices, putamen, and precuneus following acupuncture (GRF-corrected p-cluster < 0.05). These reductions showed overlap in the anterior and posterior cingulate cortices between both groups. A positive correlation was found between reduced ReHo in the amygdala and the decrease in HAMA scores (rs = 0.390, p = 0.023), while a negative correlation was observed between reduced ReHo in the hippocampus and illness duration (rs = -0.385, p = 0.025). In the animal model, EA improved body weight and reduced anxiety-like behaviors (p < 0.05). EA increased IGF-1 expression in the mPFC and amygdala, and decreased NR2B, GluR2 in the amygdala (p < 0.05).</p><p><strong>Conclusion: </strong>Acupuncture shows potential in treating anxiety disorders by modulating IGF-1 and NR2B expression, thus restoring neurotransmitter balance in the mPFC-amygdala pathway. In both animal models and clinical settings, acupuncture effectively reduced anxiety symptoms and induced positive changes in brain regions such as the amygdala and hippocampus. These findings provide preliminary evidence for using acupuncture in the treatment of GAD.</p><p><strong>Clinical trial number: </strong>MR-46-23-043956.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":"e70847"},"PeriodicalIF":5.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13093602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147721082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of GPR35 in the Anterior Cingulate Cortex Alleviates Neuropathic Pain and Depression-Related Behavior","authors":"Jianling Xu,&nbsp;Jingyong Zhou,&nbsp;Xiaojun Li,&nbsp;Tingting Qu,&nbsp;Changjian Zheng,&nbsp;Qingyu Cheng,&nbsp;Xiuyang Lei,&nbsp;Weidong Yao,&nbsp;Yongquan Chen,&nbsp;Bin Wang","doi":"10.1002/cns.70852","DOIUrl":"10.1002/cns.70852","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Neuropathic pain (NP) is frequently accompanied by anxiety and depression, and current treatments do not adequately address this comorbidity. The anterior cingulate cortex (ACC) plays a central role in sensory and emotional processing. However, the molecular pathways that connect these functions remain unclear. G protein-coupled receptor 35 (GPR35), an orphan receptor enriched in neurons, has been implicated in neuroinflammation and pain signaling. However, its specific involvement in NP and associated affective disturbances has not been fully elucidated.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Peripheral blood GPR35 expression was measured in human patients with NP and healthy controls. In mice, chronic constriction injury (CCI) was used to induce NP. Lentiviral knockdown or overexpression of GPR35 was performed in ACC cells. Behavioral assays were used to assess mechanical and thermal sensitivity, locomotor and anxiety metrics, cognitive performance, and depression-related behaviors. Molecular analyses included western blotting, RT-qPCR, immunofluorescence, RNA sequencing, and co-immunoprecipitation. Additional Nr4a1 knockdown and L-kynurenine (L-Kyna, a GPR35 agonist) administration were used to validate pathway involvement.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Patients with NP had higher circulating GPR35 levels, which positively correlated with pain intensity. CCI induced a time-dependent increase in GPR35 expression in the ACC of mice, accompanied by hypersensitivity and emotional disturbances. GPR35 knockdown in the ACC worsens mechanical and thermal hypersensitivity, impairs cognition, increases depression-related behaviors, and amplifies microglial activation and pro-inflammatory cytokine production. GPR35 overexpression reversed these effects by reducing hypersensitivity, improving affective behaviors, and restoring the inflammatory balance. Transcriptomic and biochemical analyses identified Nr4a1 as a key downstream effector of GPR35, and Nr4a1 knockdown eliminated the protective effects of GPR35 overexpression. GPR35 primarily regulated the PI3K/AKT pathway. Treatment with L-Kyna reduced pain hypersensitivity, improved depression-related behaviors, and decreased neuroinflammation in CCI mice.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;GPR35 is an essential regulator of NP and pain-related affective disturbances in the ACC. Its effects are mediated through the Nr4a1-dependent activation of the PI3K/AKT pathway and suppression of neuroinflammation. The pharmacological activatio","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.70852","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147580005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Ferroptosis Pathways for Synaptic Protection in Sevoflurane-Induced Cognitive Impairment: A Nanomedicine Approach","authors":"Bin Zhao,&nbsp;Changming Wang,&nbsp;Mingming Zhang","doi":"10.1002/cns.70850","DOIUrl":"10.1002/cns.70850","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Postoperative cognitive dysfunction (POCD) is an increasingly recognized neurological complication following surgery, particularly in elderly patients. It significantly hinders recovery and impairs the quality of life. Sevoflurane, a commonly used volatile anesthetic, has been implicated in enhancing the incidence and severity of POCD. At the molecular level, synaptic dysfunction is a major contributor to cognitive decline associated with POCD. Recent studies have highlighted ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, as a critical mechanism behind synaptic damage and cognitive decline.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This review synthesizes current research on the role of ferroptosis in POCD, focusing on its impact on synaptic dysfunction. We also explore the potential of nanomedicine, particularly intelligent responsive nanodrug delivery systems, in targeting ferroptotic pathways. These nanoplatforms, with their high brain delivery efficiency and specificity, have been shown to modulate ferroptosis signaling and reduce neuronal injury, thereby potentially promoting cognitive recovery.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Ferroptosis plays a significant role in exacerbating cognitive deficits by disrupting synaptic membranes and mitochondria, which contribute to synaptic dysfunction. Emerging evidence suggests that interventions targeting ferroptosis pathways can mitigate these effects, offering a novel therapeutic avenue for POCD. Nanomedicine approaches, especially those utilizing responsive nanodrug delivery systems, have shown promise in effectively targeting ferroptotic pathways with high specificity, leading to reductions in synaptic injury and enhanced cognitive recovery.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Ferroptosis is a key mechanism driving synaptic dysfunction and cognitive decline in POCD. Targeting ferroptotic pathways using nanomedicine-based strategies holds considerable promise for mitigating POCD and promoting cognitive recovery. Further research is needed to optimize these therapeutic approaches for clinical application in POCD management.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 4","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.70850","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147588991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}