Molecular Psychiatry最新文献

{"title":"Classification of major depressive disorder using vertex-wise brain sulcal depth, curvature, and thickness with a deep and a shallow learning model.","authors":"Roberto Goya-Maldonado, Tracy Erwin-Grabner, Ling-Li Zeng, Christopher R K Ching, Andre Aleman, Alyssa R Amod, Zeynep Basgoze, Francesco Benedetti, Bianca Besteher, Katharina Brosch, Robin Bülow, Romain Colle, Colm G Connolly, Emmanuelle Corruble, Baptiste Couvy-Duchesne, Kathryn Cullen, Udo Dannlowski, Christopher G Davey, Annemiek Dols, Jan Ernsting, Jennifer W Evans, Lukas Fisch, Paola Fuentes-Claramonte, Ali Saffet Gonul, Ian H Gotlib, Hans J Grabe, Nynke A Groenewold, Dominik Grotegerd, Tim Hahn, J Paul Hamilton, Laura K M Han, Ben J Harrison, Tiffany C Ho, Neda Jahanshad, Alec J Jamieson, Andriana Karuk, Tilo Kircher, Bonnie Klimes-Dougan, Sheri-Michelle Koopowitz, Thomas Lancaster, Ramona Leenings, Meng Li, David E J Linden, Frank P MacMaster, David M A Mehler, Susanne Meinert, Elisa Melloni, Bryon A Mueller, Benson Mwangi, Igor Nenadić, Amar Ojha, Yasumasa Okamoto, Mardien L Oudega, Brenda W J H Penninx, Sara Poletti, Edith Pomarol-Clotet, Maria J Portella, Joaquim Radua, Elena Rodríguez-Cano, Matthew D Sacchet, Raymond Salvador, Anouk Schrantee, Kang Sim, Jair C Soares, Aleix Solanes, Dan J Stein, Frederike Stein, Aleks Stolicyn, Sophia I Thomopoulos, Yara J Toenders, Aslihan Uyar-Demir, Eduard Vieta, Yolanda Vives-Gilabert, Henry Völzke, Martin Walter, Heather C Whalley, Sarah Whittle, Nils Winter, Katharina Wittfeld, Margaret J Wright, Mon-Ju Wu, Tony T Yang, Carlos Zarate, Dick J Veltman, Lianne Schmaal, Paul M Thompson","doi":"10.1038/s41380-025-03273-w","DOIUrl":"10.1038/s41380-025-03273-w","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is a complex psychiatric disorder that affects the lives of hundreds of millions of individuals around the globe. Even today, researchers debate if morphological alterations in the brain are linked to MDD, likely due to the heterogeneity of this disorder. The application of deep learning tools to neuroimaging data, capable of capturing complex non-linear patterns, has the potential to provide diagnostic and predictive biomarkers for MDD. However, previous attempts to demarcate MDD patients and healthy controls (HC) based on segmented cortical features via linear machine learning approaches have reported low accuracies. In this study, we used globally representative data from the ENIGMA-MDD working group containing 7012 participants from 31 sites (N = 2772 MDD and N = 4240 HC), which allows a comprehensive analysis with generalizable results. Based on the hypothesis that integration of vertex-wise cortical features can improve classification performance, we evaluated the classification of a DenseNet and a Support Vector Machine (SVM), with the expectation that the former would outperform the latter. As we analyzed a multi-site sample, we additionally applied the ComBat harmonization tool to remove potential nuisance effects of site. We found that both classifiers exhibited close to chance performance (balanced accuracy DenseNet: 51%; SVM: 53%), when estimated on unseen sites. Slightly higher classification performance (balanced accuracy DenseNet: 58%; SVM: 55%) was found when the cross-validation folds contained subjects from all sites, indicating site effect. In conclusion, the integration of vertex-wise morphometric features and the use of the non-linear classifier did not lead to the differentiability between MDD and HC. Our results support the notion that MDD classification on this combination of features and classifiers is unfeasible. Future studies are needed to determine whether more sophisticated integration of information from other MRI modalities such as fMRI and DWI will lead to a higher performance in this diagnostic task.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-Clozapine interventions in treatment-resistant schizophrenia: a systematic review and meta-analysis.","authors":"Richard Carr, Alistair Cannon, Valeria Finelli, Bernard Bukala, Yesim Cimen, Patritsiya Filipova, Connor Cummings, Toby Pillinger, Oliver D Howes, Robert A McCutcheon","doi":"10.1038/s41380-025-03255-y","DOIUrl":"https://doi.org/10.1038/s41380-025-03255-y","url":null,"abstract":"<p><strong>Background and hypothesis: </strong>Clozapine is the only licensed pharmacotherapy for treatment resistant schizophrenia (TRS), but in some cases is not a suitable treatment option. A review of the efficacy of non-clozapine interventions in TRS may help inform clinical decision making when clozapine treatment is not feasible.</p><p><strong>Study design: </strong>A systematic review and meta-analysis was performed investigating the efficacy of non-clozapine augmentation of antipsychotic treatment in TRS on positive, negative, and total symptoms. The review protocol is registered at PROSPERO (ID: CRD42023418053). PsycInfo, PubMed and EMBASE were searched up until July 2023. Cochrane Risk of Bias tool (v2) was used to assess study quality. Data were pooled using a random-effects model for each class of intervention to give an estimate of effect size (Hedges' g).</p><p><strong>Results: </strong>78 studies were included, of which 68 were included in the meta-analysis, comprising 3241 patients. High-dose antipsychotics (7 studies, 467 participants) did not improve any symptom domain. Augmentation of antipsychotics with glycine modulatory site agonists (9 studies, 187 participants) improved positive (g = -0.56 [-0.81, -0.31], GRADE rating Low), negative (g = -1.18 [-1.49, -0.87], GRADE rating Low) and total (g = -1.17 [-1.75, -0.59], GRADE rating Very Low) symptoms. Non-invasive stimulation (26 studies, 893 participants) moderately benefited positive symptoms (g = -0.42 [-0.65, -0.18], GRADE rating Low). Psychotherapy (10 studies, 565 participants) moderately improved positive symptoms (g = -0.56 [-1.01, -0.10], GRADE rating Low). Augmentation with antidepressants (3 studies, 187 participants) improved negative (g = -0.74 [-1.46, -0.02], GRADE rating Very Low) and total (g = -0.69 [-1.00, -0.38], GRADE rating Low) symptoms. Sample sizes were small, and publication bias was apparent for non-invasive stimulation studies.</p><p><strong>Conclusions: </strong>Several augmentation strategies, including pharmacotherapy, non-invasive stimulation, and psychotherapy demonstrated benefit in small studies, however no intervention reached the threshold of evidence to be routinely recommended as a viable alternative to clozapine. High-quality trials are needed for definitive recommendations.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcranial temporal interference stimulation for treating bipolar disorder with depressive episodes: a feasibility Study.","authors":"Hetong Zhou, Minmin Wang, Shuangyu Qi, Qianfeng Chen, Jianbo Lai, Zhengping Wu, Ruobing Liu, Liang Wang, Hui Zhou, Shaomin Zhang, Shaohua Hu","doi":"10.1038/s41380-025-03292-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03292-7","url":null,"abstract":"<p><p>Bipolar depression (BD-D) is a significant clinical challenge associated with high disease burden. Transcranial temporal interference stimulation (tTIS), a novel and noninvasive approach for targeting deep brain structures, was investigated for its efficacy and safety in BD-D patients in this trial. Thirty-six patients were recruited for a single-arm, open-label trial, and 25 completed the 5-day intervention consisting of 10 tTIS sessions targeting the left nucleus accumbens. Each session lasted 20 min, with a maximum current intensity of 2 mA and an envelope stimulation frequency of 40 Hz. Significant symptom reductions were observed following treatment, with mean HAMD-17 scores decreasing from 23.36 to 16.16 (p < 0.0001), MADRS scores from 39.12 to 31.28 (p < 0.01), HAMA scores from 19.68 to 15.44 (p < 0.05), and QIDS scores from 13.52to 9.68 (p < 0.001). Eleven participants (44.0%) met improvement criteria and seven (28.0%) achieved response. Cognitive assessments indicated improvements in memory and executive function, and changes in reward-related brain activity correlated positively with symptom reduction. Adverse events were mild, mainly transient scalp discomfort. These findings provide preliminary evidence supporting the efficacy and safety of tTIS for alleviating depressive symptoms and cognitive impairments in BD-D.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Depression and antidepressant use in pregnancy and adverse maternal and offspring outcomes: a systematic review and meta-analysis.","authors":"Tingting Liu, Na Zeng, Yingying Xu, Tengteng Fan, Feng Wang, Chang Liu, Yimiao Zhao, Shuyu Ni, Huan Mei, Shuilin Wu, Xiujun Zhang, Yongxiang Wang, Yumei Wang, Suxia Li, Jie Shi, Lin Lu, Yanping Bao","doi":"10.1038/s41380-025-03263-y","DOIUrl":"https://doi.org/10.1038/s41380-025-03263-y","url":null,"abstract":"<p><strong>Objective: </strong>Antidepressant use during pregnancy has been increasing in the last few decades. A substantial body of evidence has indicated the increased risks of adverse health outcomes for both pregnant women and their offspring. The association may be biased by uncontrolled confounding of maternity depression or mental health status. We performed a systematic review and meta-analysis to generate comprehensive estimates of the association between depression, antidepressants, and reproductive outcomes.</p><p><strong>Methods: </strong>The PubMed and Embase were searched from database inception to Jul 29, 2025, for longitudinal cohort studies of pregnant women with exposure to antidepressant or depression. The Newcastle-Ottawa Scale was used for assessing the methodological quality of included studies. Pooled estimates of risk ratio (RR) were calculated by comparing adverse outcomes between antidepressant-exposed pregnancies and unexposed pregnancies. Subsequently, we analyzed the risks of antidepressant-treated, untreated antenatal depression by adjusting for disease factors. Totally, 20 adverse health outcomes including 6 maternal and 14 children's outcomes were accessed.</p><p><strong>Results: </strong>A total of 166 studies with 51,596,405 participants were included. When antidepressant-exposed pregnancies were compared to all unexposed pregnancies (with and without depression), an increased risk for the majority (16/20) of the focused adverse outcomes was found. After adjusting for depression, results shows that certain adverse outcomes remained significant among untreated pregnancies. However, compared with untreated depressed women, the treated by antidepressant for depressed women during pregnancy was associated with the increased risk for limited outcomes of preterm birth and NICU admission.</p><p><strong>Conclution: </strong>The findings indicated that many of the adverse outcomes observed with medication may be attributable to the underlying depression itself rather than of antidepressants. More attention should be paid to depression, and health professionals should estimate the risk of depression and antidepressant comprehensively during counseling and prenatal health care.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of SENP7 and UTF1/VENTX as new loci influencing clustered protocadherin methylation across blood and brain using a genome-wide association study.","authors":"Yunfeng Liu, Maja Vukic, Eilis Hannon, Hailiang Mei, Emma Walker, Lucy Sinke, Jonathan Mill, Lucia Daxinger, Bastiaan T Heijmans","doi":"10.1038/s41380-025-03283-8","DOIUrl":"https://doi.org/10.1038/s41380-025-03283-8","url":null,"abstract":"<p><p>The epigenetic regulation of clustered protocadherin (cPCDH) genes is tightly linked to their function as specific cell surface barcodes for neural self-nonself discrimination. Differential cPCDH DNA methylation has been implicated in diverse neurological diseases as well as body weight, cancer and aging. However, the unique regulation of cPCDH methylation remains poorly understood. Therefore, we performed a genome-wide association study to evaluate the association of >7 million genetic variants with DNA methylation at 607 cPCDH CpGs measured in whole blood of 3777 individuals and validated findings in prefrontal cortex samples obtained from 523 brain donors. We observed concordant cPCDH methylation patterns in blood and prefrontal cortex, which switched between hypo-, intermediate and hypermethylation over short distances with the former overlapping with the promoter regions of each cPCDH member. Through methylation quantitative trait locus (meQTL) analysis in trans, we first confirmed the broad effect of the candidate gene SMCHD1 on cPCDH methylation in blood and then validated this effect in prefrontal cortex. Through a genome-wide analysis, we next identified the SENP7 and UTF1/VENTX loci to have widespread, subcluster-specific effects on cPCDH methylation in blood and brain. While SENP7 can indirectly affect DNA methylation through the deSUMOylation of the chromatin repressor KAP1, UTF1 and VENTX are two genes involved in embryonic development not previously implicated in epigenetic regulation. Our findings shed new light on the processes involved in cPCDH methylation that may underlie associations with neurological disease.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying affective state via clustering of temporal variability in limbic activity and mediating role of negative emotion.","authors":"Dong Yun Lee, Seulgi Lee, Sang Joon Son, Rae Woong Park, Bumhee Park","doi":"10.1038/s41380-025-03282-9","DOIUrl":"https://doi.org/10.1038/s41380-025-03282-9","url":null,"abstract":"<p><p>The amygdala and nucleus accumbens are associated with emotion management in humans. Emotions play a central role in conditions such as depression and anxiety, where emotional states characterize the core symptoms. Effective emotion regulation can alleviate these symptoms, which highlights the importance of amygdala and nucleus accumbens in mental health. Functional magnetic resonance imaging studies that incorporate temporal characteristics of brain regions are limited. Therefore, this study examined the association of temporal variability of the limbic region, specifically the amygdala and nucleus accumbens, with worsening depressive or anxiety states mediated by negative emotions. The study included 1,080 healthy subjects from the Human Connectome Project dataset, and nine functional networks were extracted from the limbic region using group independent component analysis. Spectral clustering was performed on the temporal variability of these networks. Two distinct clusters were found in healthy adults according to the temporal variability of limbic networks. The association of increased temporal variability of functional networks with worsening affective states, including depression and anxiety, was partially mediated by the level of anger-physical aggression. These findings indicate that temporal variability in limbic regions might impact the emotion of anger and the level of anger, in turn, influences affective states, even in healthy participants.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reward circuit function and treatment outcome following vALIC deep brain stimulation in treatment-resistant depression.","authors":"N Runia, L A van de Mortel, C L C Smith, I O Bergfeld, B P de Kwaasteniet, J Luigjes, J van Laarhoven, P Notten, G Beute, P van den Munckhof, P R Schuurman, D A J P Denys, G A van Wingen","doi":"10.1038/s41380-025-03284-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03284-7","url":null,"abstract":"<p><p>Depression is associated with abnormal functioning of the reward circuit. Several deep brain stimulation (DBS) targets for treatment-resistant depression (TRD) directly modulate white matter bundles of the reward circuit. Here we investigated whether baseline reward processing in the brain is associated with ventral anterior limb of the internal capsule (vALIC) DBS outcome and whether vALIC DBS changes neural activity in the reward circuit. We studied fifteen patients with TRD who performed a monetary reward task during functional magnetic resonance imaging (fMRI) before vALIC DBS surgery, after DBS parameter optimization, and during a sham-controlled crossover phase. DBS devices were switched off during scanning for MRI safety reasons. Additionally, fifteen matched healthy controls were investigated twice to account for test-retest effects. We investigated brain responses to reward anticipation, loss anticipation, reward feedback and loss feedback. Results showed that lower baseline nucleus accumbens activation during loss anticipation and higher baseline caudate nucleus and midcingulate cortex activation during reward feedback processing were associated with worse DBS outcome. No significant changes in reward processing were observed following vALIC DBS in comparison to healthy controls or after active compared to sham stimulation. Instead, increased middle frontal gyrus responses following DBS to loss feedback was associated with better DBS outcome. These results suggest that DBS efficacy in TRD is related to individual differences in reward circuit functioning at baseline and to changes in middle frontal gyrus responses following DBS.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of LXRβ in oligodendrocytes in neuronal survival.","authors":"Xiaoyu Song, Wanfu Wu, Mukesh Varshney, Andrew Roman, Jan-Åke Gustafsson, Margaret Warner","doi":"10.1038/s41380-025-03278-5","DOIUrl":"https://doi.org/10.1038/s41380-025-03278-5","url":null,"abstract":"<p><p>We have reported that mice in which the liver X receptor β (LXRβ) gene is inactivated lose dopaminergic neurons in the substantia nigra and motor neurons in the ventral horn of the spinal cord. These mice develop progressive hind limb paralysis starting at 6 months of age. Since LXRβ is not expressed in either dopaminergic neurons or motor neurons, we have focused on LXRβ-expressing cells whose function is essential for neuron survival. We now report defects in oligodendrocyte maturation in the absence of LXRβ. At 4 months of age, long before motor neuron loss occurs, there was reduction in expression of the four following genes in oligodendrocytes: The monocarboxylate transporter 1 (MCT1), which is essential for metabolic support of motor neurons; BDNF, a motor neuron trophic factor; 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), a rate-limiting enzyme in cholesterol synthesis; glutamine synthetase (GS), an enzyme crucial for the elimination of neurotoxic glutamate from synapses. Differentiation of ES cells from WT and LXRβ^-/- mice into motor neurons/oligodendrocytes revealed that LXRβ^-/- cultures showed less arborization of motor neurons and a reduced proportion of mature oligodendrocytes. Our study suggests that defects in glial cells can have profound effects on neuronal survival and that early defective oligodendrocyte maturation can lead to motor neuron death. The expression of LXRβ in oligodendrocytes should be investigated as a target for preventing neuronal loss in diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson's disease.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-lived adult-born hippocampal neurons promote successful cognitive aging.","authors":"Nicolas Blin, Vanessa Charrier, Fanny Farrugia, Justine Palhol, Antoine Presset, Estelle Cartier, Stephane Oliet, Emilie Pacary, Muriel Koehl, Dieter Chichung Lie, Nuria Masachs, Djoher Nora Abrous","doi":"10.1038/s41380-025-03286-5","DOIUrl":"https://doi.org/10.1038/s41380-025-03286-5","url":null,"abstract":"<p><p>Aging is commonly associated with a decline in memory abilities, yet some individuals remain resilient to such changes. Memory processing has been shown to rely on adult neurogenesis, a form of hippocampal plasticity, but whether the integration and role of long-lived adult-born neurons (ABNs) generated during early adult life also contribute to cognitive resilience and to such inter-individual differences remain unknown. Using a pseudo-longitudinal approach in rats characterized as resilient or vulnerable to cognitive aging, we examined the survival, senescence, morphology, glutamatergic connectivity, and mitochondrial health of ABNs. To achieve this, we combined approaches based on thymidine analogues and retroviral labeling using Moloney murine leukemia viruses. While ABNs survival, entry into senescence and dendritic gross morphology did not differ between resilient and vulnerable rats, resilient animals exhibited preserved glutamatergic synaptic input and maintained mitochondrial homeostasis in the proximal dendrites of ABNs. Interestingly, bypassing this reduction in glutamatergic inputs in vulnerable rats through direct optogenetic stimulation was sufficient to rescue their memory retrieval abilities, indicating that ABNs themselves remain intrinsically functional despite reduced input. Overall, our data indicate that maintaining long-lived ABNs within the neuronal network is essential for successful cognitive aging, highlighting their potential as a therapeutic target for restoring cognitive functions in old age.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hippocampal SGK1 promotes vulnerability to depression: the role of early life adversity, stress, and genetic risk.","authors":"Amira Millette, Milenna T van Dijk, Irina Pokhvisneva, Yifei Li, Rory Thompson, Sachin Patel, Rosemary C Bagot, Aniko Naray-Fejes-Toth, Geza Fejes-Toth, Patricia Pelufo Silveira, Gustavo Turecki, Juan Pablo Lopez, Christoph Anacker","doi":"10.1038/s41380-025-03269-6","DOIUrl":"https://doi.org/10.1038/s41380-025-03269-6","url":null,"abstract":"<p><p>Serum and Glucocorticoid-regulated Kinase 1 (SGK1) is elevated in hippocampal neurons following glucocorticoid exposure and in peripheral blood of depressed patients. However, its mechanistic role in psychopathology and its relevance to the human brain are unknown. To address this gap, we investigated human postmortem brain tissue and found higher SGK1 expression in the hippocampus of depressed suicide decedents compared to healthy subjects who died of natural causes. We observed the highest levels of SGK1 in subjects with reported early life adversity (ELA) - a major risk factor for psychiatric disorders. To determine potential genetic factors underlying increased SGK1 in the hippocampus, we computed expression-based polygenic risk scores (ePRS) for a large population sample from the ABCD study and found that a collection of genetic variants associated with high hippocampal SGK1 expression predicts depression severity and moderates associations between ELA, depressive symptoms, and suicide attempts. Similar to the human brain, hippocampal SGK1 expression was increased in mouse models of ELA, adult chronic stress, and chronic corticosterone exposure, and hippocampal-specific knockdown of SGK1 conferred resilience to stress-induced behavior abnormalities. To test SGK1 as a potential therapeutic target, we injected mice with the small molecule inhibitor, GSK650394, and found that pharmacological inhibition conferred stress resilience, increased adult hippocampal neurogenesis, and rescued stress-induced dentate gyrus hyperactivity. Our cross-species findings reveal a novel role for hippocampal SGK1 in stress resilience, highlight an interaction between ELA and SGK1 on depression and suicide risk, and establish for the first time a functional role for SGK1 in stress-induced psychopathology.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}