Yiran Li, Tian Xie, Melissa Vos, Harold Snieder, Catharina A Hartman
{"title":"Shared genetic architecture and causality between autism spectrum disorder and irritable bowel syndrome, multisite pain, and fatigue.","authors":"Yiran Li, Tian Xie, Melissa Vos, Harold Snieder, Catharina A Hartman","doi":"10.1038/s41398-024-03184-4","DOIUrl":"https://doi.org/10.1038/s41398-024-03184-4","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) often co-occurs with functional somatic syndromes (FSS), such as irritable bowel syndrome (IBS), multisite pain, and fatigue. However, the underlying genetic mechanisms and causality have not been well studied. Using large-scale genome-wide association study (GWAS) data, we investigated the shared genetic architecture and causality between ASD and FSS. Specifically, we first estimated genetic correlations and then conducted a multi-trait analysis of GWAS (MTAG) to detect potential novel genetic variants for single traits. Afterwards, polygenic risk scores (PRS) of ASD were derived from GWAS and MTAG to examine the associations with phenotypes in the large Dutch Lifelines cohort. Finally, we performed Mendelian randomization (MR) to evaluate the causality. We observed positive genetic correlations between ASD and FSS (IBS: r<sub>g</sub> = 0.27, adjusted p = 2.04 × 10<sup>-7</sup>; multisite pain: r<sub>g</sub> = 0.13, adjusted p = 1.10 × 10<sup>-3</sup>; fatigue: r<sub>g</sub> = 0.33, adjusted p = 5.21 × 10<sup>-9</sup>). Leveraging these genetic correlations, we identified 3 novel genome-wide significant independent loci for ASD by conducting MTAG, mapped to NEDD4L, MFHAS1, and RP11-10A14.4. PRS of ASD derived from both GWAS and MTAG were associated with ASD and FSS in Lifelines, and MTAG-derived PRS showed a bigger effect size, larger explained variance, and smaller p-values. We did not observe significant causality using MR. Our study found genetic associations between ASD and FSS, specifically with IBS, multisite pain, and fatigue. These findings suggest that a shared genetic architecture may partly explain the co-occurrence between ASD and FSS. Further research is needed to investigate the causality between ASD and FSS due to current limited statistical power of the GWASs.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"476"},"PeriodicalIF":5.8,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695788","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}
Xia Liu, Zongxin Ling, Yiwen Cheng, Lingbin Wu, Li Shao, Jie Gao, Wenhui Lei, Zhangcheng Zhu, Wenwen Ding, Qinghai Song, Longyou Zhao, Guolin Jin
{"title":"Oral fungal dysbiosis and systemic immune dysfunction in Chinese patients with schizophrenia.","authors":"Xia Liu, Zongxin Ling, Yiwen Cheng, Lingbin Wu, Li Shao, Jie Gao, Wenhui Lei, Zhangcheng Zhu, Wenwen Ding, Qinghai Song, Longyou Zhao, Guolin Jin","doi":"10.1038/s41398-024-03183-5","DOIUrl":"10.1038/s41398-024-03183-5","url":null,"abstract":"<p><p>Oral microbial dysbiosis contributes to the development of schizophrenia (SZ). While numerous studies have investigated alterations in the oral bacterial microbiota among SZ patients, investigations into the fungal microbiota, another integral component of the oral microbiota, are scarce. In this cross-sectional study, we enrolled 118 Chinese patients with SZ and 97 age-matched healthy controls (HCs) to evaluate the oral fungal microbiota from tongue coating samples using internal transcribed spacer 1 amplicon sequencing and assess host immunity via multiplex immunoassays. Our findings revealed that SZ patients exhibited reduced fungal richness and significant differences in β-diversity compared to HCs. Within the oral fungal communities, we identified two distinct fungal clusters (mycotypes): Candida and Malassezia, with SZ patients showing increased Malassezia and decreased Candida levels. These key functional oral fungi may serve as potential diagnostic biomarkers for SZ. Furthermore, SZ patients displayed signs of immunological dysfunction, characterized by elevated levels of pro-inflammatory cytokines such as IL-6 and TNF-α, and chemokines including MIP-1α and MCP-1. Importantly, Malassezia mycotype correlated positively with peripheral pro-inflammatory cytokines, while Candida mycotype exhibited a negative correlation with these cytokines. In conclusion, we have demonstrated, for the first time, the presence of altered oral fungal communities and systemic immune dysfunction in Chinese SZ patients compared to HCs, providing novel insights into the potential role of oral fungi as biomarkers and the broader implications for understanding SZ pathogenesis.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"475"},"PeriodicalIF":5.8,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11582559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142688866","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}
Yukitoshi Izumi, Angela M Reiersen, Eric J Lenze, Steven J Mennerick, Charles F Zorumski
{"title":"Sertraline modulates hippocampal plasticity via sigma 1 receptors, cellular stress and neurosteroids.","authors":"Yukitoshi Izumi, Angela M Reiersen, Eric J Lenze, Steven J Mennerick, Charles F Zorumski","doi":"10.1038/s41398-024-03185-3","DOIUrl":"10.1038/s41398-024-03185-3","url":null,"abstract":"<p><p>In addition to modulating serotonin transport, selective serotonin reuptake inhibitors (SSRIs) have multiple other mechanisms that may contribute to clinical effects, and some of these latter actions prompt repurposing of SSRIs for non-psychiatric indications. In a recent study of the SSRIs fluvoxamine, fluoxetine and sertraline we found that, unlike the other two SSRIs, sertraline acutely inhibited LTP at a low micromolar concentration through inverse agonism of sigma 1 receptors (S1Rs). In the present studies, we pursued mechanisms contributing to sertraline modulation of LTP in rat hippocampal slices. We found that sertraline partially inhibits synaptic responses mediated by N-methyl-D-aspartate receptors (NMDARs) via effects on NMDARs that contain GluN2B subunits. A selective S1R antagonist (NE-100), but not an S1R agonist (PRE-084) blocked effects on NMDARs, even though both S1R ligands were previously shown to prevent LTP inhibition. Both NE-100 and PRE-084, however, prevented adverse effects of sertraline on one-trial learning. Because of the important role that S1Rs play in modulating endoplasmic reticulum stress, we examined whether inhibitors of cellular stress alter effects of sertraline. We found that two stress inhibitors, ISRIB and quercetin, prevented LTP inhibition, as did inhibitors of the synthesis of endogenous neurosteroids, which are homeostatic regulators of cellular stress. These studies highlight complex effects of sertraline, S1Rs and neurosteroids on hippocampal function and have relevance for understanding therapeutic and adverse drug actions.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"474"},"PeriodicalIF":5.8,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11582653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142688870","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}
Giles W Story, Sam Ereira, Stephanie Valle, Samuel R Chamberlain, Jon E Grant, Raymond J Dolan
{"title":"A computational signature of self-other mergence in Borderline Personality Disorder.","authors":"Giles W Story, Sam Ereira, Stephanie Valle, Samuel R Chamberlain, Jon E Grant, Raymond J Dolan","doi":"10.1038/s41398-024-03170-w","DOIUrl":"10.1038/s41398-024-03170-w","url":null,"abstract":"<p><p>A tendency to merge mental representations of self and other is thought to underpin the intense and unstable relationships that feature in Borderline Personality Disorder (BPD). However, clinical theories of BPD do not specify, in computational terms, how the perspectives of self and other might become confused. To address this question, we used a probabilistic false belief task (p-FBT) to examine how individuals with BPD (N = 38) and matched controls from the general population (N = 74) selectively assigned beliefs to self or other. The p-FBT requires participants to track a gradually changing quantity, whilst also predicting another person's belief about that quantity. We found that BPD participants showed less selectivity in belief assignment compared with controls (Cohen's d = 0.64). Behaviourally, participants with BPD tended to predict that others' beliefs resembled their own. Modelling analysis revealed that BPD participants were prone to generalise their own learning signals to others. Furthermore, this generalising tendency correlated with BPD symptomatology across participants, even when controlling for demographic factors and affective psychopathology. Our results support a computational account of self-other mergence, based on a generalisation of learning across agents. Self-other generalisation in learning purports to explain key clinical features of BPD, and suggests a potential transdiagnostic marker of mentalising capability.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"473"},"PeriodicalIF":5.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11576885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676842","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":"Association of polygenic liabilities for schizophrenia and bipolar disorder with educational attainment and cognitive aging.","authors":"Chi-Shin Wu, Chia-Lin Hsu, Mei-Chen Lin, Mei-Hsin Su, Yen-Feng Lin, Chia-Yen Chen, Po-Chang Hsiao, Yi-Jiun Pan, Pei-Chun Chen, Yen-Tsung Huang, Shi-Heng Wang","doi":"10.1038/s41398-024-03182-6","DOIUrl":"10.1038/s41398-024-03182-6","url":null,"abstract":"<p><p>To elucidate the specific and shared genetic background of schizophrenia (SCZ) and bipolar disorder (BPD), this study explored the association of polygenic liabilities for SCZ and BPD with educational attainment and cognitive aging. Among 106,806 unrelated community participants from the Taiwan Biobank, we calculated the polygenic risk score (PRS) for SCZ (PRS<sub>SCZ</sub>) and BPD (PRS<sub>BPD</sub>), shared PRS between SCZ and BPD (PRS<sub>SCZ+BPD</sub>), and SCZ-specific PRS (PRS<sub>SCZvsBPD</sub>). Based on the sign-concordance of the susceptibility variants with SCZ/BPD, PRS<sub>SCZ</sub> was split into PRS<sub>SCZ_concordant</sub>/PRS<sub>SCZ_discordant</sub>, and PRS<sub>BPD</sub> was split into PRS<sub>BPD_concordant</sub>/PRS<sub>BPD_discordant</sub>. Ordinal logistic regression models were used to estimate the association with educational attainment. Linear regression models were used to estimate the associations with cognitive aging (n = 27,005), measured by the Mini-Mental State Examination (MMSE), and with MMSE change (n = 6194 with mean follow-up duration of 3.9 y) in individuals aged≥ 60 years. PRS<sub>SCZ,</sub> PRS<sub>BPD</sub>, and PRS<sub>SCZ+BPD</sub> were positively associated with educational attainment, whereas PRS<sub>SCZvsBPD</sub> was negatively associated with educational attainment. PRS<sub>SCZ</sub> was negatively associated with MMSE, while PRS<sub>BPD</sub> was positively associated with MMSE. The concordant and discordant parts of polygenic liabilities have contrasting association, PRS<sub>SCZ_concordant</sub> and PRS<sub>BPD_concordant</sub> mainly determined these effects mentioned above<sub>.</sub> PRS<sub>SCZvsBPD</sub> predicted decreases in the MMSE scores. Using a large collection of community samples, this study provided evidence for the contrasting effects of polygenic architecture in SCZ and BPD on educational attainment and cognitive aging and suggested that SCZ and BPD were not genetically homogeneous.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"472"},"PeriodicalIF":5.8,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11569198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644298","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}
Marianna Piras, Jue Lin, Marie Catherine Sadler, Setareh Ranjbar, Claire Grosu, Nermine Laaboub, Martin Preisig, Franziska Gamma, Kerstin Jessica Plessen, Armin von Gunten, Philippe Conus, Zoltan Kutalik, Chin B Eap
{"title":"Psychotropic-induced weight gain and telomere length: results from a one-year longitudinal study and a large population-based cohort.","authors":"Marianna Piras, Jue Lin, Marie Catherine Sadler, Setareh Ranjbar, Claire Grosu, Nermine Laaboub, Martin Preisig, Franziska Gamma, Kerstin Jessica Plessen, Armin von Gunten, Philippe Conus, Zoltan Kutalik, Chin B Eap","doi":"10.1038/s41398-024-03177-3","DOIUrl":"10.1038/s41398-024-03177-3","url":null,"abstract":"<p><p>Weight-inducing psychotropic treatments are risk factors for age-related diseases such as cardiovascular disorders, which are associated with both inflammation and telomere length shortening. With a longitudinal design, the present study evaluates telomere length trajectories after 1 year of weight-inducing psychotropic medication, accounting for weight changes and the inflammatory biomarker high-sensitivity C-Reactive Protein (CRP). Among 200 patients, an overall median telomere shortening of -41.2 bp was observed (p = 0.014), which is comparable with the general population's yearly telomere attrition. Linear regression showed on average -93.1 and -58.9 bp of further telomere shortening per five units of BMI for BMI values < or ≥30 kg/m<sup>2</sup>, respectively (p = 0.003 and p = 0.009, respectively). Importantly, the overall telomere shortening was predicted to be increased four-fold among patients with low baseline weight (i.e., 50 kg) and with clinically relevant weight gain (≥ 7%) after 1 year of treatment (interaction term between relevant weight gain and baseline weight: +6.3 bp, p = 0.016). Patients with relevant weight gain showed greater CRP levels (+ 49%; p = 0.016), and a telomere shortening of -36.2 bp (p = 0.010) was estimated whenever CRP level doubled. Mendelian randomization using UKBiobank data showed a causal effect of BMI on telomere shortening, notably stronger among patients receiving weight-inducing psychotropic treatments (n = 9798) than among psychiatric patients without such drugs (n = 16228) and non-psychiatric controls (n = 252932) (beta: -0.37, -0.12, -0.06, respectively; p = 0.004, p < 0.001, p < 0.001, respectively). Ultimately, telomere trajectories were associated with 1 year weight gain and increases in CRP levels, with telomere shortening strongly enhanced by BMI increments among patients receiving weight-inducing psychotropic treatments.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"471"},"PeriodicalIF":5.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639998","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}
Ebba Du Rietz, Tian Xie, Rujia Wang, Rosa Cheesman, Miguel Garcia-Argibay, Zihan Dong, Jia Zhang, Jacobien Niebuur, Melissa Vos, Harold Snieder, Henrik Larsson, Catharina A Hartman
{"title":"The contribution of attention-deficit/hyperactivity disorder polygenic load to metabolic and cardiovascular health outcomes: a large-scale population and sibling study.","authors":"Ebba Du Rietz, Tian Xie, Rujia Wang, Rosa Cheesman, Miguel Garcia-Argibay, Zihan Dong, Jia Zhang, Jacobien Niebuur, Melissa Vos, Harold Snieder, Henrik Larsson, Catharina A Hartman","doi":"10.1038/s41398-024-03178-2","DOIUrl":"10.1038/s41398-024-03178-2","url":null,"abstract":"<p><p>Emerging evidence suggests that ADHD is associated with increased risk for metabolic and cardiovascular (cardiometabolic) diseases. However, an understanding of the mechanisms underlying these associations is still limited. In this study we estimated the associations of polygenic scores (PGS) for ADHD with several cardiometabolic diseases and biomarkers. Furthermore, we investigated to what extent the PGS effect was influenced by direct and indirect genetic effects (i.e., shared familial effects). We derived ADHD-PGS in 50,768 individuals aged 18-90 years from the Dutch Lifelines Cohort study. Using generalised estimating equations, we estimated the association of PGS with cardiometabolic diseases, derived from self-report and several biomarkers measured during a physical examination. We additionally ran within-sibling PGS analyses, using fixed effects models, to disentangle direct effects of individuals' own ADHD genetic risk from confounding due to indirect genetic effects of relatives, as well as population stratification. We found that higher ADHD-PGS were statistically significantly associated with several cardiometabolic diseases (R-squared [R<sup>2</sup>] range = 0.03-0.50%) and biomarkers (related to inflammation, blood pressure, lipid metabolism, amongst others) (R<sup>2</sup> range = 0.01-0.16%) (P < 0.05). Adjustment for shared familial factors attenuated the associations between ADHD-PGS and cardiometabolic outcomes (on average 56% effect size reduction), and significant associations only remained for metabolic disease. Overall our findings suggest that increased genetic liability for ADHD confers a small but significant risk increase for cardiometabolic health outcomes in adulthood. These associations were observable in the general population, even in individuals without ADHD diagnosis, and were partly explained by familial factors shared among siblings.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"470"},"PeriodicalIF":5.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629018","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":"Circulating metabolome in relation to cognitive impairment: a community-based cohort of older adults.","authors":"Yuhui Huang, Xuehui Sun, Qingxia Huang, Qiumin Huang, Xiao Chen, Xiaofeng Zhou, Hui Chen, Jie Shen, Mengyan Gao, Yiying Gong, Hui Zhang, Huiru Tang, Xiaofeng Wang, Xiaoyan Jiang, Yan Zheng, Changzheng Yuan","doi":"10.1038/s41398-024-03147-9","DOIUrl":"10.1038/s41398-024-03147-9","url":null,"abstract":"<p><p>The role of circulating metabolome in cognitive impairment is inconclusive, and whether the associations are in the severity-dependent manner remains unclear. We aimed to identify plasma metabolites associated with cognitive impairment and evaluate the added predictive capacity of metabolite biomarkers on incident cognitive impairment beyond traditional risk factors. In the Rugao Longevity and Ageing Study (RuLAS), plasma metabolome was profiled by nuclear magnetic resonance spectroscopy. Participants were classified into the cognitively normal, moderately impaired, and severely impaired groups according to their performance in two objective cognitive tests. A two-step strategy of cross-sectional discovery followed by prospective validation was applied. In the discovery stage, we included 1643 participants (age: 78.9 ± 4.5 years) and conducted multinomial logistic regression. In the validation stage, we matched 68 incident cases of cognitive impairment (moderately-to-severely impaired) during the 2-year follow-up with 204 cognitively normal controls by age and sex at a 1:3 ratio, and conducted conditional logistic regression. We identified 28 out of 78 metabolites cross-sectionally related to severely impaired cognition, among which IDL particle number, ApoB in IDL, leucine, and valine were prospectively associated with 28%, 28%, 29%, and 33% lower risk of developing cognitive impairment, respectively. Incorporating 13 metabolite biomarkers selected through Lasso regression into the traditional risk factors-based prediction model substantially improved the ability to predict incident cognitive impairment (AUROC: 0.839 vs. 0.703, P < 0.001; AUPRC: 0.705 vs. 0.405, P < 0.001). This study identified specific plasma metabolites related to cognitive impairment. Incorporation of specific metabolites substantially improved the prediction performance for cognitive impairment.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"469"},"PeriodicalIF":5.8,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629009","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}
Tianwen Huang, Yangyang He, Ruijuan Cheng, Qiuping Zhang, Xiang Zhong, Kenji Hashimoto, Yi Liu, Yaoyu Pu
{"title":"Ketamine attenuates kidney damage and depression-like behaviors in mice with cisplatin-induced acute kidney injury.","authors":"Tianwen Huang, Yangyang He, Ruijuan Cheng, Qiuping Zhang, Xiang Zhong, Kenji Hashimoto, Yi Liu, Yaoyu Pu","doi":"10.1038/s41398-024-03176-4","DOIUrl":"10.1038/s41398-024-03176-4","url":null,"abstract":"<p><p>Acute kidney injury (AKI) is a serious condition characterized by decreased urine output, often accompanied by psychiatric symptoms like depression. However, there are limited pharmacological treatments available for AKI and its associated depressive symptoms. In this study, we investigated whether cisplatin-induced AKI in mice leads to depression-like behaviors and whether ketamine could alleviate both the kidney injury and these behaviors. Mice with cisplatin-induced AKI exhibited elevated levels of creatinine and urea, kidney damage, increased kidney injury molecule-1 protein, and pathological changes in the liver, colon, and spleen. They also showed depression-like behaviors and reduced expression of synaptic proteins in the prefrontal cortex. Remarkably, a single dose of ketamine significantly reduced these symptoms and pathological changes. Interestingly, the beneficial effects of ketamine on the kidneys, other organs, and depression-like behaviors, were reversed by the tropomyosin receptor kinase B (TrkB) inhibitor ANA-12. Western blot analysis revealed the involvement of the TrkB and ERK (extracellular signal-regulated kinase)-CREB (cAMP response element binding protein) signaling pathway. Additionally, metabolomics analysis indicated that blood metabolites, such as C16-ceramide, may contribute to the effects of ketamine in this model. These findings suggest that cisplatin-induced nephrotoxicity in AKI mice contributes to depression-like behaviors, and ketamine can alleviate both kidney damage and depression-like symptoms by modulating the TrkB and ERK-CREB signaling pathways, as well as altering blood metabolites. However, the role of the kidney-brain axis in these depression-like behaviors remains unclear. Furthermore, ketamine may have therapeutic potential for treating kidney diseases such as AKI, along with associated depressive symptoms.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"468"},"PeriodicalIF":5.8,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629012","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}
Lexi J Hand, Louise M Paterson, Anne R Lingford-Hughes
{"title":"Re-evaluating our focus in addiction: emotional dysregulation is a critical driver of relapse to drug use.","authors":"Lexi J Hand, Louise M Paterson, Anne R Lingford-Hughes","doi":"10.1038/s41398-024-03159-5","DOIUrl":"10.1038/s41398-024-03159-5","url":null,"abstract":"<p><p>Most addiction research has focused on reward- and impulsivity-related neurocircuitry. However, the impact of the withdrawal/negative affect stage in the addiction cycle has been somewhat overlooked, despite it being commonly evident in the clinic. This stage crucially drives negative reinforcement of repeated drug use and relapse, yet less is known about its neural underpinnings. How negative emotional processing is dysregulated in substance dependence is incompletely understood and may manifest differentially across the types of substances. In turn, the regions involved in negative emotional processing may show different patterns of dysregulation. Understanding how neurocircuitry involved in negative states differs across various substances may help inform new targets for treatments. Following a comprehensive literature search of studies examining negative emotional processing in substance dependence, a quantitative approach was deemed inappropriate. Instead, we employed a narrative approach to exploring neural responses to tasks involving emotional processing in alcohol, cocaine, opioid and cannabis dependence. Regions that were found to be dysregulated included the amygdala, insula, anterior cingulate, and medial prefrontal cortex. However, patterns of reactivity differed across alcohol, cocaine, opioid and cannabis dependence. Brain activation in alcohol dependence broadly appeared blunted in response to negative affective stimuli and emotional faces, whilst conversely appeared heightened in cocaine dependence. In opioid dependence, the amygdala was consistently implicated, whilst the insula, anterior cingulate, and medial prefrontal cortex were implicated in cannabis dependence. However, there was wide variability amongst the studies, with very few studies investigating opioid and cannabis dependence. These findings suggest emotional dysregulation varies according to the type of substance dependence. However, the variability in findings and lack of studies highlights the need for more research in this area. Further characterisation of emotional dysregulation in substance dependence will enable identification of treatment targets. More targeted treatments that modulate negative emotional processing could substantially improve outcomes by aiding relapse prevention.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"467"},"PeriodicalIF":5.8,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629015","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}