Pub Date : 2024-11-19DOI: 10.1038/s41398-024-03170-w
Giles W Story, Sam Ereira, Stephanie Valle, Samuel R Chamberlain, Jon E Grant, Raymond J Dolan
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.
{"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":"https://doi.org/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":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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 (PRSSCZ) and BPD (PRSBPD), shared PRS between SCZ and BPD (PRSSCZ+BPD), and SCZ-specific PRS (PRSSCZvsBPD). Based on the sign-concordance of the susceptibility variants with SCZ/BPD, PRSSCZ was split into PRSSCZ_concordant/PRSSCZ_discordant, and PRSBPD was split into PRSBPD_concordant/PRSBPD_discordant. 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. PRSSCZ, PRSBPD, and PRSSCZ+BPD were positively associated with educational attainment, whereas PRSSCZvsBPD was negatively associated with educational attainment. PRSSCZ was negatively associated with MMSE, while PRSBPD was positively associated with MMSE. The concordant and discordant parts of polygenic liabilities have contrasting association, PRSSCZ_concordant and PRSBPD_concordant mainly determined these effects mentioned above. PRSSCZvsBPD 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.
{"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}
Pub Date : 2024-11-15DOI: 10.1038/s41398-024-03177-3
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
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/m2, 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.
{"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}
Pub Date : 2024-11-13DOI: 10.1038/s41398-024-03178-2
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
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 [R2] range = 0.03-0.50%) and biomarkers (related to inflammation, blood pressure, lipid metabolism, amongst others) (R2 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.
{"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}
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.
{"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}
Pub Date : 2024-11-09DOI: 10.1038/s41398-024-03176-4
Tianwen Huang, Yangyang He, Ruijuan Cheng, Qiuping Zhang, Xiang Zhong, Kenji Hashimoto, Yi Liu, Yaoyu Pu
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.
急性肾损伤(AKI)是一种以尿量减少为特征的严重疾病,通常伴有抑郁症等精神症状。然而,目前针对 AKI 及其相关抑郁症状的药物治疗非常有限。在这项研究中,我们调查了顺铂诱导的小鼠 AKI 是否会导致抑郁样行为,以及氯胺酮是否能减轻肾损伤和这些行为。顺铂诱导的 AKI 小鼠表现出肌酐和尿素水平升高、肾脏损伤、肾损伤分子-1 蛋白增加以及肝脏、结肠和脾脏的病理变化。他们还表现出类似抑郁的行为,前额叶皮层的突触蛋白表达减少。值得注意的是,单剂量氯胺酮能明显减轻这些症状和病理变化。有趣的是,氯胺酮对肾脏、其他器官和抑郁样行为的有益影响被肌球蛋白受体激酶B(TrkB)抑制剂ANA-12逆转。Western印迹分析显示,TrkB和ERK(细胞外信号调节激酶)-CREB(cAMP反应元件结合蛋白)信号通路参与其中。此外,代谢组学分析表明,血液代谢物(如 C16-神经酰胺)可能有助于氯胺酮在该模型中的作用。这些研究结果表明,顺铂诱导的AKI小鼠肾毒性会导致抑郁样行为,而氯胺酮可以通过调节TrkB和ERK-CREB信号通路以及改变血液代谢物来减轻肾损伤和抑郁样症状。然而,肾-脑轴在这些抑郁样行为中的作用仍不清楚。此外,氯胺酮可能具有治疗肾脏疾病(如 AKI)以及相关抑郁症状的潜力。
{"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}
Pub Date : 2024-11-09DOI: 10.1038/s41398-024-03159-5
Lexi J Hand, Louise M Paterson, Anne R Lingford-Hughes
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.
{"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}
Pub Date : 2024-11-07DOI: 10.1038/s41398-024-03175-5
Bona Kim, Alisa Kostaki, Sarah McClymont, Stephen G Matthews
Antenatal corticosteroids (ACS) are administered where there is risk of preterm birth to promote fetal lung development and improve perinatal survival. However, treatment may be associated with increased risk of developing neurobehavioural disorders. We have recently identified that ACS results in significant changes to DNA methylation patterns in the newborn and juvenile prefrontal cortex (PFC) of exposed guinea pig offspring. Methylation changes at transcription factor binding sites (TFBS) for PLAGL1, TFAP2C, ZNF263, and SP1 were consistently noted at both post-natal stages, suggesting a long-lasting signature of ACS exposure. In this study, we determined if comparable methylation changes are also present in the newborn blood of ACS-exposed guinea pig offspring, as this would determine whether blood methylation patterns may be used as a peripheral biomarker of changes in the brain. Pregnant guinea pigs were treated with saline or betamethasone (1 mg/kg) on gestational days 50/51. gDNA from whole blood of term-born offspring on post-natal day (PND) 1 was used for reduced representation bisulfite sequencing. Overall, 1677 differentially methylated CpG sites (DMCs) were identified in response to ACS. While no specific DMCs identified in the blood overlapped with those previously reported in the PFC of PND1 offspring, significant differential methylation at TFBSs for PLAGL1, TFAP2C, EGR1, ZNF263, and SP1 was persistently observed. Furthermore, re-examination of our previously reported data of DMCs in human neonatal blood following ACS identified the presence of this same TFBS signature in human infants, suggesting the potential for clinical translation of our epigenomic data.
{"title":"Identification of a DNA methylation signature in whole blood of newborn guinea pigs and human neonates following antenatal betamethasone exposure.","authors":"Bona Kim, Alisa Kostaki, Sarah McClymont, Stephen G Matthews","doi":"10.1038/s41398-024-03175-5","DOIUrl":"10.1038/s41398-024-03175-5","url":null,"abstract":"<p><p>Antenatal corticosteroids (ACS) are administered where there is risk of preterm birth to promote fetal lung development and improve perinatal survival. However, treatment may be associated with increased risk of developing neurobehavioural disorders. We have recently identified that ACS results in significant changes to DNA methylation patterns in the newborn and juvenile prefrontal cortex (PFC) of exposed guinea pig offspring. Methylation changes at transcription factor binding sites (TFBS) for PLAGL1, TFAP2C, ZNF263, and SP1 were consistently noted at both post-natal stages, suggesting a long-lasting signature of ACS exposure. In this study, we determined if comparable methylation changes are also present in the newborn blood of ACS-exposed guinea pig offspring, as this would determine whether blood methylation patterns may be used as a peripheral biomarker of changes in the brain. Pregnant guinea pigs were treated with saline or betamethasone (1 mg/kg) on gestational days 50/51. gDNA from whole blood of term-born offspring on post-natal day (PND) 1 was used for reduced representation bisulfite sequencing. Overall, 1677 differentially methylated CpG sites (DMCs) were identified in response to ACS. While no specific DMCs identified in the blood overlapped with those previously reported in the PFC of PND1 offspring, significant differential methylation at TFBSs for PLAGL1, TFAP2C, EGR1, ZNF263, and SP1 was persistently observed. Furthermore, re-examination of our previously reported data of DMCs in human neonatal blood following ACS identified the presence of this same TFBS signature in human infants, suggesting the potential for clinical translation of our epigenomic data.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"465"},"PeriodicalIF":8.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11543945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606275","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}
Pub Date : 2024-11-07DOI: 10.1038/s41398-024-03163-9
Karoliina Kurkinen, Olli Kärkkäinen, Soili M Lehto, Ilona Luoma, Siiri-Liisi Kraav, Petri Kivimäki, Sebastian Therman, Tommi Tolmunen
In adolescence, psychotic-like experiences (PLE) may indicate potential prodromal symptoms preceding the onset of psychosis. Metabolomic studies have shown promise in providing valuable insights into predicting psychosis with enhanced precision compared to conventional clinical features. This study investigated metabolomic alterations associated with PLE in 76 depressed adolescents aged 14-20 years. Serum concentrations of 92 metabolites were analyzed with liquid chromatography-mass spectrometry. PLE were assessed using the Youth Experiences and Health (YEAH) questionnaire. The associations between PLE symptom dimensions (delusions, paranoia, hallucinations, negative symptoms, thought disorder, and dissociation) and metabolite concentrations were analyzed in linear regression models adjusted for different covariates. The symptom dimensions consistently correlated with the metabolome in different models, except those adjusted for cannabis use. Specifically, the hallucination dimension was associated with 13 metabolites (acetoacetic acid, allantoin, asparagine, decanoylcarnitine, D-glucuronic acid, guanidinoacetic acid, hexanoylcarnitine, homogentisic acid, leucine, NAD+, octanoylcarnitine, trimethylamine-N-oxide, and valine) in the various linear models. However, when adjusting for cannabis use, eight metabolites were associated with hallucinations (adenine, AMP, cAMP, chenodeoxycholic acid, cholic acid, L-kynurenine, neopterin, and D-ribose-5-phosphate). The results suggest diverse mechanisms underlying PLE in adolescence; hallucinatory experiences may be linked to inflammatory functions, while cannabis use may engage an alternative metabolic pathway related to increased energy demand and ketogenesis in inducing PLE. The limited sample of individuals with depression restricts the generalizability of these findings. Future research should explore whether various experiences and related metabolomic changes jointly predict the onset of psychoses and related disorders.
{"title":"An exploratory study of metabolomics in endogenous and cannabis-use-associated psychotic-like experiences in adolescence.","authors":"Karoliina Kurkinen, Olli Kärkkäinen, Soili M Lehto, Ilona Luoma, Siiri-Liisi Kraav, Petri Kivimäki, Sebastian Therman, Tommi Tolmunen","doi":"10.1038/s41398-024-03163-9","DOIUrl":"10.1038/s41398-024-03163-9","url":null,"abstract":"<p><p>In adolescence, psychotic-like experiences (PLE) may indicate potential prodromal symptoms preceding the onset of psychosis. Metabolomic studies have shown promise in providing valuable insights into predicting psychosis with enhanced precision compared to conventional clinical features. This study investigated metabolomic alterations associated with PLE in 76 depressed adolescents aged 14-20 years. Serum concentrations of 92 metabolites were analyzed with liquid chromatography-mass spectrometry. PLE were assessed using the Youth Experiences and Health (YEAH) questionnaire. The associations between PLE symptom dimensions (delusions, paranoia, hallucinations, negative symptoms, thought disorder, and dissociation) and metabolite concentrations were analyzed in linear regression models adjusted for different covariates. The symptom dimensions consistently correlated with the metabolome in different models, except those adjusted for cannabis use. Specifically, the hallucination dimension was associated with 13 metabolites (acetoacetic acid, allantoin, asparagine, decanoylcarnitine, D-glucuronic acid, guanidinoacetic acid, hexanoylcarnitine, homogentisic acid, leucine, NAD<sup>+</sup>, octanoylcarnitine, trimethylamine-N-oxide, and valine) in the various linear models. However, when adjusting for cannabis use, eight metabolites were associated with hallucinations (adenine, AMP, cAMP, chenodeoxycholic acid, cholic acid, L-kynurenine, neopterin, and D-ribose-5-phosphate). The results suggest diverse mechanisms underlying PLE in adolescence; hallucinatory experiences may be linked to inflammatory functions, while cannabis use may engage an alternative metabolic pathway related to increased energy demand and ketogenesis in inducing PLE. The limited sample of individuals with depression restricts the generalizability of these findings. Future research should explore whether various experiences and related metabolomic changes jointly predict the onset of psychoses and related disorders.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"466"},"PeriodicalIF":8.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11543670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606272","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}
Pub Date : 2024-11-07DOI: 10.1038/s41398-024-03174-6
Caroline Gora, Ana Dudas, Lucas Court, Anil Annamneedi, Gaëlle Lefort, Thiago S Nakahara, Nicolas Azzopardi, Adrien Acquistapace, Anne-Lyse Laine, Anne-Charlotte Trouillet, Lucile Drobecq, Emmanuel Pecnard, Benoît Piégu, Pascale Crépieux, Pablo Chamero, Lucie P Pellissier
Autism spectrum disorders (ASD) are complex, polygenic and heterogenous neurodevelopmental conditions. The severity of autism-associated variants is influenced by environmental factors, particularly social experiences during the critical neurodevelopmental period. While early behavioral interventions have shown efficacy in some children with autism, pharmacological support for core features - impairments in social interaction and communication, and stereotyped or restricted behaviors - is currently lacking. In this study, we examined how the social environment influences both wild-type (WT) and Shank3 knockout (KO) mice, a model reflecting core autism-like traits. Our findings revealed that chronic social isolation enhanced social interaction and olfactory neuron responses in WT animals. Furthermore, it restored impairments in social novelty preference and olfactory function, as well as self-grooming in Shank3 KO mice. Conversely, an enriched social environment heightened social interest toward novel conspecifics in WT mice, but elicited the opposite effect in Shank3 KO mice. Notably, Shank3 KO mice displayed distinct social responses when exposed to WT or Shank3 KO mice. These results offer novel insights that could favor the implementation of behavioral interventions and inclusive classroom programs for children with ASD.
自闭症谱系障碍(ASD)是一种复杂、多基因和异质性的神经发育疾病。自闭症相关变异的严重程度受环境因素的影响,尤其是神经发育关键时期的社会经历。虽然早期行为干预对一些自闭症儿童有疗效,但目前还缺乏针对核心特征(社会交往和沟通障碍以及刻板或限制性行为)的药物支持。在这项研究中,我们考察了社会环境如何影响野生型(WT)小鼠和 Shank3 基因敲除(KO)小鼠(一种反映类似自闭症核心特征的模型)。我们的研究结果表明,慢性社会隔离增强了 WT 动物的社会互动和嗅觉神经元反应。此外,它还能恢复 Shank3 KO 小鼠在社会新奇偏好和嗅觉功能以及自我梳理方面的损伤。相反,在丰富的社会环境中,WT 小鼠对新的同种动物的社会兴趣增强了,但在 Shank3 KO 小鼠中却产生了相反的效果。值得注意的是,Shank3 KO小鼠在与WT或Shank3 KO小鼠接触时会表现出不同的社会反应。这些结果提供了新的见解,有助于对患有自闭症的儿童实施行为干预和包容性课堂计划。
{"title":"Effect of the social environment on olfaction and social skills in wild-type and a mouse model of autism.","authors":"Caroline Gora, Ana Dudas, Lucas Court, Anil Annamneedi, Gaëlle Lefort, Thiago S Nakahara, Nicolas Azzopardi, Adrien Acquistapace, Anne-Lyse Laine, Anne-Charlotte Trouillet, Lucile Drobecq, Emmanuel Pecnard, Benoît Piégu, Pascale Crépieux, Pablo Chamero, Lucie P Pellissier","doi":"10.1038/s41398-024-03174-6","DOIUrl":"10.1038/s41398-024-03174-6","url":null,"abstract":"<p><p>Autism spectrum disorders (ASD) are complex, polygenic and heterogenous neurodevelopmental conditions. The severity of autism-associated variants is influenced by environmental factors, particularly social experiences during the critical neurodevelopmental period. While early behavioral interventions have shown efficacy in some children with autism, pharmacological support for core features - impairments in social interaction and communication, and stereotyped or restricted behaviors - is currently lacking. In this study, we examined how the social environment influences both wild-type (WT) and Shank3 knockout (KO) mice, a model reflecting core autism-like traits. Our findings revealed that chronic social isolation enhanced social interaction and olfactory neuron responses in WT animals. Furthermore, it restored impairments in social novelty preference and olfactory function, as well as self-grooming in Shank3 KO mice. Conversely, an enriched social environment heightened social interest toward novel conspecifics in WT mice, but elicited the opposite effect in Shank3 KO mice. Notably, Shank3 KO mice displayed distinct social responses when exposed to WT or Shank3 KO mice. These results offer novel insights that could favor the implementation of behavioral interventions and inclusive classroom programs for children with ASD.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"464"},"PeriodicalIF":5.8,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11542099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590726","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}