Pub Date : 2024-10-02DOI: 10.1038/s41398-024-03100-w
Priyam Narain, Aleksa Petković, Marko Šušić, Salma Haniffa, Mariam Anwar, Marc Arnoux, Nizar Drou, Giuseppe Antonio-Saldi, Dipesh Chaudhury
The molecular mechanisms that link stress and biological rhythms still remain unclear. The habenula (Hb) is a key brain region involved in regulating diverse types of emotion-related behaviours while the suprachiasmatic nucleus (SCN) is the body's central clock. To investigate the effects of chronic social stress on transcription patterns, we performed gene expression analysis in the Hb and SCN of stress-naïve and stress-exposed mice. Our analysis revealed a large number of differentially expressed genes and enrichment of synaptic and cell signalling pathways between resilient and stress-naïve mice at zeitgeber 16 (ZT16) in both the Hb and SCN. This transcriptomic signature was nighttime-specific and observed only in stress-resilient mice. In contrast, there were relatively few differences between the stress-susceptible and stress-naïve groups across time points. Our results reinforce the functional link between circadian gene expression patterns and differential responses to stress, thereby highlighting the importance of temporal expression patterns in homoeostatic stress responses.
{"title":"Nighttime-specific differential gene expression in suprachiasmatic nucleus and habenula is associated with resilience to chronic social stress.","authors":"Priyam Narain, Aleksa Petković, Marko Šušić, Salma Haniffa, Mariam Anwar, Marc Arnoux, Nizar Drou, Giuseppe Antonio-Saldi, Dipesh Chaudhury","doi":"10.1038/s41398-024-03100-w","DOIUrl":"10.1038/s41398-024-03100-w","url":null,"abstract":"<p><p>The molecular mechanisms that link stress and biological rhythms still remain unclear. The habenula (Hb) is a key brain region involved in regulating diverse types of emotion-related behaviours while the suprachiasmatic nucleus (SCN) is the body's central clock. To investigate the effects of chronic social stress on transcription patterns, we performed gene expression analysis in the Hb and SCN of stress-naïve and stress-exposed mice. Our analysis revealed a large number of differentially expressed genes and enrichment of synaptic and cell signalling pathways between resilient and stress-naïve mice at zeitgeber 16 (ZT16) in both the Hb and SCN. This transcriptomic signature was nighttime-specific and observed only in stress-resilient mice. In contrast, there were relatively few differences between the stress-susceptible and stress-naïve groups across time points. Our results reinforce the functional link between circadian gene expression patterns and differential responses to stress, thereby highlighting the importance of temporal expression patterns in homoeostatic stress responses.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366636","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 : 2024-10-01DOI: 10.1038/s41398-024-03128-y
Alinny R Isaac, Mariana G Chauvet, Ricardo Lima-Filho, Beatriz de A Wagner, Bruno G Caroli, Renata E P Leite, Claudia K Suemoto, Paula Villela Nunes, Fernanda G De Felice, Sergio T Ferreira, Mychael V Lourenco
Major depressive disorder (MDD) is a significant cause of disability in adults worldwide. However, the underlying causes and mechanisms of MDD are not fully understood, and many patients are refractory to available therapeutic options. Impaired control of brain mRNA translation underlies several neurodevelopmental and neurodegenerative conditions, including autism spectrum disorders and Alzheimer's disease (AD). Nonetheless, a potential role for mechanisms associated with impaired translational control in depressive-like behavior remains elusive. A key pathway controlling translation initiation relies on the phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α-P) which, in turn, blocks the guanine exchange factor activity of eIF2B, thereby reducing global translation rates. Here we report that the expression of EIF2B5 (which codes for eIF2Bε, the catalytic subunit of eIF2B) is reduced in postmortem MDD prefrontal cortex from two distinct human cohorts and in the frontal cortex of social isolation-induced depressive-like behavior model mice. Further, pharmacological treatment with anisomycin or with salubrinal, an inhibitor of the eIF2α phosphatase GADD34, induces depressive-like behavior in adult C57BL/6J mice. Salubrinal-induced depressive-like behavior is blocked by ISRIB, a compound that directly activates eIF2B regardless of the phosphorylation status of eIF2α, suggesting that increased eIF2α-P promotes depressive-like states. Taken together, our results suggest that impaired eIF2-associated translational control may participate in the pathophysiology of MDD, and underscore eIF2-eIF2B translational axis as a potential target for the development of novel approaches for MDD and related mood disorders.
{"title":"Defective regulation of the eIF2-eIF2B translational axis underlies depressive-like behavior in mice and correlates with major depressive disorder in humans.","authors":"Alinny R Isaac, Mariana G Chauvet, Ricardo Lima-Filho, Beatriz de A Wagner, Bruno G Caroli, Renata E P Leite, Claudia K Suemoto, Paula Villela Nunes, Fernanda G De Felice, Sergio T Ferreira, Mychael V Lourenco","doi":"10.1038/s41398-024-03128-y","DOIUrl":"10.1038/s41398-024-03128-y","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is a significant cause of disability in adults worldwide. However, the underlying causes and mechanisms of MDD are not fully understood, and many patients are refractory to available therapeutic options. Impaired control of brain mRNA translation underlies several neurodevelopmental and neurodegenerative conditions, including autism spectrum disorders and Alzheimer's disease (AD). Nonetheless, a potential role for mechanisms associated with impaired translational control in depressive-like behavior remains elusive. A key pathway controlling translation initiation relies on the phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α-P) which, in turn, blocks the guanine exchange factor activity of eIF2B, thereby reducing global translation rates. Here we report that the expression of EIF2B5 (which codes for eIF2Bε, the catalytic subunit of eIF2B) is reduced in postmortem MDD prefrontal cortex from two distinct human cohorts and in the frontal cortex of social isolation-induced depressive-like behavior model mice. Further, pharmacological treatment with anisomycin or with salubrinal, an inhibitor of the eIF2α phosphatase GADD34, induces depressive-like behavior in adult C57BL/6J mice. Salubrinal-induced depressive-like behavior is blocked by ISRIB, a compound that directly activates eIF2B regardless of the phosphorylation status of eIF2α, suggesting that increased eIF2α-P promotes depressive-like states. Taken together, our results suggest that impaired eIF2-associated translational control may participate in the pathophysiology of MDD, and underscore eIF2-eIF2B translational axis as a potential target for the development of novel approaches for MDD and related mood disorders.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11442801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354534","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 : 2024-10-01DOI: 10.1038/s41398-024-03117-1
Yun Wang, Changshuo Wang, Jingjing Zhou, Xiongying Chen, Rui Liu, Zhifang Zhang, Yuan Feng, Lei Feng, Jing Liu, Yuan Zhou, Gang Wang
This study investigated how resting-state functional connectivity (rsFC) of the subgenual anterior cingulate cortex (sgACC) predicts antidepressant response in patients with major depressive disorder (MDD). Eighty-seven medication-free MDD patients underwent baseline resting-state functional MRI scans. After 12 weeks of escitalopram treatment, patients were classified into remission depression (RD, n = 42) and nonremission depression (NRD, n = 45) groups. We conducted two analyses: a voxel-wise rsFC analysis using sgACC as a seed to identify group differences, and a prediction model based on the sgACC rsFC map to predict treatment efficacy. Haufe transformation was used to interpret the predictive rsFC features. The RD group showed significantly higher rsFC between the sgACC and regions in the fronto-parietal network (FPN), including the bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral inferior parietal lobule (IPL), compared to the NRD group. These sgACC rsFC measures correlated positively with symptom improvement. Baseline sgACC rsFC also significantly predicted treatment response after 12 weeks, with a mean accuracy of 72.64% (p < 0.001), mean area under the curve of 0.74 (p < 0.001), mean specificity of 0.82, and mean sensitivity of 0.70 in 10-fold cross-validation. The predictive voxels were mainly within the FPN. The rsFC between the sgACC and FPN is a valuable predictor of antidepressant response in MDD patients. These findings enhance our understanding of the neurobiological mechanisms underlying treatment response and could help inform personalized treatment strategies for MDD.
{"title":"Contribution of resting-state functional connectivity of the subgenual anterior cingulate to prediction of antidepressant efficacy in patients with major depressive disorder.","authors":"Yun Wang, Changshuo Wang, Jingjing Zhou, Xiongying Chen, Rui Liu, Zhifang Zhang, Yuan Feng, Lei Feng, Jing Liu, Yuan Zhou, Gang Wang","doi":"10.1038/s41398-024-03117-1","DOIUrl":"10.1038/s41398-024-03117-1","url":null,"abstract":"<p><p>This study investigated how resting-state functional connectivity (rsFC) of the subgenual anterior cingulate cortex (sgACC) predicts antidepressant response in patients with major depressive disorder (MDD). Eighty-seven medication-free MDD patients underwent baseline resting-state functional MRI scans. After 12 weeks of escitalopram treatment, patients were classified into remission depression (RD, n = 42) and nonremission depression (NRD, n = 45) groups. We conducted two analyses: a voxel-wise rsFC analysis using sgACC as a seed to identify group differences, and a prediction model based on the sgACC rsFC map to predict treatment efficacy. Haufe transformation was used to interpret the predictive rsFC features. The RD group showed significantly higher rsFC between the sgACC and regions in the fronto-parietal network (FPN), including the bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral inferior parietal lobule (IPL), compared to the NRD group. These sgACC rsFC measures correlated positively with symptom improvement. Baseline sgACC rsFC also significantly predicted treatment response after 12 weeks, with a mean accuracy of 72.64% (p < 0.001), mean area under the curve of 0.74 (p < 0.001), mean specificity of 0.82, and mean sensitivity of 0.70 in 10-fold cross-validation. The predictive voxels were mainly within the FPN. The rsFC between the sgACC and FPN is a valuable predictor of antidepressant response in MDD patients. These findings enhance our understanding of the neurobiological mechanisms underlying treatment response and could help inform personalized treatment strategies for MDD.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362140","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 : 2024-10-01DOI: 10.1038/s41398-024-03131-3
Yitong Ling, Shiqi Yuan, Xiaxuan Huang, Shanyuan Tan, Hongtao Cheng, Li Li, Shuna Li, Liying Huang, Anding Xu, Jun Lyu
The role of alcohol consumption as a mediator in the risk between sarcopenia and dementia remains inadequately studied. There is currently limited research on whether the association between sarcopenia and the risk of Alzheimer's disease (AD) is influenced by genetic susceptibility. Our study incorporated a total of 483,637 baseline non-dementia participants, who were classified into groups of individuals with no sarcopenia and those with probable sarcopenia based on the definition. We employed Cox proportional hazards models to evaluate the association between probable sarcopenia and the risk of all cause dementia (ACD), AD, and vascular dementia (VD). We conducted mediation analysis to explore the role of alcohol consumption in the association between probable sarcopenia and the risk of ACD, AD, and VD. During the median follow-up period of 13.6 years, we documented 9000 new cases of ACD (including 4061 AD and 2025 VD). Fully adjusted multivariate model revealed a significant correlation between probable sarcopenia and elevated risk for ACD (HR = 1.54, 95% CI: 1.46-1.62, p < 0.001), AD (HR = 1.32, 95% CI: 1.21-1.43, p < 0.001), and VD (HR = 1.69, 95% CI: 1.52-1.89, p < 0.001). Mediation analysis elucidates that alcohol consumption explained 12.8%, 15.2%, and 11.1% of the associations of probable sarcopenia with the risk of ACD, AD, and VD, respectively. An interactive relationship prevails between probable sarcopenia and genetic factors (p for interaction <0.001), and regardless of the degree of genetic risk, probable sarcopenia correlates with an elevated AD risk. Our study reveals a significant association between probable sarcopenia and an increased risk of dementia, with alcohol consumption playing a mediating role in this association. There is an interaction between probable sarcopenia and genetic susceptibility related to the risk of AD.
{"title":"Association between probable sarcopenia and dementia risk: a prospective cohort study with mediation analysis.","authors":"Yitong Ling, Shiqi Yuan, Xiaxuan Huang, Shanyuan Tan, Hongtao Cheng, Li Li, Shuna Li, Liying Huang, Anding Xu, Jun Lyu","doi":"10.1038/s41398-024-03131-3","DOIUrl":"10.1038/s41398-024-03131-3","url":null,"abstract":"<p><p>The role of alcohol consumption as a mediator in the risk between sarcopenia and dementia remains inadequately studied. There is currently limited research on whether the association between sarcopenia and the risk of Alzheimer's disease (AD) is influenced by genetic susceptibility. Our study incorporated a total of 483,637 baseline non-dementia participants, who were classified into groups of individuals with no sarcopenia and those with probable sarcopenia based on the definition. We employed Cox proportional hazards models to evaluate the association between probable sarcopenia and the risk of all cause dementia (ACD), AD, and vascular dementia (VD). We conducted mediation analysis to explore the role of alcohol consumption in the association between probable sarcopenia and the risk of ACD, AD, and VD. During the median follow-up period of 13.6 years, we documented 9000 new cases of ACD (including 4061 AD and 2025 VD). Fully adjusted multivariate model revealed a significant correlation between probable sarcopenia and elevated risk for ACD (HR = 1.54, 95% CI: 1.46-1.62, p < 0.001), AD (HR = 1.32, 95% CI: 1.21-1.43, p < 0.001), and VD (HR = 1.69, 95% CI: 1.52-1.89, p < 0.001). Mediation analysis elucidates that alcohol consumption explained 12.8%, 15.2%, and 11.1% of the associations of probable sarcopenia with the risk of ACD, AD, and VD, respectively. An interactive relationship prevails between probable sarcopenia and genetic factors (p for interaction <0.001), and regardless of the degree of genetic risk, probable sarcopenia correlates with an elevated AD risk. Our study reveals a significant association between probable sarcopenia and an increased risk of dementia, with alcohol consumption playing a mediating role in this association. There is an interaction between probable sarcopenia and genetic susceptibility related to the risk of AD.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362139","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 : 2024-09-30DOI: 10.1038/s41398-024-03103-7
Elizabeth L Fisher, Ryan Smith, Kyna Conn, Andrew W Corcoran, Laura K Milton, Jakob Hohwy, Claire J Foldi
Psilocybin has shown promise as a novel pharmacological intervention for treatment of depression, where post-acute effects of psilocybin treatment have been associated with increased positive mood and decreased pessimism. Although psilocybin is proving to be effective in clinical trials for treatment of psychiatric disorders, the information processing mechanisms affected by psilocybin are not well understood. Here, we fit active inference and reinforcement learning computational models to a novel two-armed bandit reversal learning task capable of capturing engagement behaviour in rats. The model revealed that after receiving psilocybin, rats achieve more rewards through increased task engagement, mediated by modification of forgetting rates and reduced loss aversion. These findings suggest that psilocybin may afford an optimism bias that arises through altered belief updating, with translational potential for clinical populations characterised by lack of optimism.
{"title":"Psilocybin increases optimistic engagement over time: computational modelling of behaviour in rats.","authors":"Elizabeth L Fisher, Ryan Smith, Kyna Conn, Andrew W Corcoran, Laura K Milton, Jakob Hohwy, Claire J Foldi","doi":"10.1038/s41398-024-03103-7","DOIUrl":"10.1038/s41398-024-03103-7","url":null,"abstract":"<p><p>Psilocybin has shown promise as a novel pharmacological intervention for treatment of depression, where post-acute effects of psilocybin treatment have been associated with increased positive mood and decreased pessimism. Although psilocybin is proving to be effective in clinical trials for treatment of psychiatric disorders, the information processing mechanisms affected by psilocybin are not well understood. Here, we fit active inference and reinforcement learning computational models to a novel two-armed bandit reversal learning task capable of capturing engagement behaviour in rats. The model revealed that after receiving psilocybin, rats achieve more rewards through increased task engagement, mediated by modification of forgetting rates and reduced loss aversion. These findings suggest that psilocybin may afford an optimism bias that arises through altered belief updating, with translational potential for clinical populations characterised by lack of optimism.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11442808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354538","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 : 2024-09-30DOI: 10.1038/s41398-024-03116-2
Aaron Klaiber, Yasmin Schmid, Anna M Becker, Isabelle Straumann, Livio Erne, Alen Jelusic, Jan Thomann, Dino Luethi, Matthias E Liechti
Classic psychedelics have regained interest in research and therapy. Despite the long tradition of the human use of mescaline, modern data on its dose-dependent acute effects and pharmacokinetics are lacking. Additionally, its mechanism of action has not been investigated in humans. We used a randomized, double-blind, placebo-controlled, crossover design in 16 healthy subjects (8 women) who received placebo, mescaline (100, 200, 400, and 800 mg), and 800 mg mescaline together with the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor antagonist ketanserin (40 mg) to assess subjective effects, autonomic effects, adverse effects, and pharmacokinetics up to 30 h after drug administration. Mescaline at doses >100 mg induced dose-dependent acute subjective effects. Mescaline increased systolic and diastolic blood pressure at doses >100 mg, with no difference between doses of 200-800 mg. Heart rate increased dose-dependently. Pharmacokinetics of mescaline were dose-proportional. Maximal concentrations were reached after approximately 2 h, and the plasma elimination half-life was approximately 3.5 h. The average duration of subjective effects increased from 6.4 to 14 h with increasing doses of 100-800 mg mescaline. Nausea and emesis were frequent adverse effects at the 800 mg dose. Co-administration of ketanserin attenuated and shortened acute effects of 800 mg mescaline to become comparable to the 100 and 200 mg doses. There were no ceiling effects of the subjective response within the investigated dose range, but tolerability was lower at the highest doses. These results may assist with dose finding for future research and suggest that acute effects of mescaline are primarily mediated by 5-HT2A receptors.
{"title":"Acute dose-dependent effects of mescaline in a double-blind placebo-controlled study in healthy subjects.","authors":"Aaron Klaiber, Yasmin Schmid, Anna M Becker, Isabelle Straumann, Livio Erne, Alen Jelusic, Jan Thomann, Dino Luethi, Matthias E Liechti","doi":"10.1038/s41398-024-03116-2","DOIUrl":"10.1038/s41398-024-03116-2","url":null,"abstract":"<p><p>Classic psychedelics have regained interest in research and therapy. Despite the long tradition of the human use of mescaline, modern data on its dose-dependent acute effects and pharmacokinetics are lacking. Additionally, its mechanism of action has not been investigated in humans. We used a randomized, double-blind, placebo-controlled, crossover design in 16 healthy subjects (8 women) who received placebo, mescaline (100, 200, 400, and 800 mg), and 800 mg mescaline together with the serotonin 5-hydroxytryptamine-2A (5-HT<sub>2A</sub>) receptor antagonist ketanserin (40 mg) to assess subjective effects, autonomic effects, adverse effects, and pharmacokinetics up to 30 h after drug administration. Mescaline at doses >100 mg induced dose-dependent acute subjective effects. Mescaline increased systolic and diastolic blood pressure at doses >100 mg, with no difference between doses of 200-800 mg. Heart rate increased dose-dependently. Pharmacokinetics of mescaline were dose-proportional. Maximal concentrations were reached after approximately 2 h, and the plasma elimination half-life was approximately 3.5 h. The average duration of subjective effects increased from 6.4 to 14 h with increasing doses of 100-800 mg mescaline. Nausea and emesis were frequent adverse effects at the 800 mg dose. Co-administration of ketanserin attenuated and shortened acute effects of 800 mg mescaline to become comparable to the 100 and 200 mg doses. There were no ceiling effects of the subjective response within the investigated dose range, but tolerability was lower at the highest doses. These results may assist with dose finding for future research and suggest that acute effects of mescaline are primarily mediated by 5-HT<sub>2A</sub> receptors.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11442856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354532","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 : 2024-09-30DOI: 10.1038/s41398-024-03124-2
Chen-Wei Huang, Ting Hu, Hong Zheng, Yi-Lin Wu, Jia-Mei Li, Yi-Ming Wang, Wen-Jun Su, Wei Wang, Yun-Zi Liu, Chun-Lei Jiang
Depression is a significant mental health issue with extensive economic implications, and recent studies suggest it may be transmitted between individuals. However, the mechanisms of this contagion remain unclear, and the social buffering effect has been understudied. This research employs three rodent models, including stress crossover, cohabitation-induced, and non-contact induced depression contagion models, to explore these mechanisms. Here, we report that that naive mice cohabiting with depressed mice showed increased corticosterone levels and depressive behaviors, unlike those with stressed mice, who did not exhibit these changes and even mitigated desperation in stressed mice. Non-contact cohabitation did not produce significant behavioral differences, but exposure to bedding from depressed mice reduced sucrose preference in naive mice. This study introduces reliable models of depression contagion, suggesting it operates independently of stress transmission. The interplay between depression contagion and social buffering may vary in different contexts. These findings provide new insights into the mechanisms of depression contagion and potential strategies for preventing depressive disorders.
{"title":"Contagion of depression: a double-edged sword.","authors":"Chen-Wei Huang, Ting Hu, Hong Zheng, Yi-Lin Wu, Jia-Mei Li, Yi-Ming Wang, Wen-Jun Su, Wei Wang, Yun-Zi Liu, Chun-Lei Jiang","doi":"10.1038/s41398-024-03124-2","DOIUrl":"10.1038/s41398-024-03124-2","url":null,"abstract":"<p><p>Depression is a significant mental health issue with extensive economic implications, and recent studies suggest it may be transmitted between individuals. However, the mechanisms of this contagion remain unclear, and the social buffering effect has been understudied. This research employs three rodent models, including stress crossover, cohabitation-induced, and non-contact induced depression contagion models, to explore these mechanisms. Here, we report that that naive mice cohabiting with depressed mice showed increased corticosterone levels and depressive behaviors, unlike those with stressed mice, who did not exhibit these changes and even mitigated desperation in stressed mice. Non-contact cohabitation did not produce significant behavioral differences, but exposure to bedding from depressed mice reduced sucrose preference in naive mice. This study introduces reliable models of depression contagion, suggesting it operates independently of stress transmission. The interplay between depression contagion and social buffering may vary in different contexts. These findings provide new insights into the mechanisms of depression contagion and potential strategies for preventing depressive disorders.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11443097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354533","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 : 2024-09-28DOI: 10.1038/s41398-024-03112-6
Valentina Bassareo, Riccardo Maccioni, Giuseppe Talani, Simone Zuffa, Yasin El Abiead, Irene Lorrai, Tomoya Kawamura, Sofia Pantis, Roberta Puliga, Romina Vargiu, Daniele Lecca, Paolo Enrico, Alessandra Peana, Laura Dazzi, Pieter C Dorrestein, Pietro Paolo Sanna, Enrico Sanna, Elio Acquas
The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.
酒精和咖啡因的消费影响着全球数十亿人的生活。尽管最近有证据表明咖啡因会削弱酒精的强化作用,但却缺乏咖啡因对酒精刺激的间叶多巴胺(DA)功能的影响特征。酒精作为salsolinol的原药,可兴奋后腹侧被盖区(pVTA)的DA神经元,并增加核团外壳(AcbSh)的DA释放。在这里,我们展示了咖啡因通过对 A2A 腺苷受体(A2AR)的拮抗作用,阻止了酒精对间叶 DA 功能的依赖性激活,这种激活在体内是通过对 AcbSh DA 的脑微量透析评估的,在体外是通过对 pVTA DA 神经元发射的电生理记录评估的。因此,虽然A1R拮抗剂DPCPX不能阻止酒精对DA功能的影响,但咖啡因和A2AR拮抗剂SCH 58261都能阻止酒精依赖性体内pVTA产生salsolinol和AcbSh DA增加,以及酒精依赖性体外pVTA DA神经元兴奋。然而,咖啡因也能阻止直接的鲨烯醇和吗啡刺激的DA功能,这表明咖啡因也能发挥这些抑制作用,而不影响酒精诱导的鲨烯醇的形成或生物利用度。最后,pVTA 的非靶向代谢组学研究表明,咖啡因能拮抗酒精介导的对脂质信号转导和能量代谢相关分子(如磷脂酰胆碱、脂肪酰胺、肉毒碱)的影响,这可能代表咖啡因在损害酒精介导的刺激间叶 DA 传递方面的另一种与香豆素醇无关的机制。总之,这项研究的结果增强了咖啡因和 A2AR 拮抗剂在未来开发酒精使用障碍的预防/治疗策略方面的潜力。
{"title":"Receptor and metabolic insights on the ability of caffeine to prevent alcohol-induced stimulation of mesolimbic dopamine transmission.","authors":"Valentina Bassareo, Riccardo Maccioni, Giuseppe Talani, Simone Zuffa, Yasin El Abiead, Irene Lorrai, Tomoya Kawamura, Sofia Pantis, Roberta Puliga, Romina Vargiu, Daniele Lecca, Paolo Enrico, Alessandra Peana, Laura Dazzi, Pieter C Dorrestein, Pietro Paolo Sanna, Enrico Sanna, Elio Acquas","doi":"10.1038/s41398-024-03112-6","DOIUrl":"10.1038/s41398-024-03112-6","url":null,"abstract":"<p><p>The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A<sub>2A</sub> adenosine receptors (A<sub>2A</sub>R), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A<sub>1</sub>R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A<sub>2A</sub>R antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A<sub>2A</sub>R antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354539","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}
Low-frequency repetitive transcranial magnetic stimulation (rTMS) has emerged as an effective intervention for alleviating symptoms of psychiatric disorders, particularly schizophrenia characterized by persistent auditory verbal hallucinations (AVH). However, the underlying mechanism of its action remain elusive. This study employed a randomized controlled design to investigate the impact of low-frequency rTMS on the neural connectivity at the stimulate site, specifically left temporoparietal junction (TPJ), in schizophrenia patients with suffering from AVH. Using Dynamic Causal Modeling (DCM), this study assessed changes in directed connectivity patterns and their correlations with clinical symptomatology. The results demonstrated significant improvements in AVH. Notably, significant changes in connectivity were observed, including both abnormal functional connectivity and effective connectivity among multiple brain regions. Particularly, the inhibition effects from the left precentral gyrus and left medial superior frontal gyrus to the left TPJ were closely associated with improvements in AVH. These findings underscore the potential of rTMS to effectively modulate neural pathways implicated in hallucinations in schizophrenia, thereby providing a neurobiological foundation for its therapeutic effects.
{"title":"Targeting auditory verbal hallucinations in schizophrenia: effective connectivity changes induced by low-frequency rTMS.","authors":"Xie Yuanjun, Muzhen Guan, Tian Zhang, Chaozong Ma, Lingling Wang, Xinxin Lin, Chenxi Li, Zhongheng Wang, Ma Zhujing, Huaning Wang, Fang Peng","doi":"10.1038/s41398-024-03106-4","DOIUrl":"https://doi.org/10.1038/s41398-024-03106-4","url":null,"abstract":"<p><p>Low-frequency repetitive transcranial magnetic stimulation (rTMS) has emerged as an effective intervention for alleviating symptoms of psychiatric disorders, particularly schizophrenia characterized by persistent auditory verbal hallucinations (AVH). However, the underlying mechanism of its action remain elusive. This study employed a randomized controlled design to investigate the impact of low-frequency rTMS on the neural connectivity at the stimulate site, specifically left temporoparietal junction (TPJ), in schizophrenia patients with suffering from AVH. Using Dynamic Causal Modeling (DCM), this study assessed changes in directed connectivity patterns and their correlations with clinical symptomatology. The results demonstrated significant improvements in AVH. Notably, significant changes in connectivity were observed, including both abnormal functional connectivity and effective connectivity among multiple brain regions. Particularly, the inhibition effects from the left precentral gyrus and left medial superior frontal gyrus to the left TPJ were closely associated with improvements in AVH. These findings underscore the potential of rTMS to effectively modulate neural pathways implicated in hallucinations in schizophrenia, thereby providing a neurobiological foundation for its therapeutic effects.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354540","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 : 2024-09-28DOI: 10.1038/s41398-024-03109-1
Sijia Chen, Shixin Ding, Yingting Pang, Yuxi Jin, Peng Sun, Yue Li, Min Cao, Yimiao Wang, Ze Wang, Tianqi Wang, Ying Zou, Yanli Zhang, Ming Xiao
Early social isolation (SI) leads to various abnormalities in emotion and behavior during adulthood. However, the negative impact of SI on offspring remains unclear. This study has discovered that paternal early SI causes social memory deficits and anxiety-like behavior in F1 young adult mice, with alterations of myelin and synapses in the medial prefrontal cortex (mPFC). The 2-week SI in the F1 progeny exacerbates social memory impairment and hypomyelination in the mPFC. Furthermore, the down-regulation of miR-124, a key inhibitor of myelinogenesis, or over-expression of its target gene Nr4a1 in the mPFC of the F1 mice improves social interaction ability and enhances oligodendrocyte maturation and myelin formation. Mechanistically, elevated levels of miR-124 in the sperm of paternal SI mice are transmitted epigenetically to offspring, altering the expression levels of miR-124/Nr4a1/glucocorticoid receptors in mPFC oligodendrocytes. This, in turn, impedes the establishment of myelinogenesis-dependent social behavior. This study unveils a novel mechanism through which miR-124 mediates the intergenerational effects of early isolation stress, ultimately impairing the establishment of social behavior and neurodevelopment.
早期社会隔离(SI)会导致成年后情绪和行为的各种异常。然而,社会隔离对后代的负面影响仍不清楚。这项研究发现,父系早期社会隔离会导致 F1 年轻成年小鼠的社会记忆缺陷和焦虑样行为,并改变内侧前额叶皮层(mPFC)的髓鞘和突触。对 F1 后代进行 2 周的 SI 会加剧 mPFC 中的社会记忆障碍和髓鞘化不足。此外,在F1小鼠的mPFC中下调miR-124(一种髓鞘生成的关键抑制因子)或过度表达其靶基因Nr4a1可改善社交互动能力,并促进少突胶质细胞的成熟和髓鞘的形成。从机理上讲,父系 SI 小鼠精子中 miR-124 水平的升高会通过表观遗传传递给子代,从而改变 mPFC 少突胶质细胞中 miR-124/Nr4a1/ 糖皮质激素受体的表达水平。这反过来又阻碍了依赖髓鞘生成的社会行为的建立。这项研究揭示了一种新的机制,通过这种机制,miR-124介导了早期隔离应激的代际效应,最终损害了社会行为和神经发育的建立。
{"title":"Dysregulated miR-124 mediates impaired social memory behavior caused by paternal early social isolation.","authors":"Sijia Chen, Shixin Ding, Yingting Pang, Yuxi Jin, Peng Sun, Yue Li, Min Cao, Yimiao Wang, Ze Wang, Tianqi Wang, Ying Zou, Yanli Zhang, Ming Xiao","doi":"10.1038/s41398-024-03109-1","DOIUrl":"10.1038/s41398-024-03109-1","url":null,"abstract":"<p><p>Early social isolation (SI) leads to various abnormalities in emotion and behavior during adulthood. However, the negative impact of SI on offspring remains unclear. This study has discovered that paternal early SI causes social memory deficits and anxiety-like behavior in F1 young adult mice, with alterations of myelin and synapses in the medial prefrontal cortex (mPFC). The 2-week SI in the F1 progeny exacerbates social memory impairment and hypomyelination in the mPFC. Furthermore, the down-regulation of miR-124, a key inhibitor of myelinogenesis, or over-expression of its target gene Nr4a1 in the mPFC of the F1 mice improves social interaction ability and enhances oligodendrocyte maturation and myelin formation. Mechanistically, elevated levels of miR-124 in the sperm of paternal SI mice are transmitted epigenetically to offspring, altering the expression levels of miR-124/Nr4a1/glucocorticoid receptors in mPFC oligodendrocytes. This, in turn, impedes the establishment of myelinogenesis-dependent social behavior. This study unveils a novel mechanism through which miR-124 mediates the intergenerational effects of early isolation stress, ultimately impairing the establishment of social behavior and neurodevelopment.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354535","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}