Pub Date : 2024-07-13DOI: 10.1038/s41380-024-02656-9
Fabien Chauveau, Alexandra Winkeler, Sylvie Chalon, Hervé Boutin, Guillaume Becker
Over the last decades, the role of neuroinflammation in neuropsychiatric conditions has attracted an exponentially growing interest. A key driver for this trend was the ability to image brain inflammation in vivo using PET radioligands targeting the Translocator Protein 18 kDa (TSPO), which is known to be expressed in activated microglia and astrocytes upon inflammatory events as well as constitutively in endothelial cells. TSPO is a mitochondrial protein that is expressed mostly by microglial cells upon activation but is also expressed by astrocytes in some conditions and constitutively by endothelial cells. Therefore, our current understanding of neuroinflammation dynamics is hampered by the lack of alternative targets available for PET imaging. We performed a systematic search and review on radiotracers developed for neuroinflammation PET imaging apart from TSPO. The following targets of interest were identified through literature screening (including previous narrative reviews): P2Y12R, P2X7R, CSF1R, COX (microglial targets), MAO-B, I2BS (astrocytic targets), CB2R & S1PRs (not specific of a single cell type). We determined the level of development and provided a scoping review for each target. Strikingly, astrocytic biomarker MAO-B has progressed in clinical investigations the furthest, while few radiotracers (notably targeting S1P1Rs, CSF1R) are being implemented in clinical investigations. Other targets such as CB2R and P2X7R have proven disappointing in clinical studies (e.g. poor signal, lack of changes in disease conditions, etc.). While astrocytic targets are promising, development of new biomarkers and tracers specific for microglial activation has proven challenging.
过去几十年来,神经炎症在神经精神疾病中的作用引起了越来越多的关注。这一趋势的主要驱动力是利用 PET 放射配体靶向 18 kDa 转运蛋白(TSPO)对体内脑部炎症进行成像的能力,众所周知,在炎症事件发生时,活化的小胶质细胞和星形胶质细胞以及内皮细胞都会表达 TSPO。TSPO 是一种线粒体蛋白,主要在小胶质细胞活化时表达,但在某些情况下星形胶质细胞也会表达,内皮细胞也会组成性表达。因此,由于缺乏可用于 PET 成像的替代靶点,我们目前对神经炎症动态的了解受到了阻碍。我们对 TSPO 以外用于神经炎症 PET 成像的放射性同位素进行了系统搜索和回顾。通过文献筛选(包括之前的叙述性综述),我们确定了以下感兴趣的靶点:P2Y12R、P2X7R、CSF1R、COX(小胶质细胞靶点)、MAO-B、I2BS(星形胶质细胞靶点)、CB2R 和 S1PRs(非单细胞类型特异性)。我们确定了每个靶点的发展水平,并对其进行了范围审查。令人吃惊的是,星形胶质细胞生物标记物 MAO-B 在临床研究中的进展最快,而正在进行临床研究的放射性标记物(特别是针对 S1P1Rs 和 CSF1R)却很少。其他靶点,如 CB2R 和 P2X7R,在临床研究中的表现令人失望(如信号差、疾病状况缺乏变化等)。虽然星形胶质细胞靶点很有希望,但开发专门用于小胶质细胞激活的新生物标记物和示踪剂已被证明具有挑战性。
{"title":"PET imaging of neuroinflammation: any credible alternatives to TSPO yet?","authors":"Fabien Chauveau, Alexandra Winkeler, Sylvie Chalon, Hervé Boutin, Guillaume Becker","doi":"10.1038/s41380-024-02656-9","DOIUrl":"https://doi.org/10.1038/s41380-024-02656-9","url":null,"abstract":"<p><p>Over the last decades, the role of neuroinflammation in neuropsychiatric conditions has attracted an exponentially growing interest. A key driver for this trend was the ability to image brain inflammation in vivo using PET radioligands targeting the Translocator Protein 18 kDa (TSPO), which is known to be expressed in activated microglia and astrocytes upon inflammatory events as well as constitutively in endothelial cells. TSPO is a mitochondrial protein that is expressed mostly by microglial cells upon activation but is also expressed by astrocytes in some conditions and constitutively by endothelial cells. Therefore, our current understanding of neuroinflammation dynamics is hampered by the lack of alternative targets available for PET imaging. We performed a systematic search and review on radiotracers developed for neuroinflammation PET imaging apart from TSPO. The following targets of interest were identified through literature screening (including previous narrative reviews): P2Y12R, P2X7R, CSF1R, COX (microglial targets), MAO-B, I2BS (astrocytic targets), CB2R & S1PRs (not specific of a single cell type). We determined the level of development and provided a scoping review for each target. Strikingly, astrocytic biomarker MAO-B has progressed in clinical investigations the furthest, while few radiotracers (notably targeting S1P1Rs, CSF1R) are being implemented in clinical investigations. Other targets such as CB2R and P2X7R have proven disappointing in clinical studies (e.g. poor signal, lack of changes in disease conditions, etc.). While astrocytic targets are promising, development of new biomarkers and tracers specific for microglial activation has proven challenging.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141600787","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}
Pub Date : 2024-07-13DOI: 10.1038/s41380-024-02659-6
Liming Qin, Zhili Liu, Sile Guo, Ying Han, Xiankun Wang, Wen Ren, Jiewen Chen, Hefu Zhen, Chao Nie, Ke-Ke Xing, Tao Chen, Thomas C Südhof, Yuzhe Sun, Bo Zhang
Neuroligin-3 (Nlgn3) is an autism-associated cell-adhesion molecule that interacts with neurexins and is robustly expressed in both neurons and astrocytes. Neuronal Nlgn3 is an essential regulator of synaptic transmission but the function of astrocytic Nlgn3 is largely unknown. Given the high penetrance of Nlgn3 mutations in autism and the emerging role of astrocytes in neuropsychiatric disorders, we here asked whether astrocytic Nlgn3 might shape neural circuit properties in the cerebellum similar to neuronal Nlgn3. Imaging of tagged Nlgn3 protein produced by CRISPR/Cas9-mediated genome editing showed that Nlgn3 is enriched in the cell body but not the fine processes of cerebellar astrocytes (Bergmann glia). Astrocyte-specific knockout of Nlgn3 did not detectably alter the number of synapses, synaptic transmission, or astrocyte morphology in mouse cerebellum. However, spatial transcriptomic analyses revealed a significant shift in gene expression among multiple cerebellar cell types after the deletion of astrocytic Nlgn3. Hence, in contrast to neuronal Nlgn3, astrocytic Nlgn3 in the cerebellum is not involved in shaping synapses but may modulate gene expression in specific brain areas.
{"title":"Astrocytic Neuroligin-3 influences gene expression and social behavior, but is dispensable for synapse number.","authors":"Liming Qin, Zhili Liu, Sile Guo, Ying Han, Xiankun Wang, Wen Ren, Jiewen Chen, Hefu Zhen, Chao Nie, Ke-Ke Xing, Tao Chen, Thomas C Südhof, Yuzhe Sun, Bo Zhang","doi":"10.1038/s41380-024-02659-6","DOIUrl":"10.1038/s41380-024-02659-6","url":null,"abstract":"<p><p>Neuroligin-3 (Nlgn3) is an autism-associated cell-adhesion molecule that interacts with neurexins and is robustly expressed in both neurons and astrocytes. Neuronal Nlgn3 is an essential regulator of synaptic transmission but the function of astrocytic Nlgn3 is largely unknown. Given the high penetrance of Nlgn3 mutations in autism and the emerging role of astrocytes in neuropsychiatric disorders, we here asked whether astrocytic Nlgn3 might shape neural circuit properties in the cerebellum similar to neuronal Nlgn3. Imaging of tagged Nlgn3 protein produced by CRISPR/Cas9-mediated genome editing showed that Nlgn3 is enriched in the cell body but not the fine processes of cerebellar astrocytes (Bergmann glia). Astrocyte-specific knockout of Nlgn3 did not detectably alter the number of synapses, synaptic transmission, or astrocyte morphology in mouse cerebellum. However, spatial transcriptomic analyses revealed a significant shift in gene expression among multiple cerebellar cell types after the deletion of astrocytic Nlgn3. Hence, in contrast to neuronal Nlgn3, astrocytic Nlgn3 in the cerebellum is not involved in shaping synapses but may modulate gene expression in specific brain areas.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603904","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}
Pub Date : 2024-07-12DOI: 10.1038/s41380-024-02657-8
Pablo Eduardo Pereira Dutra, Marleide da Mota Gomes, Mauro Vitor Mendlowicz, Akos Heinemann, Antonio Egidio Nardi
{"title":"Celebration of the Sesquicentennial of Otto Loewi (1873-1961): The Nobel Prize Laureate Physiologist and Pharmacologist.","authors":"Pablo Eduardo Pereira Dutra, Marleide da Mota Gomes, Mauro Vitor Mendlowicz, Akos Heinemann, Antonio Egidio Nardi","doi":"10.1038/s41380-024-02657-8","DOIUrl":"https://doi.org/10.1038/s41380-024-02657-8","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141600786","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}
Pub Date : 2024-07-09DOI: 10.1038/s41380-024-02652-z
Canhua Xiao, Gang Peng, Karen N Conneely, Hongyu Zhao, Jennifer C Felger, Evanthia C Wommack, Kristin A Higgins, Dong M Shin, Nabil F Saba, Deborah W Bruner, Andrew H Miller
Cancer patients are commonly affected by fatigue. Herein, we sought to examine epigenetic modifications (i.e., DNA methylation) related to fatigue in peripheral blood among patients during and after treatment for head and neck cancer (HNC). Further, we determined whether these modifications were associated with gene expression and inflammatory protein markers, which we have previously linked to fatigue in HNC. This prospective, longitudinal study enrolled eligible patients with data collected at pre-radiotherapy, end of radiotherapy, and six months and one-year post-radiotherapy. Fatigue data were reported by patients using the Multidimensional Fatigue Inventory (MFI)-20. DNA methylation (Illumina MethylationEPIC) and gene expression (Applied Biosystems Clariom S) arrays and assays for seven inflammatory markers (R&D Systems multiplex) were performed. Mixed models and enrichment analyses were applied to establish the associations. A total of 386 methylation loci were associated with fatigue among 145 patients (False Discovery Rate [FDR] < 0.05). Enrichment analyses showed the involvement of genes related to immune and inflammatory responses, insulin and lipid metabolism, neuropsychological disorders, and tumors. We further identified 16 methylation-gene expression pairs (FDR < 0.05), which were linked to immune and inflammatory responses and lipid metabolism. Ninety-one percent (351) of the 386 methylation loci were also significantly associated with inflammatory markers (e.g., interleukin 6, c-reactive protein; FDR < 0.05), which further mediated the association between methylation and fatigue (FDR < 0.05). These data suggest that epigenetic modifications associated with inflammation and immunometabolism, in conjunction with relevant gene expression and protein markers, are potential targets for treating fatigue in HNC patients. The findings also merit future prospective studies in other cancer populations as well as interventional investigations.
癌症患者通常会感到疲劳。在此,我们试图研究头颈癌(HNC)患者在治疗期间和治疗后外周血中与疲劳有关的表观遗传修饰(即 DNA 甲基化)。此外,我们还确定了这些修饰是否与基因表达和炎症蛋白标志物有关,我们以前曾将这些基因表达和炎症蛋白标志物与 HNC 患者的疲劳联系起来。这项前瞻性纵向研究招募了符合条件的患者,收集了放疗前、放疗结束、放疗后六个月和一年的数据。患者使用多维疲劳量表(MFI)-20报告疲劳数据。进行了DNA甲基化(Illumina MethylationEPIC)和基因表达(Applied Biosystems Clariom S)阵列和七种炎症标志物(R&D Systems multiplex)的检测。应用混合模型和富集分析建立关联。在 145 名患者中,共有 386 个甲基化位点与疲劳相关(假发现率 [FDR] 为 0.5%)。
{"title":"DNA methylation profiles of cancer-related fatigue associated with markers of inflammation and immunometabolism.","authors":"Canhua Xiao, Gang Peng, Karen N Conneely, Hongyu Zhao, Jennifer C Felger, Evanthia C Wommack, Kristin A Higgins, Dong M Shin, Nabil F Saba, Deborah W Bruner, Andrew H Miller","doi":"10.1038/s41380-024-02652-z","DOIUrl":"https://doi.org/10.1038/s41380-024-02652-z","url":null,"abstract":"<p><p>Cancer patients are commonly affected by fatigue. Herein, we sought to examine epigenetic modifications (i.e., DNA methylation) related to fatigue in peripheral blood among patients during and after treatment for head and neck cancer (HNC). Further, we determined whether these modifications were associated with gene expression and inflammatory protein markers, which we have previously linked to fatigue in HNC. This prospective, longitudinal study enrolled eligible patients with data collected at pre-radiotherapy, end of radiotherapy, and six months and one-year post-radiotherapy. Fatigue data were reported by patients using the Multidimensional Fatigue Inventory (MFI)-20. DNA methylation (Illumina MethylationEPIC) and gene expression (Applied Biosystems Clariom S) arrays and assays for seven inflammatory markers (R&D Systems multiplex) were performed. Mixed models and enrichment analyses were applied to establish the associations. A total of 386 methylation loci were associated with fatigue among 145 patients (False Discovery Rate [FDR] < 0.05). Enrichment analyses showed the involvement of genes related to immune and inflammatory responses, insulin and lipid metabolism, neuropsychological disorders, and tumors. We further identified 16 methylation-gene expression pairs (FDR < 0.05), which were linked to immune and inflammatory responses and lipid metabolism. Ninety-one percent (351) of the 386 methylation loci were also significantly associated with inflammatory markers (e.g., interleukin 6, c-reactive protein; FDR < 0.05), which further mediated the association between methylation and fatigue (FDR < 0.05). These data suggest that epigenetic modifications associated with inflammation and immunometabolism, in conjunction with relevant gene expression and protein markers, are potential targets for treating fatigue in HNC patients. The findings also merit future prospective studies in other cancer populations as well as interventional investigations.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141559290","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}
Pub Date : 2024-07-07DOI: 10.1038/s41380-024-02650-1
Sang Jin Rhee, Linda Abrahamsson, Jan Sundquist, Kristina Sundquist, Kenneth S. Kendler
Using a case-controlled study including siblings of major depression (MD) and control probands, born 1970–1990 and followed through 2018, we sought to clarify the degree to which the familial liability to MD is reflected in its clinical features, and the pattern of psychiatric disorders at elevated risk in the siblings of MD probands. The study population included full-siblings of 197,309 MD and matched 197,309 control probands. The proband-sibling tetrachoric correlation of for MD was +0.20. Both linear and quadratic effects of younger AAO and number of episodes significantly increased the risk of MD in siblings. Male sex, anxiety disorder, alcohol use disorder (AUD), inpatient treatment, psychotic symptoms, severity, and antidepressant prescription in MD probands increased the risk of MD in siblings. Cox proportional hazard models (hazard ratios, 95% CI) revealed a significantly increased risk of attention deficit hyperactivity disorder (1.82, 1.76–1.88), generalized anxiety disorder (1.79, 1.74–1.85), bipolar disorder (1.78, 1.70–1.85), MD (1.74, 1.72–1.76), obsessive-compulsive disorder (1.72, 1.65–1.80), phobic anxiety disorder (1.71, 1.65–1.76), and panic disorder (1.68, 1.64–1.72) in MD co-siblings. The HRs for AUD (1.64, 1.60–1.68), post-traumatic stress disorder (1.62, 1.59–1.66) were modestly lower, and the lowest was seen for schizophrenia (1.42, 1.30–1.54). The overall pattern of increased risk of these disorders was similar in reared-apart half-siblings and cousins of MD probands. Our findings suggest that MD is familial, and a range of important clinical factors predict its familial liability. The familial liability to MD, mostly due to genetic factors, is shared with a broad range of psychiatric disorders.
{"title":"The risks for major psychiatric disorders in the siblings of probands with major depressive disorder","authors":"Sang Jin Rhee, Linda Abrahamsson, Jan Sundquist, Kristina Sundquist, Kenneth S. Kendler","doi":"10.1038/s41380-024-02650-1","DOIUrl":"https://doi.org/10.1038/s41380-024-02650-1","url":null,"abstract":"<p>Using a case-controlled study including siblings of major depression (MD) and control probands, born 1970–1990 and followed through 2018, we sought to clarify the degree to which the familial liability to MD is reflected in its clinical features, and the pattern of psychiatric disorders at elevated risk in the siblings of MD probands. The study population included full-siblings of 197,309 MD and matched 197,309 control probands. The proband-sibling tetrachoric correlation of for MD was +0.20. Both linear and quadratic effects of younger AAO and number of episodes significantly increased the risk of MD in siblings. Male sex, anxiety disorder, alcohol use disorder (AUD), inpatient treatment, psychotic symptoms, severity, and antidepressant prescription in MD probands increased the risk of MD in siblings. Cox proportional hazard models (hazard ratios, 95% CI) revealed a significantly increased risk of attention deficit hyperactivity disorder (1.82, 1.76–1.88), generalized anxiety disorder (1.79, 1.74–1.85), bipolar disorder (1.78, 1.70–1.85), MD (1.74, 1.72–1.76), obsessive-compulsive disorder (1.72, 1.65–1.80), phobic anxiety disorder (1.71, 1.65–1.76), and panic disorder (1.68, 1.64–1.72) in MD co-siblings. The HRs for AUD (1.64, 1.60–1.68), post-traumatic stress disorder (1.62, 1.59–1.66) were modestly lower, and the lowest was seen for schizophrenia (1.42, 1.30–1.54). The overall pattern of increased risk of these disorders was similar in reared-apart half-siblings and cousins of MD probands. Our findings suggest that MD is familial, and a range of important clinical factors predict its familial liability. The familial liability to MD, mostly due to genetic factors, is shared with a broad range of psychiatric disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":11.0,"publicationDate":"2024-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141553435","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}
Previous studies have shown an association between the thalamocortical dysconnectivity and treatment-resistant depression (TRD). Whether a single subanesthetic dose of ketamine may change thalamocortical connectivity among patients with TRD is unclear. Whether these changes in thalamocortical connectivity is associated with the antidepressant and antisuicidal effects of ketamine treatment is also unclear. Two resting-state functional MRIs were collected in two clinical trials of 48 patients with TRD (clinical trial 1; 32 receiving ketamine, 16 receiving a normal saline placebo) and 48 patients with TRD and strong suicidal ideation (clinical trial 2; 24 receiving ketamine, 24 receiving midazolam), respectively. All participants underwent rs-fMRI before and 3 days after infusion. Seed-based functional connectivity (FC) was analyzed in the left/right thalamus. FCs between the bilateral thalamus and right middle frontal cortex (BA46) and between the left thalamus and left anterior paracingulate gyrus (BA8) increased among patients in the ketamine group in clinical trials 1 and 2, respectively. FCs between the right thalamus and bilateral frontal pole (BA9) and between the right thalamus and left rostral paracingulate gyrus (BA10) decreased among patients in the ketamine group in clinical trials 1 and 2, respectively. However, the associations between those FC changes and clinical symptom changes did not survive statistical significance after multiple comparison corrections. Whether ketamine-related changes in thalamocortical connectivity may be associated with ketamine's antidepressant and antisuicidal effects would need further investigation. Clinical trials registration: UMIN Clinical Trials Registry (UMIN-CTR): Registration number: UMIN000016985 and UMIN000033916.
{"title":"Thalamocortical functional connectivity and rapid antidepressant and antisuicidal effects of low-dose ketamine infusion among patients with treatment-resistant depression.","authors":"Pei-Chi Tu, Wan-Chen Chang, Tung-Ping Su, Wei-Chen Lin, Cheng-Ta Li, Ya-Mei Bai, Shih-Jen Tsai, Mu-Hong Chen","doi":"10.1038/s41380-024-02640-3","DOIUrl":"https://doi.org/10.1038/s41380-024-02640-3","url":null,"abstract":"<p><p>Previous studies have shown an association between the thalamocortical dysconnectivity and treatment-resistant depression (TRD). Whether a single subanesthetic dose of ketamine may change thalamocortical connectivity among patients with TRD is unclear. Whether these changes in thalamocortical connectivity is associated with the antidepressant and antisuicidal effects of ketamine treatment is also unclear. Two resting-state functional MRIs were collected in two clinical trials of 48 patients with TRD (clinical trial 1; 32 receiving ketamine, 16 receiving a normal saline placebo) and 48 patients with TRD and strong suicidal ideation (clinical trial 2; 24 receiving ketamine, 24 receiving midazolam), respectively. All participants underwent rs-fMRI before and 3 days after infusion. Seed-based functional connectivity (FC) was analyzed in the left/right thalamus. FCs between the bilateral thalamus and right middle frontal cortex (BA46) and between the left thalamus and left anterior paracingulate gyrus (BA8) increased among patients in the ketamine group in clinical trials 1 and 2, respectively. FCs between the right thalamus and bilateral frontal pole (BA9) and between the right thalamus and left rostral paracingulate gyrus (BA10) decreased among patients in the ketamine group in clinical trials 1 and 2, respectively. However, the associations between those FC changes and clinical symptom changes did not survive statistical significance after multiple comparison corrections. Whether ketamine-related changes in thalamocortical connectivity may be associated with ketamine's antidepressant and antisuicidal effects would need further investigation. Clinical trials registration: UMIN Clinical Trials Registry (UMIN-CTR): Registration number: UMIN000016985 and UMIN000033916.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141545049","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}
Pub Date : 2024-07-05DOI: 10.1038/s41380-024-02655-w
Margareth Nogueira, Daiane C Ferreira Golbert, Richardson Menezes, Raíssa Nóbrega de Almeida, Nicole L Galvão-Coelho, Andressa N Siroky, Thiago Z Lima, Helton Maia, Katarina E Leão, Richardson N Leão
Serotonergic psychedelics have potential therapeutic effects in treating anxiety and mood disorders, often after a single dose, and are suggested to have plasticity-inducing action. However, a comprehensive mechanism of action is still lacking. Here, we investigated how a single dose of the short-acting 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) acts on gene expression from microdissected brain regions (anterior cingulate cortex - ACC; basolateral amygdala - BLA; ventral hippocampus CA1 region - vCA1 and dentate gyrus-DG) of naive and stressed mice. Specifically, we compared gene expression of Arc, Zif268, BDNF, CREB, mTORC1, NR2A, TRIP8b, and NFkB in mice injected with 5-MeO-DMT or saline at different time points (1 h, 5 h, or 5 days prior). 5-MeO-DMT altered mRNA expression of immediate early genes Arc and ZiF268 in the ACC, BLA, and vCA1, while NR2A expression was decreased after 5 h in the vCA1. We also found a long-term increase in TRIP8b, a gene related to the modulation of neuronal activity, in the vCA1 after 5 days. Behaviorally, 5-MeO-DMT treated mice showed mixed anxiolytic and anxiogenic effects in the elevated plus maze and open field test 24 h or 5 days after treatment. However, pre-treated mice subjected to acute stress showed both lower corticosterone levels and robust anxiolytic effects of 5-MeO-DMT administration. Together, our findings provide insights into the molecular actions of 5-MeO-DMT in the brain related to anxiolytic effects of behavior.
{"title":"Serotonergic psychedelic 5-MeO-DMT alters plasticity-related gene expression and generates anxiolytic effects in stressed mice.","authors":"Margareth Nogueira, Daiane C Ferreira Golbert, Richardson Menezes, Raíssa Nóbrega de Almeida, Nicole L Galvão-Coelho, Andressa N Siroky, Thiago Z Lima, Helton Maia, Katarina E Leão, Richardson N Leão","doi":"10.1038/s41380-024-02655-w","DOIUrl":"https://doi.org/10.1038/s41380-024-02655-w","url":null,"abstract":"<p><p>Serotonergic psychedelics have potential therapeutic effects in treating anxiety and mood disorders, often after a single dose, and are suggested to have plasticity-inducing action. However, a comprehensive mechanism of action is still lacking. Here, we investigated how a single dose of the short-acting 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) acts on gene expression from microdissected brain regions (anterior cingulate cortex - ACC; basolateral amygdala - BLA; ventral hippocampus CA1 region - vCA1 and dentate gyrus-DG) of naive and stressed mice. Specifically, we compared gene expression of Arc, Zif268, BDNF, CREB, mTORC1, NR2A, TRIP8b, and NFkB in mice injected with 5-MeO-DMT or saline at different time points (1 h, 5 h, or 5 days prior). 5-MeO-DMT altered mRNA expression of immediate early genes Arc and ZiF268 in the ACC, BLA, and vCA1, while NR2A expression was decreased after 5 h in the vCA1. We also found a long-term increase in TRIP8b, a gene related to the modulation of neuronal activity, in the vCA1 after 5 days. Behaviorally, 5-MeO-DMT treated mice showed mixed anxiolytic and anxiogenic effects in the elevated plus maze and open field test 24 h or 5 days after treatment. However, pre-treated mice subjected to acute stress showed both lower corticosterone levels and robust anxiolytic effects of 5-MeO-DMT administration. Together, our findings provide insights into the molecular actions of 5-MeO-DMT in the brain related to anxiolytic effects of behavior.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141538238","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}
Pub Date : 2024-07-04DOI: 10.1038/s41380-024-02654-x
Shan Gao, Ping Zhu, Tao Wang, Zhifa Han, Yanli Xue, Yan Zhang, Longcai Wang, Haihua Zhang, Yan Chen, Guiyou Liu
{"title":"Alzheimer's disease genome-wide association studies in the context of statistical heterogeneity.","authors":"Shan Gao, Ping Zhu, Tao Wang, Zhifa Han, Yanli Xue, Yan Zhang, Longcai Wang, Haihua Zhang, Yan Chen, Guiyou Liu","doi":"10.1038/s41380-024-02654-x","DOIUrl":"https://doi.org/10.1038/s41380-024-02654-x","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534864","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}
Pub Date : 2024-07-04DOI: 10.1038/s41380-024-02653-y
Jeffery L. Dunning, Catherine Lopez, Colton Krull, Max Kreifeldt, Maggie Angelo, Leeann Shu, Charu Ramakrishnan, Karl Deisseroth, Candice Contet
The parasubthalamic nucleus (PSTN) is activated by refeeding after food deprivation and several PSTN subpopulations have been shown to suppress feeding. However, no study to date directly addressed the role of PSTN neurons activated upon food access in the control of ensuing food consumption. Here we identify consumption latency as a sensitive behavioral indicator of PSTN activity, and show that, in hungry mice, the ensemble of refeeding-activated PSTN neurons drastically increases the latency to initiate refeeding with both familiar and a novel, familiar food, but does not control the amount of food consumed. In thirsty mice, this ensemble also delays sucrose consumption but accelerates water consumption, possibly reflecting anticipatory prandial thirst, with again no influence on the amount of fluid consumed. We next sought to identify which subpopulations of PSTN neurons might be driving these latency effects, using cell-type and pathway-specific chemogenetic manipulations. Our results suggest a prominent role of PSTN Tac1 neurons projecting to the central amygdala in the hindrance of feeding initiation. While PSTN Crh neurons also delay the latency of hungry mice to ingest familiar foods, they surprisingly promote the consumption of novel, palatable substances. Furthermore, PSTN Crh neurons projecting to the bed nucleus of the stria terminalis accelerate rehydration in thirsty mice. Our results demonstrate the key role of endogenous PSTN activity in the control of feeding and drinking initiation and delineate specific circuits mediating these effects, which may have relevance for eating disorders.
{"title":"The parasubthalamic nucleus refeeding ensemble delays feeding initiation and hastens water drinking","authors":"Jeffery L. Dunning, Catherine Lopez, Colton Krull, Max Kreifeldt, Maggie Angelo, Leeann Shu, Charu Ramakrishnan, Karl Deisseroth, Candice Contet","doi":"10.1038/s41380-024-02653-y","DOIUrl":"https://doi.org/10.1038/s41380-024-02653-y","url":null,"abstract":"<p>The parasubthalamic nucleus (PSTN) is activated by refeeding after food deprivation and several PSTN subpopulations have been shown to suppress feeding. However, no study to date directly addressed the role of PSTN neurons activated upon food access in the control of ensuing food consumption. Here we identify consumption latency as a sensitive behavioral indicator of PSTN activity, and show that, in hungry mice, the ensemble of refeeding-activated PSTN neurons drastically increases the latency to initiate refeeding with both familiar and a novel, familiar food, but does not control the amount of food consumed. In thirsty mice, this ensemble also delays sucrose consumption but accelerates water consumption, possibly reflecting anticipatory prandial thirst, with again no influence on the amount of fluid consumed. We next sought to identify which subpopulations of PSTN neurons might be driving these latency effects, using cell-type and pathway-specific chemogenetic manipulations. Our results suggest a prominent role of PSTN <i>Tac1</i> neurons projecting to the central amygdala in the hindrance of feeding initiation. While PSTN <i>Crh</i> neurons also delay the latency of hungry mice to ingest familiar foods, they surprisingly promote the consumption of novel, palatable substances. Furthermore, PSTN <i>Crh</i> neurons projecting to the bed nucleus of the stria terminalis accelerate rehydration in thirsty mice. Our results demonstrate the key role of endogenous PSTN activity in the control of feeding and drinking initiation and delineate specific circuits mediating these effects, which may have relevance for eating disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":11.0,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141521514","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}
Pub Date : 2024-07-03DOI: 10.1038/s41380-024-02648-9
Ashley M. Otero, Meghan G. Connolly, Rafael J. Gonzalez-Ricon, Selena S. Wang, Jacob M. Allen, Adrienne M. Antonson
Epidemiological studies link exposure to viral infection during pregnancy, including influenza A virus (IAV) infection, with increased incidence of neurodevelopmental disorders (NDDs) in offspring. Models of maternal immune activation (MIA) using viral mimetics demonstrate that activation of maternal intestinal T helper 17 (TH17) cells, which produce effector cytokine interleukin (IL)-17, leads to aberrant fetal brain development, such as neocortical malformations. Fetal microglia and border-associated macrophages (BAMs) also serve as potential cellular mediators of MIA-induced cortical abnormalities. However, neither the inflammation-induced TH17 cell pathway nor fetal brain-resident macrophages have been thoroughly examined in models of live viral infection during pregnancy. Here, we inoculated pregnant mice with two infectious doses of IAV and evaluated peak innate and adaptive immune responses in the dam and fetus. While respiratory IAV infection led to dose-dependent maternal colonic shortening and microbial dysregulation, there was no elevation in intestinal TH17 cells nor IL-17. Systemically, IAV resulted in consistent dose- and time-dependent increases in IL-6 and IFN-γ. Fetal cortical abnormalities and global changes in fetal brain transcripts were observable in the high-but not the moderate-dose IAV group. Profiling of fetal microglia and BAMs revealed dose- and time-dependent differences in the numbers of meningeal but not choroid plexus BAMs, while microglial numbers and proliferative capacity of Iba1+ cells remained constant. Fetal brain-resident macrophages increased phagocytic CD68 expression, also in a dose- and time-dependent fashion. Taken together, our findings indicate that certain features of MIA are conserved between mimetic and live virus models, while others are not. Overall, we provide consistent evidence of an infection severity threshold for downstream maternal inflammation and fetal cortical abnormalities, which recapitulates a key feature of the epidemiological data and further underscores the importance of using live pathogens in NDD modeling to better evaluate the complete immune response and to improve translation to the clinic.
{"title":"Influenza A virus during pregnancy disrupts maternal intestinal immunity and fetal cortical development in a dose- and time-dependent manner","authors":"Ashley M. Otero, Meghan G. Connolly, Rafael J. Gonzalez-Ricon, Selena S. Wang, Jacob M. Allen, Adrienne M. Antonson","doi":"10.1038/s41380-024-02648-9","DOIUrl":"https://doi.org/10.1038/s41380-024-02648-9","url":null,"abstract":"<p>Epidemiological studies link exposure to viral infection during pregnancy, including influenza A virus (IAV) infection, with increased incidence of neurodevelopmental disorders (NDDs) in offspring. Models of maternal immune activation (MIA) using viral mimetics demonstrate that activation of maternal intestinal T helper 17 (T<sub>H</sub>17) cells, which produce effector cytokine interleukin (IL)-17, leads to aberrant fetal brain development, such as neocortical malformations. Fetal microglia and border-associated macrophages (BAMs) also serve as potential cellular mediators of MIA-induced cortical abnormalities. However, neither the inflammation-induced T<sub>H</sub>17 cell pathway nor fetal brain-resident macrophages have been thoroughly examined in models of live viral infection during pregnancy. Here, we inoculated pregnant mice with two infectious doses of IAV and evaluated peak innate and adaptive immune responses in the dam and fetus. While respiratory IAV infection led to dose-dependent maternal colonic shortening and microbial dysregulation, there was no elevation in intestinal T<sub>H</sub>17 cells nor IL-17. Systemically, IAV resulted in consistent dose- and time-dependent increases in IL-6 and IFN-γ. Fetal cortical abnormalities and global changes in fetal brain transcripts were observable in the high-but not the moderate-dose IAV group. Profiling of fetal microglia and BAMs revealed dose- and time-dependent differences in the numbers of meningeal but not choroid plexus BAMs, while microglial numbers and proliferative capacity of Iba1<sup>+</sup> cells remained constant. Fetal brain-resident macrophages increased phagocytic CD68 expression, also in a dose- and time-dependent fashion. Taken together, our findings indicate that certain features of MIA are conserved between mimetic and live virus models, while others are not. Overall, we provide consistent evidence of an infection severity threshold for downstream maternal inflammation and fetal cortical abnormalities, which recapitulates a key feature of the epidemiological data and further underscores the importance of using live pathogens in NDD modeling to better evaluate the complete immune response and to improve translation to the clinic.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":11.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141495916","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}